spalde-v3-lexical
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"26874": 0.2719337046146393, "27642": 0.06886265426874161, "27777": 0.5990082025527954, "27854": 0.0842406153678894, "28025": 0.05694137513637543, "28436": 0.24859806895256042, "28619": 0.03360854089260101, "28919": 0.25467249751091003, "29295": 0.08961215615272522} | 15472716 | DNA-PKcs and Ku are essential components of the complex that catalyzes non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs). Ku, a heterodimeric protein, binds to DNA ends and facilitates recruitment of the catalytic subunit, DNA-PKcs. We have investigated the effect of DNA strand orientation and sequence bias on the activation of DNA-PK. In addition, we assessed the effect of the position and strand orientation of cisplatin adducts on kinase activation. A series of duplex DNA substrates with site-specific cisplatin–DNA adducts placed in three different orientations on the duplex DNA were prepared. Terminal biotin modification and streptavidin (SA) blocking was employed to direct DNA-PK binding to the unblocked termini with a specific DNA strand orientation and cisplatin–DNA adduct position. DNA-PK kinase activity was measured and the results reveal that DNA strand orientation and sequence bias dramatically influence kinase activation, only a portion of which could be attributed to Ku-DNA binding activity. In addition, cisplatin–DNA adduct position resulted in differing degrees of inhibition depending on distance from the terminus as well as strand orientation. These results highlight the importance of how local variations in DNA structure, chemistry and sequence influence DNA-PK activation and potentially NHEJ. | Differential activation of DNA-PK based on DNA strand orientation and sequence bias |
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0.804835319519043, "26083": 0.3750596046447754, "26224": 0.007782140281051397, "26244": 0.1384023278951645, "26261": 1.0587663650512695, "26402": 0.11865071207284927, "26462": 0.01934296265244484, "26512": 0.04953393340110779, "26520": 0.46363574266433716, "26524": 0.77198725938797, "26773": 0.42926809191703796, "26835": 0.08244366943836212, "27099": 0.4145384132862091, "27321": 0.18004031479358673, "27354": 0.7854343056678772, "27427": 0.06977381557226181, "27642": 0.4855078160762787, "27777": 0.06703783571720123, "27806": 0.24859806895256042, "27854": 0.06429435312747955, "28024": 0.14518201351165771, "28154": 0.11256109178066254, "28315": 0.841701865196228, "28691": 0.12470348179340363, "28835": 0.11951763927936554, "28848": 0.13414156436920166, "29290": 0.23633737862110138, "29458": 0.41195443272590637, "29490": 0.14349138736724854} | 15473205 | The African trypanosome, Trypanosoma brucei, maintains an integral link between cell cycle regulation and differentiation during its intricate life cycle. Whilst extensive changes in phosphorylation have been documented between the mammalian bloodstream form and the insect procyclic form, relatively little is known about the parasite's protein kinases (PKs) involved in the control of cellular proliferation and differentiation. To address this, a T. brucei kinome-wide RNAi cell line library was generated, allowing independent inducible knockdown of each of the parasite's 190 predicted protein kinases. Screening of this library using a cell viability assay identified ≥42 PKs that are required for normal bloodstream form proliferation in culture. A secondary screen identified 24 PKs whose RNAi-mediated depletion resulted in a variety of cell cycle defects including in G1/S, kinetoplast replication/segregation, mitosis and cytokinesis, 15 of which are novel cell cycle regulators. A further screen identified for the first time two PKs, named repressor of differentiation kinase (RDK1 and RDK2), depletion of which promoted bloodstream to procyclic form differentiation. RDK1 is a membrane-associated STE11-like PK, whilst RDK2 is a NEK PK that is essential for parasite proliferation. RDK1 acts in conjunction with the PTP1/PIP39 phosphatase cascade to block uncontrolled bloodstream to procyclic form differentiation, whilst RDK2 is a PK whose depletion efficiently induces differentiation in the absence of known triggers. Thus, the RNAi kinome library provides a valuable asset for functional analysis of cell signalling pathways in African trypanosomes as well as drug target identification and validation. | Regulators of Trypanosoma brucei Cell Cycle Progression and Differentiation Identified Using a Kinome-Wide RNAi Screen |
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"28732": 0.010684899985790253, "28767": 0.4041621685028076, "28775": 0.2516399025917053, "29025": 0.056018441915512085, "29090": 0.36494144797325134, "29295": 0.10906458646059036, "29361": 0.01934296265244484, "29439": 0.9194108247756958, "29458": 0.7314660549163818} | 15476777 | BACKGROUND Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. METHODS We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. FINDINGS 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU. INTERPRETATION FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. FUNDING Cancer Research UK and the Medical Research Council. | Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial |
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0.2652147710323334, "28833": 0.18004031479358673, "29145": 0.5455666780471802, "29206": 0.026976587250828743} | 15478227 | The wild species of the genus Oryza contain a largely untapped reservoir of agronomically important genes for rice improvement. Here we report the 261-Mb de novo assembled genome sequence of Oryza brachyantha. Low activity of long-terminal repeat retrotransposons and massive internal deletions of ancient long-terminal repeat elements lead to the compact genome of Oryza brachyantha. We model 32,038 protein-coding genes in the Oryza brachyantha genome, of which only 70% are located in collinear positions in comparison with the rice genome. Analysing breakpoints of non-collinear genes suggests that double-strand break repair through non-homologous end joining has an important role in gene movement and erosion of collinearity in the Oryza genomes. Transition of euchromatin to heterochromatin in the rice genome is accompanied by segmental and tandem duplications, further expanded by transposable element insertions. The high-quality reference genome sequence of Oryza brachyantha provides an important resource for functional and evolutionary studies in the genus Oryza. | Whole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genome evolution |
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0.007782140281051397, "27011": 0.5685047507286072, "27065": 1.0137293338775635, "27109": 0.2659635543823242, "27159": 0.4950772523880005, "27312": 1.4651343822479248, "27404": 0.23864774405956268, "28436": 0.1332872211933136, "28472": 0.21765978634357452, "28616": 0.1619328260421753, "28711": 0.2852376699447632, "28731": 0.29109421372413635, "28927": 0.010684899985790253, "29021": 0.083342544734478, "29347": 0.05139094591140747, "29361": 0.12814582884311676, "29401": 0.3269403576850891} | 15482274 | OBJECTIVE To determine whether ultrasound imaging can reduce the risk of failed lumbar punctures or epidural catheterisations, when compared with standard palpation methods, and whether ultrasound imaging can reduce traumatic procedures, insertion attempts, and needle redirections. DESIGN Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2012, without restriction by language or publication status. REVIEW METHODS Randomised trials that compared ultrasound imaging with standard methods (no imaging) in the performance of a lumbar puncture or epidural catheterisation were identified. RESULTS 14 studies with a total of 1334 patients were included (674 patients assigned to the ultrasound group, 660 to the control group). Five studies evaluated lumbar punctures and nine evaluated epidural catheterisations. Six of 624 procedures conducted in the ultrasound group failed; 44 of 610 procedures in the control group failed. Ultrasound imaging reduced the risk of failed procedures (risk ratio 0.21 (95% confidence interval 0.10 to 0.43), P<0.001). Risk reduction was similar when subgroup analysis was performed for lumbar punctures (risk ratio 0.19 (0.07 to 0.56), P=0.002) or epidural catheterisations (0.23 (0.09 to 0.60), P=0.003). Ultrasound imaging also significantly reduced the risk of traumatic procedures (risk ratio 0.27 (0.11 to 0.67), P=0.005), the number of insertion attempts (mean difference -0.44 (-0.64 to -0.24), P<0.001), and the number of needle redirections (mean difference -1.00 (-1.24 to -0.75), P<0.001). CONCLUSIONS Ultrasound imaging can reduce the risk of failed or traumatic lumbar punctures and epidural catheterisations, as well as the number of needle insertions and redirections. Ultrasound may be a useful adjunct for these procedures. | Ultrasound imaging for lumbar punctures and epidural catheterisations: systematic review and meta-analysis. |
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immunity depends on both rapid and long-term antibody production against invading pathogens. This is achieved by the generation of spatially distinct extrafollicular plasmablast and follicular germinal center (GC) B cell populations, but the signals that guide responding B cells to these alternative compartments have not been fully elucidated. Here, we show that expression of the orphan G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) by activated B cells was essential for their movement to extrafollicular sites and induction of early plasmablast responses. Conversely, downregulation of EBI2 enabled B cells to access the center of follicles and promoted efficient GC formation. EBI2 therefore provides a previously uncharacterized dimension to B cell migration that is crucial for coordinating rapid versus long-term antibody responses. | Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. |
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"24790": 0.0019512200960889459, "24905": 0.08513788133859634, "24960": 0.9936857223510742, "25002": 1.0271050930023193, "25194": 0.07159364968538284, "25354": 1.0492360591888428, "25456": 0.009718249551951885, "25714": 1.049919843673706, "26061": 1.1695996522903442, "26237": 0.07431721687316895, "26244": 0.022212404757738113, "26402": 0.22392450273036957, "26709": 1.036847710609436, "27133": 1.0742288827896118, "27144": 0.007782140281051397, "27321": 0.0019512200960889459, "27598": 0.3325583338737488, "27710": 0.8925741910934448, "27777": 0.037378571927547455, "28086": 0.03925827145576477, "28723": 0.0606246218085289, "28788": 0.08603433519601822, "28964": 1.3759875297546387, "29129": 0.11343330889940262, "29217": 0.015504186972975731, "29494": 0.6425731778144836} | 15491308 | Human mesenchymal stem cells (MSCs) have therapeutic potential because of their ability to self-renew and differentiate into multiple tissues. However, senescence often occurs in MSCs when they are cultured in vitro and the molecular mechanisms underlying this effect remain unclear. In this study, we found that NAD-dependent protein deacetylase SIRT1 is differentially expressed in both human bone marrow-derived MSCs (B-MSCs) and adipose tissue-derived MSCs after increasing passages of cell culture. Using lentiviral shRNA we demonstrated that selective knockdown of SIRT1 in human MSCs at early passage slows down cell growth and accelerates cellular senescence. Conversely, overexpression of SIRT1 delays senescence in B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic and osteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1. However, resveratrol, which has been used as an activator of SIRT1 deacetylase activity, only transiently promotes proliferation of B-MSCs. Our findings will help us understand the role of SIRT1 in the aging of normal diploid cells and may contribute to the prevention of human MSCs senescence thus benefiting MSCs-based tissue engineering and therapies. | SIRT1 is required for long-term growth of human mesenchymal stem cells |
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0.0029254043474793434, "29060": 0.2822965085506439, "29441": 0.053244512528181076, "29486": 0.08871890604496002} | 15491404 | The synapse is a highly organized cellular specialization whose structure and composition are reorganized, both positively and negatively, depending on the strength of input signals. The mechanisms orchestrating these changes are not well understood. A plausible locus for the reorganization of synapse components and structure is actin, because it serves as both cytoskeleton and scaffold for synapses and exists in a dynamic equilibrium between F-actin and G-actin that is modulated bidirectionally by cellular signaling. Using a new FRET-based imaging technique to monitor F-actin/G-actin equilibrium, we show here that tetanic stimulation causes a rapid, persistent shift of actin equilibrium toward F-actin in the dendritic spines of rat hippocampal neurons. This enlarges the spines and increases postsynaptic binding capacity. In contrast, prolonged low-frequency stimulation shifts the equilibrium toward G-actin, resulting in a loss of postsynaptic actin and of structure. This bidirectional regulation of actin is actively involved in protein assembly and disassembly and provides a substrate for bidirectional synaptic plasticity. | Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity |
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Rather than simply reacting to CNS injury, infection, or pathology, emerging lines of evidence indicate that microglia sculpt the structure of the CNS, refine neuronal circuitry and network connectivity, and contribute to plasticity. These physiological functions of microglia in the normal CNS begin during development and persist into maturity. Here, we develop a conceptual framework for functions of microglia beyond neuroinflammation and discuss the rich repertoire of signaling and communication motifs in microglia that are critical both in pathology and for the normal physiology of the CNS. | Sublime Microglia: Expanding Roles for the Guardians of the CNS |
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incidence of cancer among women with and without a history of pre-eclampsia. DESIGN Cohort study. SETTING Jerusalem perinatal study of women who delivered in three large hospitals in West Jerusalem during 1964-76. PARTICIPANTS 37 033 women. MAIN OUTCOME MEASURES Age adjusted and multivariable adjusted hazard ratios for cancer incidence for the entire cohort and for women who were primiparous at study entry. RESULTS Cancer developed in 91 women who had pre-eclampsia and 2204 who did not (hazard ratio 1.27, 95% confidence interval 1.03 to 1.57). The risk of site specific cancers was increased, particularly of the stomach, ovary epithelium, breast, and lung or larynx. The incidence of cancer of the stomach, breast, ovary, kidney, and lung or larynx was increased in primiparous women at study entry who had a history pre-eclampsia. CONCLUSIONS A history of pre-eclampsia is associated with increases in overall risk of cancer and incidence at several sites. This may be explained by environmental and genetic factors common to the development of pre-eclampsia and cancer in this population. | Cancer after pre-eclampsia: follow up of the Jerusalem perinatal study cohort. |
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"26305": 0.06154331564903259, "26402": 0.0913962796330452, "26462": 0.1718502640724182, "26520": 0.8433839678764343, "26524": 0.0038986403960734606, "26563": 0.8559102416038513, "26642": 0.14518201351165771, "27099": 0.3027053773403168, "27870": 0.02887592278420925, "27881": 0.757441520690918, "28024": 0.17267228662967682, "28086": 0.17922431230545044, "28156": 0.17922431230545044, "28327": 0.6911921501159668, "28522": 0.7995813488960266, "28775": 0.5209306478500366, "28964": 1.6439902782440186, "29076": 0.11256109178066254, "29129": 0.28963330388069153, "29170": 0.0038986403960734606, "29172": 0.007782140281051397, "29206": 0.8649974465370178, "29290": 0.26446542143821716, "29320": 0.29036402702331543, "29494": 0.8022117614746094} | 15521377 | Cellular senescence is a stable form of cell-cycle arrest which is thought to limit the proliferative potential of premalignant cells [1]. The senescence phenotype was initially described by Hayflick and Moorhead in 1961 on human fibroblasts undergoing replicative exhaustion in culture [2]. It has been shown that senescence can be triggered in different cell types in response to diverse forms of cellular damage or stress (for review see [1]). Importantly, while senescence was denounced as a tissue culture phenomenon for many years, recent in vivo studies demonstrated that cellular senescence represents a potent failsafe mechanism against tumorigenesis and contributes to the cytotoxicity of certain anticancer agents (see for example [3-7]). Interestingly, senescent cells have also been observed in certain aged or damaged tissues and there is growing evidence that senescence checkpoints can affect the regenerative reserve of tissues and organismal aging [8-11]. However, senescence may also have positive effects on organ maintenance by limiting pathological responses to acute forms of injury such as fibrotic scarring in response to chemical induced liver injury [12]. Over the past years it was also shown that senescent cells can communicate with their environment by secreting a myriad of cytokines and growth factors. Interestingly, this "senescence associated secretory phenotype (SASP)" seems to be a double edged sword regarding tumor initiation and maintenance: i) On the one hand, it has been shown that the SASP can have pro-tumorigenic effects. In an experimental system it was shown that senescent mesenchymal cells can enhance the tumorigenicity of surrounding breast cancer cells [13]. ii) Similarly, it is possible that the SASP enhances selection of transformed cell clones in aged organ systems. It has been shown that loss of proliferative competition of non-transformed cells can accelerate leukemogenesis [14]. It remains to be seen whether aberrant secretion of cytokines and growth factors by the SASP can accelerated this process in aged and chronically damage organ systems. iii) In contrast to its pro-tumorigenic aspect, the SASP could also have anti-tumor effects. A recent study showed that in a mosaic liver cancer mouse model the activation of p53 induced senescence, an upregulation of inflammatory cytokines, and activation of innate immune responses leading to tumour cell clearance [15]. iv) In further support that the SASP could have anti-tumor activities, a series of recent papers showed that components of the SASP can stabilize the senescence cell cycle arrest via an autoregulatory feedback loop [16,17] or induces apoptosis of tumor cells [18]. In addition to its effects on tumorigenesis, the SASP could also influence tissue aging. Studies on aging telomere dysfunctional mice have provided direct experimental evidence for an in vivo activation of the SASP in response to telomere dysfunction [19]. Interestingly, this in vivo SASP provoked alterations in stem cell differentiation (skewing of hematopoiesis towards reduction in lymphopoiesis and enhancement of myelopoiesis) that are also characteristic signs of human aging. Figure 1. Different cellular stresses can induce senescence including telomere shortening, DNA damage, and oncogene activation. Senescence of tumor cells ... In light of the many possible roles o the SASP in aging and carcinogenesis, it appears to be of utmost importance to decipher regulatory pathways controlling the SASP. In a current publication, Bhaumik et al. have identified 2 microRNAs (miR-146a/b) that negatively regulate the secretion of IL-6 and IL-8 - two of the SASP [20]. The authors show that these microRNAs are up-regulated at late stages of senescence, many days after a permanent cell cycle arrest has been established. Interestingly, the inhibitory miRs are most strongly up-regulated in senescence of cell lines that show a strong SASP but not in cell lines characterized by a weak SASP. The authors propose a new concept indicating that miRs 146a and b function in a negative feedback loop preventing an over-activation of the SASP in senescent cells. The authors present some initial data suggesting that activation of this negative feedback loop involves IL-1 receptor, IRAK-1, and NFκB signalling leading to an up-regulation of miRs-146a and b. A direct proof that this proposed feedback loop suppresses over-activation of the SASP remains to be demonstrated in future studies. The authors show that blockage of IL-1-receptor signalling prevents both the up-regulation of miRs-146a and b as well as Il-6 secretion. To confirm their new concept, it would be important to show that a selective blockage of miRs-146a and b results in over-activation of the SASP. The work by Bhaumik et al. places mir-146a/b as central players to control IL-6 and IL-8 expression within the SASP. MicroRNAs are emerging therapeutic targets because their expression levels can be effectively modulated via the use of antagomirs (see for example [21]). Also, for increasing microRNA expression, microRNAs can be delivered into cellsin vivo (see for example [22]). Therefore, it will be interesting to functionally test the impact of mir-146 inhibition on tumorigenesis and aging in relevant mouse models. Such studies will be of particular interest, as recent work showed that IL-6 secretion by senescent cells is relevant for initiating and maintaining the senescene response via an autocrine loop [17]. A reduction of miR-146 could increase IL-6 levels in senescent cells, which should stabilize the senescence program and reduce the risk of malignant transformation. Furthermore, it can be speculated that reduction of mir-146 a/b will increase NfκB activation via IRAK1. As NfκB is modulating the expression of various inflammation associated genes, this may also lead to increased clearance of senescent tumor cells by the innate immune system. However, it should be mentioned that Il-6 secreted by senescent cells can also act as a mitogen for surrounding cells, thus potentially increasing the risk of malignant transformation [13,17]. Besides its function in SASP modulation, miR-146 was also reported to target the mRNAs of the BRCA1 and BRCA2 tumor suppressors. In a recent study a G to C polymorphism in miR-146, which leads to an increased processing and release of the mature microRNA, can predict an early onset of breast cancer [23]. Taken together, the study of Bhaumik et al. opens an interesting new research area dealing with the gene regulatory mechanisms that control activation of the SASP. Given the diverse roles of the SASP in modulating tumor progression, immune surveillance of damaged cells, and the stabilization of the senescence arrest itself, it will be of great interest to analyse the influence of SASP regulatory pathways during aging and cancer. | Keeping your senescent cells under control |
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"24552": 0.38174858689308167, "25002": 0.8813109993934631, "25194": 0.7836518287658691, "25714": 0.31489628553390503, "25761": 1.004473328590393, "25971": 0.13755162060260773, "26014": 0.014542185701429844, "26243": 0.1677299439907074, "26288": 0.29981520771980286, "26369": 0.15860503911972046, "26402": 0.15526613593101501, "26709": 0.11343330889940262, "26773": 0.3339579105377197, "26830": 0.2622140049934387, "26972": 0.010684899985790253, "27099": 0.09850110858678818, "27108": 0.11691460013389587, "27118": 0.6275664567947388, "27295": 0.2184450328350067, "27574": 0.04113444685935974, "28156": 0.5925496220588684, "28577": 0.0752234235405922, "28696": 1.2387138605117798, "28879": 0.8195732831954956, "28938": 0.3170322775840759, "29477": 0.08603433519601822} | 15535511 | Dopaminergic midbrain neurons integrate signals on food palatability and food-associated reward into the complex control of energy homeostasis. To define the role of insulin receptor (IR) signaling in this circuitry, we inactivated IR signaling in tyrosine hydroxylase (Th)-expressing cells of mice (IR(ΔTh)). IR inactivation in Th-expressing cells of mice resulted in increased body weight, increased fat mass, and hyperphagia. While insulin acutely stimulated firing frequency in 50% of dopaminergic VTA/SN neurons, this response was abolished in IR(ΔTh) mice. Moreover, these mice exhibited an altered response to cocaine under food-restricted conditions. Taken together, these data provide in vivo evidence for a critical role of insulin signaling in catecholaminergic neurons to control food intake and energy homeostasis. | Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. |
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In the late 1970s, the International Union Against Cancer and the World Health Organization (WHO) introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical cancer research joined together to undertake the review of these response evaluation criteria on the basis of their experience and knowledge. After several years of intensive discussions, new guidelines are ready and will replace the previous WHO criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors (Recist) Group and integrated into the present guidelines. This special article provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesion (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified. All other aspects of response evaluation have been discussed, reviewed, and amended whenever suitable. | [New guidelines to evaluate the response to treatment in solid tumors]. |
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"28282": 1.2726531028747559, "28283": 0.6872705817222595, "28696": 0.10203468054533005, "29060": 0.2145126610994339, "29300": 0.034552380442619324} | 15548965 | Ionotropic glutamate receptor (iGluR) subunits contain a large N-terminal domain (NTD) that precedes the agonist-binding domain (ABD) and participates in subunit oligomerization. In NMDA receptors (NMDARs), the NTDs of NR2A and NR2B subunits also form binding sites for the endogenous inhibitor Zn(2+) ion. Although these allosteric sites have been characterized in detail, the molecular mechanisms by which the NTDs communicate with the rest of the receptor to promote its inhibition remain unknown. Here, we identify the ABD dimer interface as a major structural determinant that permits coupling between the NTDs and the channel gate. The strength of this interface also controls proton inhibition, another form of allosteric modulation of NMDARs. Conformational rearrangements at the ABD dimer interface thus appear to be a key mechanism conserved in all iGluR subfamilies, but have evolved to fulfill different functions: fast desensitization at AMPA and kainate receptors, allosteric inhibition at NMDARs. | Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition |
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Full development of Mycobacterium smegmatis biofilms requires addition of supplemental iron above 1 μM ferrous sulphate, although addition of iron is not needed for planktonic growth. Microarray analysis of the M. smegmatis transcriptome shows that iron-responsive genes – especially those involved in siderophore synthesis and iron uptake – are strongly induced during biofilm formation reflecting a response to iron deprivation, even when 2 μM iron is present. The acquisition of iron under these conditions is specifically dependent on the exochelin synthesis and uptake pathways, and the strong defect of an iron–exochelin uptake mutant suggests a regulatory role of iron in the transition to biofilm growth. In contrast, although the expression of mycobactin and iron ABC transport operons is highly upregulated during biofilm formation, mutants in these systems form normal biofilms in low-iron (2 μM) conditions. A close correlation between iron availability and matrix-associated fatty acids implies a possible metabolic role in the late stages of biofilm maturation, in addition to the early regulatory role. M. smegmatis surface motility is similarly dependent on iron availability, requiring both supplemental iron and the exochelin pathway to acquire it. | The role of iron in Mycobacterium smegmatis biofilm formation: the exochelin siderophore is essential in limiting iron conditions for biofilm formation but not for planktonic growth |
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0.08064348995685577, "22458": 0.9178520441055298, "22935": 0.0038986403960734606, "22963": 0.2501201331615448, "22991": 0.5162794589996338, "23267": 1.0116009712219238, "23284": 0.14349138736724854, "23900": 0.8559102416038513, "24171": 0.06337817758321762, "24226": 0.04207121208310127, "24345": 0.00875066313892603, "24374": 0.6405166387557983, "24528": 0.055094651877880096, "25086": 0.083342544734478, "25117": 0.07341018319129944, "25409": 0.6624060273170471, "25510": 0.2607102394104004, "25572": 0.11951763927936554, "25643": 1.0648454427719116, "26236": 0.06886265426874161, "26563": 1.0492360591888428, "26786": 0.2478361576795578, "27144": 0.22704219818115234, "27833": 1.3160102367401123, "27881": 0.7009293437004089, "28093": 0.27564704418182373, "28207": 0.20977331697940826, "28378": 0.8195732831954956, "28436": 0.1510767638683319, "29295": 0.21135559678077698, "29477": 1.1287524700164795} | 15559582 | In a comparative study of pre- and postmenopausal women with benign and malignant breast disease, a number of differences were observed in circulating plasma prolactin and lipid concentrations. Plasma lipids, phospholipids, triglycerides, cholesterol and free fatty acids were all higher in blood obtained from breast cancer patients prior to surgery. HDL-Cholesterol levels were significantly lower in these patients. These differences remained when the patient groups were sub-divided according to menopausal status. Plasma prolactin concentrations were also found to be higher in cancer compared with non-cancer patients, this effect being more marked in premenopausal than in postmenopausal patients. Premenopausal patients with invasive or poorly differentiated disease had significantly higher prolactin levels than those with non-invasive disease. No correlations were found between plasma prolactin and any of the lipid fractions. | Plasma lipids and prolactin in patients with breast cancer. |
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"29516": 0.06977381557226181, "29607": 0.13499516248703003} | 15561961 | Hypercholesterolemia is associated with impairments in endothelium-dependent vascular relaxations. Paradoxically, endothelial production of nitrogen oxides is increased in early stages of hypercholesterolemia. Prior work has shown that oxidized low density lipoprotein (LDL) has both stimulatory and inhibitory effects on endothelial nitric oxide synthase expression (eNOS) and has focused on lysophosphatidyl choline (LPC) as a component of oxidized LDL which may modulate this effect. Another biologically active component of oxidized LDL is 13-hydroperoxyoctadecadienoic acid (13-HPODE), an oxidized form of linoleic acid. The purpose of this study was to determine the effect of HPODE on the expression of eNOS in bovine aortic endothelial cells (BAECs). Twenty four hour treatment of endothelial cells with HPODE caused a dose-dependent increase in eNOS mRNA levels as assessed by Northern analysis. The time response studies show that HPODE treatment significantly increased eNOS mRNA levels at 12 and 24 h. Concomitant with the increase in eNOS mRNA levels, 20 microM HPODE treatment significantly increased eNOS protein content and enzyme activity. Nuclear run-on studies indicated that the rate of transcription of eNOS gene was significantly elevated 4 h after HPODE treatment when compared to control cultures. Also, actinomycin D studies demonstrated that the half-life of eNOS mRNA was increased from 6 h to 12 h by HPODE treatment. Thus, HPODE-induced up-regulation of eNOS expression is mediated by both transcriptional and posttranscriptional mechanisms. These observations suggest that endothelial cells may attempt to compensate for oxidative injury by increasing expression of eNOS in early stages of hypercholesterolemia. | expression by oxidized linoleic |
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Based on its ability to modulate growth factor-mediated cell proliferation, we evaluated its efficacy in multiple myeloma (MM). EGCG induced both dose- and time-dependent growth arrest and subsequent apoptotic cell death in MM cell lines including IL-6-dependent cells and primary patient cells, without significant effect on the growth of peripheral blood mononuclear cells (PBMCs) and normal fibroblasts. Treatment with EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCG interacts with the 67-kDa laminin receptor 1 (LR1), which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMCs. RNAi-mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18). Expression of related genes at the protein level were also confirmed by Western blot analysis. These data demonstrate potent and specific antimyeloma activity of EGCG and provide the rationale for its clinical evaluation. | Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications. |
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0.6233867406845093, "29290": 0.2026219218969345, "29480": 0.5495203733444214} | 15570691 | Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G(1) cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)-proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. | Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. |
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single nucleotide polymorphisms (htSNPs) that is presently being taken in two large nested case-control studies within a multiethnic cohort (MEC), which are engaged in a search for associations between risk of prostate and breast cancer and common genetic variations in candidate genes. Based on a preliminary sample of 70 control subjects chosen at random from each of the 5 ethnic groups in the MEC we estimate haplotype frequencies using a variant of the Excoffier-Slatkin E-M algorithm after genotyping a high density of SNPs selected every 3–5 kb in and surrounding a candidate gene. In order to evaluate the performance of a candidate set of htSNPS (which will be genotyped in the much larger case-control sample) we treat the haplotype frequencies estimate above as known, and carry out a formal calculation of the uncertainty of the number of copies of common haplotypes carried by an individual, summarizing this calculation as a coefficient of determination, R2h. A candidate set of htSNPS of a given size is chosen so as to maximize the minimum value of R2h over the common haplotypes, h. | Choosing Haplotype-Tagging SNPS Based on Unphased Genotype Data Using a Preliminary Sample of Unrelated Subjects with an Example from the Multiethnic Cohort Study |
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| Several lines of evidence suggest a role for the gut microbiome in type 1 diabetes. Treating diabetes-prone rodents with probiotics or antibiotics prevents the development of the disorder. Diabetes-prone rodents also have a distinctly different gut microbiome compared with healthy rodents. Recent studies in children with a high genetic risk for type 1 diabetes demonstrate significant differences in the gut microbiome between children who develop autoimmunity for the disease and those who remain healthy. However, the differences in microbiome composition between autoimmune and healthy children are not consistent across all studies because of the strong environmental influences on microbiome composition, particularly diet and geography. Controlling confounding factors of microbiome composition uncovers bacterial associations with disease. For example, in a human cohort from a single Finnish city where geography is confined, a strong association between one dominant bacterial species, Bacteroides dorei, and type 1 diabetes was discovered (Davis-Richardson et al. Front Microbiol 2014;5:678). Beyond this, recent DNA methylation analyses suggest that a thorough epigenetic analysis of the gut microbiome may be warranted. These studies suggest a testable model whereby a diet high in fat and gluten and low in resistant starch may be the primary driver of gut dysbiosis. This dysbiosis may cause a lack of butyrate production by gut bacteria, which, in turn, leads to the development of a permeable gut followed by autoimmunity. The bacterial community responsible for these changes in butyrate production may vary around the world, but bacteria of the genus Bacteroides are thought to play a key role. | A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes |
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Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models. | METHODS AND RESULTS |
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"26514": 0.040196798741817474, "26520": 0.0029254043474793434, "26534": 0.4462870955467224, "26651": 0.841701865196228, "26773": 0.8957691192626953, "26838": 0.12814582884311676, "27022": 0.24325250089168549, "27099": 0.06429435312747955, "27295": 0.02887592278420925, "27698": 0.22157983481884003, "27814": 0.015504186972975731, "27854": 0.052318159490823746, "28297": 0.17840765416622162, "28467": 0.06977381557226181, "28696": 0.2976420819759369, "28848": 0.9643365740776062, "29226": 0.013579257763922215, "29290": 0.6989894509315491} | 15590539 | Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs. | Dual Regulation of miRNA Biogenesis Generates Target Specificity in Neurotrophin-Induced Protein Synthesis |
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"24335": 0.9900637865066528, "24545": 0.06703783571720123, "25006": 0.2145126610994339, "25145": 0.06520967930555344, "25212": 0.11691460013389587, "25221": 0.5387523174285889, "25505": 0.09584271162748337, "25540": 0.11778303235769272, "25714": 0.43623676896095276, "25852": 0.055094651877880096, "25969": 0.29255300760269165, "26013": 0.7389566898345947, "26305": 0.06977381557226181, "26378": 0.1229778528213501, "26402": 0.058784693479537964, "26487": 0.011650617234408855, "26646": 1.6522579193115234, "26835": 0.5646255612373352, "27152": 0.02887592278420925, "27321": 0.0174254160374403, "27777": 0.37907835841178894, "27781": 0.04674193635582924, "28297": 0.8861536383628845, "28389": 0.2516399025917053, "28788": 0.6332852244377136, "28873": 0.8400169610977173, "29290": 0.2852376699447632, "29486": 0.3241194784641266, "29494": 0.5162794589996338} | 15593561 | Epstein-Barr virus (EBV), an oncogenic human herpesvirus, induces cell proliferation after infection of resting B lymphocytes, its reservoir in vivo. The viral latent proteins are necessary for permanent B cell growth, but it is unknown whether they are sufficient. EBV was recently found to encode microRNAs (miRNAs) that are expressed in infected B cells and in some EBV-associated lymphomas. EBV miRNAs are grouped into two clusters located either adjacent to the BHRF1 gene or in introns contained within the viral BART transcripts. To understand the role of the BHRF1 miRNA cluster, we have constructed a virus mutant that lacks all its three members (Δ123) and a revertant virus. Here we show that the B cell transforming capacity of the Δ123 EBV mutant is reduced by more than 20-fold, relative to wild type or revertant viruses. B cells exposed to the knock-out virus displayed slower growth, and exhibited a two-fold reduction in the percentage of cells entering the cell cycle S phase. Furthermore, they displayed higher latent gene expression levels and latent protein production than their wild type counterparts. Therefore, the BHRF1 miRNAs accelerate B cell expansion at lower latent gene expression levels. Thus, this miRNA cluster simultaneously enhances expansion of the virus reservoir and reduces the viral antigenic load, two features that have the potential to facilitate persistence of the virus in the infected host. Thus, the EBV BHRF1 miRNAs may represent new therapeutic targets for the treatment of some EBV-associated lymphomas. | A Viral microRNA Cluster Strongly Potentiates the Transforming Properties of a Human Herpesvirus |
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"25746": 0.10026945173740387, "25761": 1.0409941673278809, "25932": 0.7907629609107971, "26296": 0.7881022095680237, "26305": 0.2837681770324707, "26402": 0.10203468054533005, "26520": 1.1786550283432007, "26534": 0.17922431230545044, "26601": 0.23247487843036652, "26633": 0.41389304399490356, "26773": 0.4450363218784332, "26775": 0.009718249551951885, "26874": 0.18329764902591705, "26986": 0.9849710464477539, "26994": 1.0695481300354004, "27391": 0.10026945173740387, "27642": 0.5444341897964478, "27777": 0.022212404757738113, "27854": 0.018384648486971855, "27881": 0.10379679501056671, "28024": 0.6543170213699341, "28154": 0.018384648486971855, "28227": 0.24171993136405945, "28424": 0.016465263441205025, "28667": 0.8433839678764343, "28976": 0.27934664487838745, "29031": 1.6156684160232544, "29206": 0.0770333781838417, "29290": 0.34577593207359314, "29490": 0.06429435312747955} | 15600979 | EMSY links the BRCA2 pathway to sporadic breast/ovarian cancer. It encodes a nuclear protein that binds to the BRCA2 N-terminal domain implicated in chromatin/transcription regulation, but when sporadically amplified/overexpressed, increased EMSY level represses BRCA2 transactivation potential and induces chromosomal instability, mimicking the activity of BRCA2 mutations in the development of hereditary breast/ovarian cancer. In addition to chromatin/transcription regulation, EMSY may also play a role in the DNA-damage response, suggested by its ability to localize at chromatin sites of DNA damage/repair. This implies that EMSY overexpression may also repress BRCA2 in DNA-damage replication/checkpoint and recombination/repair, coordinated processes that also require its interacting proteins: PALB2, the partner and localizer of BRCA2; RPA, replication/checkpoint protein A; and RAD51, the inseparable recombination/repair enzyme. Here, using a well-characterized recombination/repair assay system, we demonstrate that a slight increase in EMSY level can indeed repress these two processes independently of transcriptional interference/repression. Since EMSY, RPA and PALB2 all bind to the same BRCA2 region, these findings further support a scenario wherein: (a) EMSY amplification may mimic BRCA2 deficiency, at least by overriding RPA and PALB2, crippling the BRCA2/RAD51 complex at DNA-damage and replication/transcription sites; and (b) BRCA2/RAD51 may coordinate these processes by employing at least EMSY, PALB2 and RPA. We extensively discuss the molecular details of how this can happen to ascertain its implications for a novel recombination mechanism apparently conceived as checkpoint rather than a DNA repair system for cell division, survival, death, and human diseases, including the tissue specificity of cancer predisposition, which may renew our thinking about targeted therapy and prevention. | EMSY overexpression disrupts the BRCA2/RAD51 pathway in the DNA-damage response: implications for chromosomal instability/recombination syndromes as checkpoint diseases |
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"26163": 0.8247235417366028, "26191": 0.10379679501056671, "26226": 0.0029254043474793434, "26251": 0.043007105588912964, "26702": 0.02792670577764511, "26780": 0.3554046154022217, "26786": 0.1889725625514984, "27321": 0.06154331564903259, "27651": 0.11691460013389587, "27663": 0.016465263441205025, "27833": 0.22157983481884003, "27896": 0.33953672647476196, "27921": 0.9857001900672913, "28253": 0.1358480453491211, "28268": 0.32270604372024536, "28403": 0.39367714524269104, "28479": 1.013020396232605, "29167": 0.1602703034877777, "29172": 0.053244512528181076} | 15615957 | UNLABELLED Fruit and vegetable consumption has been inversely associated with the risk of chronic diseases including cancer and cardiovascular disease, with the beneficial effects attributed to a variety of protective antioxidants, carotenoids and phytonutrients. The objective of the present study was to determine the effect of supplementation with dehydrated concentrates from mixed fruit and vegetable juices (Juice Plus+R) on serum antioxidant and folate status, plasma homocysteine levels and markers for oxidative stress and DNA damage. Japanese subjects (n=60; age 27.8 yrs; BMI 22.1) were recruited to participate in a double-blind placebo controlled study and were randomized into 2 groups of 30, matched for sex, age, BMI and smoking status (39 males, 22 smokers; 21 females, 13 smokers). Subjects were given encapsulated supplements containing mixed fruit and vegetable juice concentrates or a matching placebo for 28 days, with blood and urine samples collected at baseline, day 14 and day 28 for analytical testing. Compared with the placebo, 28 day supplementation significantly increased the concentration of serum beta-carotene 528% (p<0.0001), lycopene 80.2% (p<0.0005), and alpha tocopherol 39.5% (p<0.0001). Serum folate increased 174.3% (p<0.0001) and correlated with a decrease in plasma homocysteine of -19.9% (p<0.03). Compared with baseline, measures of oxidative stress decreased with serum lipid peroxides declining -10.5% (p<0.02) and urine 8OHdG decreasing -21.1% (p<0.02). Evaluation of data from smokers only (n=17) after 28 days of active supplementation showed comparable changes. CONCLUSION In the absence of dietary modification, supplementation with the fruit and vegetable juice concentrate capsules proved to be a highly bioavailable source of phytonutrients. Important antioxidants were elevated to desirable levels associated with decreased risk of disease while markers of oxidative stress were reduced, and folate status improved with a concomitant decrease in homocysteine, and these benefits occurred to a similar extent in smokers when compared to non-smokers. | Original Article |
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"29474": 0.1229778528213501} | 15617300 | The Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) is an international public repository for high-throughput microarray and next-generation sequence functional genomic data sets submitted by the research community. The resource supports archiving of raw data, processed data and metadata which are indexed, cross-linked and searchable. All data are freely available for download in a variety of formats. GEO also provides several web-based tools and strategies to assist users to query, analyse and visualize data. This article reports current status and recent database developments, including the release of GEO2R, an R-based web application that helps users analyse GEO data. | NCBI GEO: archive for functional genomics data sets—update |
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0.7463917136192322, "29107": 0.31845372915267944, "29206": 0.4067663550376892} | 15617866 | Paratransgenesis, the genetic manipulation of insect symbiotic microorganisms, is being considered as a potential method to control vector-borne diseases such as malaria. The feasibility of paratransgenic malaria control has been hampered by the lack of candidate symbiotic microorganisms for the major vector Anopheles gambiae. In other systems, densonucleosis viruses (DNVs) are attractive agents for viral paratransgenesis because they infect important vector insects, can be genetically manipulated and are transmitted to subsequent generations. However, An. gambiae has been shown to be refractory to DNV dissemination. We discovered, cloned and characterized the first known DNV (AgDNV) capable of infection and dissemination in An. gambiae. We developed a flexible AgDNV-based expression vector to express any gene of interest in An. gambiae using a two-plasmid helper-transducer system. To demonstrate proof-of-concept of the viral paratransgenesis strategy, we used this system to transduce expression of an exogenous gene (enhanced green fluorescent protein; EGFP) in An. gambiae mosquitoes. Wild-type and EGFP-transducing AgDNV virions were highly infectious to An. gambiae larvae, disseminated to and expressed EGFP in epidemiologically relevant adult tissues such as midgut, fat body and ovaries and were transmitted to subsequent mosquito generations. These proof-of-principle data suggest that AgDNV could be used as part of a paratransgenic malaria control strategy by transduction of anti-Plasmodium peptides or insect-specific toxins in Anopheles mosquitoes. AgDNV will also be extremely valuable as an effective and easy-to-use laboratory tool for transient gene expression or RNAi in An. gambiae. | Viral Paratransgenesis in the Malaria Vector Anopheles gambiae |
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Here we show that disruption of L3mbtl2 results in embryonic lethality with failure of gastrulation. This correlates with compromised proliferation and abnormal differentiation of L3mbtl2(-/-) embryonic stem (ES) cells. L3mbtl2 regulates genes by recruiting a Polycomb Repressive Complex1 (PRC1)-related complex, resembling the previously described E2F6-complex, and including G9A, Hdac1, and Ring1b. The presence of L3mbtl2 at target genes is associated with H3K9 dimethylation, low histone acetylation, and H2AK119 ubiquitination, but the latter is neither dependent on L3mbtl2 nor sufficient for repression. Genome-wide studies revealed that the L3mbtl2-dependent complex predominantly regulates genes not bound by canonical PRC1 and PRC2. However, some developmental regulators are repressed by the combined activity of all three complexes. Together, we have uncovered a highly selective, essential role for an atypical PRC1-family complex in ES cells and early development. | The polycomb group protein L3mbtl2 assembles an atypical PRC1-family complex that is essential in pluripotent stem cells and early development. |
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"28154": 0.7809720039367676, "28207": 0.09050461649894714, "28279": 0.23247487843036652, "28311": 0.0317181795835495, "28739": 0.03831886500120163} | 15648443 | BACKGROUND Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma. | Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial |
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1.1031591892242432, "26166": 0.4093637466430664, "26402": 0.10555581003427505, "26468": 0.14602625370025635, "26534": 0.24325250089168549, "26757": 0.1229778528213501, "26773": 0.9333322048187256, "26914": 0.15610189735889435, "27697": 0.05970508232712746, "27777": 0.11517547070980072, "27790": 0.09584271162748337, "27854": 0.18978065252304077, "28297": 0.16110190749168396, "28696": 0.053244512528181076, "28767": 0.11256109178066254, "28848": 0.7163142561912537, "28855": 0.1401015669107437, "29222": 0.6363908052444458, "29226": 0.2689530849456787, "29290": 0.38441169261932373, "29441": 0.034552380442619324, "29486": 0.3916989266872406} | 15655418 | Long-term memory and synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. The CPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. The precise mechanism by which these molecules regulate memory formation is however poorly understood. We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene in order to investigate its role in long-term memory formation. We show that the Orb2A and Orb2B isoforms, while both essential, have distinct functions in memory formation. These two isoforms have common glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2B the latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both its glutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB to regulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventional manner to form stable Orb2 complexes that are essential for memory to persist. | Drosophila CPEB Orb2A Mediates Memory Independent of Its RNA-Binding Domain |
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1.108330488204956, "28788": 0.13414156436920166, "28815": 0.08244366943836212, "29290": 0.2145126610994339} | 15657779 | Little is known about the expression and possible functions of unopposed gap junction hemichannels in the brain. Emerging evidence suggests that gap junction hemichannels can act as stand-alone functional channels in astrocytes. With immunocytochemistry, dye uptake, and HPLC measurements, we show that astrocytes in vitro express functional hemichannels that can mediate robust efflux of glutamate and aspartate. Functional hemichannels were confirmed by passage of extracellular lucifer yellow (LY) into astrocytes in nominal divalent cation-free solution (DCFS) and the ability to block this passage with gap junction blocking agents. Glutamate/aspartate release (or LY loading) in DCFS was blocked by multivalent cations (Ca2+, Ba2+, Sr2+, Mg2+, and La3+) and by gap junction blocking agents (carbenoxolone, octanol, heptanol, flufenamic acid, and 18alpha-glycyrrhetinic acid) with affinities close to those reported for blockade of gap junction intercellular communication. Glutamate efflux via hemichannels was also accompanied by greatly reduced glutamate uptake. Glutamate release in DCFS, however, was not significantly mediated by reversal of the glutamate transporter: release did not saturate and was not blocked by glutamate transporter blockers. Control experiments in DCFS precluded glutamate release by volume-sensitive anion channels, P2X7 purinergic receptor pores, or general purinergic receptor activation. Blocking intracellular Ca2+ mobilization by BAPTA-AM or thapsigargin did not inhibit glutamate release in DCFS. Divalent cation removal also induced glutamate release from intact CNS white matter (acutely isolated optic nerve) that was blocked by carbenoxolone, suggesting the existence of functional hemichannels in situ. Our results indicated that astrocyte hemichannels could influence CNS levels of extracellular glutamate with implications for normal and pathological brain function. | Functional hemichannels in astrocytes: a novel mechanism of glutamate release. |
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"26963": 0.22626367211341858, "27009": 0.15526613593101501, "27226": 0.23710809648036957, "27777": 0.37102460861206055, "27781": 0.08603433519601822, "27854": 0.28082266449928284, "27965": 0.08603433519601822, "28024": 0.3930181860923767, "28134": 1.1714173555374146, "28424": 0.055094651877880096, "28432": 0.3923587501049042, "28691": 0.04487626627087593, "28815": 0.053244512528181076, "28911": 0.9108069539070129, "28976": 0.06795065850019455, "29133": 0.25088030099868774, "29431": 0.23015019297599792} | 15659108 | Rad52 promotes the annealing of complementary strands of DNA bound by replication protein A (RPA) during discrete repair pathways. Here, we used a fluorescence resonance energy transfer (FRET) between two fluorescent dyes incorporated into DNA substrates to probe the mechanism by which human Rad52 (hRad52) interacts with and mediates annealing of ssDNA-hRPA complexes. Human Rad52 bound ssDNA or ssDNA-hRPA complex in two, concentration-dependent modes. At low hRad52 concentrations, ssDNA was wrapped around the circumference of the protein ring, while at higher protein concentrations, ssDNA was stretched between multiple hRad52 rings. Annealing by hRad52 occurred most efficiently when each complementary DNA strand or each ssDNA-hRPA complex was bound by hRad52 in a wrapped configuration, suggesting homology search and annealing occur via two hRad52-ssDNA complexes. In contrast to the wild type protein, hRad52(RQK/AAA) and hRad52(1-212) mutants with impaired ability to bind hRPA protein competed with hRPA for binding to ssDNA and failed to counteract hRPA-mediated duplex destabilization highlighting the importance of hRad52-hRPA interactions in promoting efficient DNA annealing. | Human Rad52 binds and wraps single-stranded DNA and mediates annealing via two hRad52–ssDNA complexes |
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"26419": 0.2145126610994339, "26534": 0.15777134895324707, "26741": 0.5990082025527954, "26786": 0.03831886500120163, "27698": 0.09406650811433792, "27781": 0.06246116757392883, "27794": 0.890972912311554, "27814": 0.010684899985790253, "27833": 1.269914150238037, "28093": 0.29619070887565613, "28309": 0.35334911942481995, "28424": 0.2247048318386078, "28436": 0.10993985831737518, "28696": 0.07431721687316895, "28873": 0.3588210940361023, "29048": 0.7500885725021362, "29166": 0.05694137513637543, "29299": 0.3615458607673645, "29458": 0.2018241584300995, "29491": 0.12384103983640671, "29610": 0.0029254043474793434} | 15663829 | BACKGROUND Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded. METHODS AND FINDINGS We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders. CONCLUSIONS Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions. Please see later in the article for the Editors' Summary. | Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of Causal Association from Population Studies |
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"29486": 0.12470348179340363, "29514": 0.04394211992621422} | 15669393 | Transient activation of estrogen receptors (ER) in the developing brain during a limited perinatal "window of time" is recognized as a key mechanism of defeminization of neural control of reproductive function and sexual behavior. Two major ER isoforms, alpha and beta, are present in neural circuits that govern ovarian cycle and sexual behavior. Using highly selective ER agonists, this study provides the first evidence for distinct contribution of individual ER isoforms to the process of estrogen dependent defeminization. Neonatal activation of the ERalpha in female rats resulted in abrogation of cyclic ovarian activity and female sexual behavior in adulthood. These effects are associated with male-like alterations in the morphology of the anteroventral periventricular (AVPV) and sexually dimorphic nucleus of the preoptic area (SDN-POA), as well as refractoriness to estrogen-mediated induction of sexual receptivity. Exposure to an ERbeta-selective agonist induced persistent estrus and had a strong defeminizing effect on the hypothalamic gonadotropin "surge generator" AVPV. However, neonatal ERbeta activation failed to alter female sexual behavior, responsiveness to estrogens and morphometric features of the behaviorally relevant SDN-POA. Thus, although co-present in several brain regions involved in the control of female reproductive function, ER isoforms convey different, and probably not synergistic, chemical signals in the course of neonatal sex-specific brain organization. | brain organization |
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"24501": 0.0606246218085289, "24755": 0.012615402229130268, "26163": 0.1710275560617447, "26462": 0.1946154683828354, "26989": 0.3027053773403168, "27118": 0.043007105588912964, "27483": 0.11256109178066254, "27615": 0.27934664487838745, "29003": 0.32270604372024536, "29073": 0.03266380727291107} | 15670968 | Many countries use the cost-effectiveness thresholds recommended by the World Health Organization's Choosing Interventions that are Cost-Effective project (WHO-CHOICE) when evaluating health interventions. This project sets the threshold for cost-effectiveness as the cost of the intervention per disability-adjusted life-year (DALY) averted less than three times the country's annual gross domestic product (GDP) per capita. Highly cost-effective interventions are defined as meeting a threshold per DALY averted of once the annual GDP per capita. We argue that reliance on these thresholds reduces the value of cost-effectiveness analyses and makes such analyses too blunt to be useful for most decision-making in the field of public health. Use of these thresholds has little theoretical justification, skirts the difficult but necessary ranking of the relative values of locally-applicable interventions and omits any consideration of what is truly affordable. The WHO-CHOICE thresholds set such a low bar for cost-effectiveness that very few interventions with evidence of efficacy can be ruled out. The thresholds have little value in assessing the trade-offs that decision-makers must confront. We present alternative approaches for applying cost-effectiveness criteria to choices in the allocation of health-care resources. | Thresholds for the cost–effectiveness of interventions: alternative approaches |
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0.0174254160374403, "25212": 0.10818854719400406, "25627": 0.04953393340110779, "25670": 0.1510767638683319, "25775": 0.04113444685935974, "25870": 0.18978065252304077, "25947": 0.35677260160446167, "26262": 0.2493593990802765, "26264": 0.5092619061470032, "26319": 0.1685553640127182, "26462": 0.13755162060260773, "26497": 1.0001721382141113, "26638": 0.04767346754670143, "26651": 0.2317005842924118, "26683": 0.32553088665008545, "26836": 0.013579257763922215, "26838": 0.06612417846918106, "27794": 1.0001721382141113, "28081": 0.026025565341114998, "28321": 0.0770333781838417, "28575": 0.009718249551951885, "28739": 0.021256839856505394, "28767": 0.5685047507286072, "28846": 0.1602703034877777, "29076": 0.052318159490823746, "29101": 0.5267143249511719, "29172": 0.1734936386346817, "29458": 0.09495500475168228} | 15678772 | OBJECTIVE To determine whether exposure to low doses of ionising radiation in infancy affects cognitive function in adulthood. DESIGN Population based cohort study. SETTING Sweden. PARTICIPANTS 3094 men who had received radiation for cutaneous haemangioma before age 18 months during 1930-59. MAIN OUTCOME MEASURES Radiation dose to frontal and posterior parts of the brain, and association between dose and intellectual capacity at age 18 or 19 years based on cognitive tests (learning ability, logical reasoning, spatial recognition) and high school attendance. RESULTS The proportion of boys who attended high school decreased with increasing doses of radiation to both the frontal and the posterior parts of the brain from about 32% among those not exposed to around 17% in those who received > 250 mGy. For the frontal dose, the multivariate odds ratio was 0.47 (95% confidence interval 0.26 to 0.85, P for trend 0.0003) and for the posterior dose it was 0.59 (0.23 to 1.47, 0.0005). A negative dose-response relation was also evident for the three cognitive tests for learning ability and logical reasoning but not for the test of spatial recognition. CONCLUSIONS Low doses of ionising radiation to the brain in infancy influence cognitive abilities in adulthood. | Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study. |
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"27854": 0.2711893916130066, "28156": 0.5909284353256226, "28180": 0.3381449282169342, "28215": 0.10026945173740387, "28228": 0.034552380442619324, "28282": 0.04487626627087593, "28620": 0.40806588530540466, "28687": 0.32270604372024536, "28688": 0.0752234235405922, "29170": 0.08513788133859634, "29577": 0.0038986403960734606} | 15685921 | Patch-clamp recordings were made from retinal ganglion cells in the mouse retina. Under dark adaptation, blockage of BK(Ca) channels increases the spontaneous excitatory postsynaptic currents (EPSCs) and light-evoked On-EPSCs, while it decreases the light-evoked Off inhibitory postsynaptic currents (IPSCs). However, under light adaptation it decreases the light-evoked On-EPSCs, the spontaneous IPSCs and the light-evoked On- and Off-IPSCs. Blockage of BK(Ca) channels significantly altered the outputs of RGCs by changing their light-evoked responses into a bursting pattern and increasing the light-evoked depolarization of the membrane potentials, while it did not significantly change the peak firing rates of light-evoked responses. | Differential effects of charybdotoxin on the activity of retinal ganglion cells in the dark- and light-adapted mouse retina |
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"28828": 0.5139457583427429, "28974": 0.014542185701429844, "28989": 0.06429435312747955, "29101": 0.12470348179340363, "29107": 0.3374483287334442, "29190": 0.021256839856505394, "29325": 0.09672962874174118, "29370": 0.41840189695358276, "29388": 0.32129061222076416, "29477": 0.015504186972975731} | 15692098 | Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non-classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p. G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant-negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A. | Hutchinson-Gilford progeria syndrome: review of the phenotype |
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"27480": 0.09406650811433792, "27641": 0.18004031479358673, "27781": 0.15023678541183472, "27929": 0.06154331564903259, "28227": 0.1384023278951645, "28466": 0.18654440343379974, "28817": 0.03831886500120163, "28828": 0.29036402702331543, "28829": 0.2539152204990387, "28873": 0.9084475636482239, "29048": 0.684319257736206, "29191": 0.176772341132164, "29295": 0.07431721687316895, "29536": 0.5584990978240967} | 15707049 | Interstitial lung disease (ILD) is a common manifestation of systemic autoimmunity characterized by progressive inflammation or scarring of the lungs. Patients who develop these complications can exhibit significantly impaired gas exchange that may result in hypoxemia, pulmonary hypertension, and even death. Unfortunately, little is understood about how these diseases arise, including the role of specific defects in immune tolerance. Another key question is whether autoimmune responses targeting the lung parenchyma are critical to ILD pathogenesis, including that of isolated idiopathic forms. We show that a specific defect in central tolerance brought about by mutations in the autoimmune regulator gene (Aire) leads to an autoreactive T cell response to a lung antigen named vomeromodulin and the development of ILD. We found that a human patient and mice with defects in Aire develop similar lung pathology, demonstrating that the AIRE-deficient model of autoimmunity is a suitable translational system in which to unravel fundamental mechanisms of ILD pathogenesis. | Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance. |
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To evaluate the in vivo role of ERAP1, we have generated ERAP1-deficient mice. Cell surface expression of the class Ia molecules H-2Kb and H-2Db and of the class Ib molecule Qa-2 was significantly reduced in these animals. Although cells from mutant animals exhibited reduced capacity to present several self- and foreign antigens to Kb-, Db-, or Qa-1b–restricted CD8+ cytotoxic T cells, presentation of some antigens was unaffected or significantly enhanced. Consistent with these findings, mice generated defective CD8+ T cell responses against class I–presented antigens. These findings reveal an important in vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules. | In vivo role of ER-associated peptidase activity in tailoring peptides for presentation by MHC class Ia and class Ib molecules |
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"26520": 0.1064341589808464, "26572": 0.15693697333335876, "26651": 0.2674594223499298, "26773": 0.53589928150177, "26986": 0.9021284580230713, "27144": 0.40546512603759766, "27781": 0.08154398202896118, "27854": 0.2822965085506439, "28207": 0.42225050926208496, "28436": 0.21922965347766876, "28522": 0.8074519634246826, "28828": 0.16524957120418549, "28991": 0.846739649772644, "29323": 1.0587663650512695, "29458": 0.5590575933456421, "29490": 0.13755162060260773} | 15721252 | INTRODUCTION Alterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines. METHODS Forty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response. RESULTS Cell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade. CONCLUSIONS These studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991 | PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro |
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cells") that can promote or inhibit tumorigenesis by mechanisms that have not been fully elucidated. Here, we postulated that stromal cells in the tumor microenvironment alter the tumor cell secretome, including those proteins required for tumor growth and dissemination, and we developed an in vitro model to test this hypothesis. Coculturing a murine K-ras mutant lung adenocarcinoma cell line (LKR-13) with a murine lung stromal cell (macrophage, endothelial cell, or fibroblast) enhanced stromal cell migration, induced endothelial tube formation, increased LKR-13 cell proliferation, and regulated the secretion of proteins involved in angiogenesis, inflammation, cell proliferation, and epithelial-to-mesenchymal transition. Among these proteins, CXCL1 has been reported to promote NSCLC development, whereas interleukin-18 (IL-18) has an undefined role. Genetic and pharmacologic strategies to inhibit CXCL1 and IL-18 revealed that stromal cell migration, LKR-13 cell proliferation, and LKR-13 cell tumorigenicity required one or both of these proteins. We conclude that stromal cells enhanced LKR-13 cell tumorigenicity partly through their effects on the secretome of LKR-13 cells. Strategies to inhibit tumor/stromal cell interactions may be useful as therapeutic approaches in NSCLC patients. | Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. |
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"26874": 0.3464667797088623, "27598": 0.011650617234408855, "27642": 0.9076598286628723, "27989": 0.13414156436920166, "28041": 0.48670899868011475, "28086": 0.983511209487915, "28424": 0.0174254160374403, "28788": 0.15275461971759796, "28964": 1.2198615074157715, "29109": 0.05139094591140747, "29454": 0.7295845746994019} | 15728433 | Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Stem cells are characterized by self-renewal, pluripotency, and quiescence; their long life span, limited capacity to dilute cellular waste and spent organelles due to quiescence, along with their requirement for remodeling in order to differentiate, all suggest that they require autophagy more than other cell types. Here, we review the current literature on the role of autophagy in embryonic and adult stem cells, including hematopoietic, mesenchymal, and neuronal stem cells, highlighting the diverse and contrasting roles autophagy plays in their biology. Furthermore, we review the few studies on stem cells, lysosomal activity, and autophagy. Novel techniques to detect autophagy in primary cells are required to study autophagy in different stem cell types. These will help to elucidate the importance of autophagy in stem cells during transplantation, a promising therapeutic approach for many diseases. | Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging |
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0.28890204429626465, "28696": 0.12038381397724152, "28873": 0.23092569410800934, "29206": 0.22392450273036957} | 15778034 | H2A.Z is an evolutionary conserved histone variant involved in transcriptional regulation, antisilencing, silencing, and genome stability. The mechanism(s) by which H2A.Z regulates these various biological functions remains poorly defined, in part due to the lack of knowledge regarding its physical location along chromosomes and the bearing it has in regulating chromatin structure. Here we mapped H2A.Z across the yeast genome at an approximately 300-bp resolution, using chromatin immunoprecipitation combined with tiling microarrays. We have identified 4,862 small regions—typically one or two nucleosomes wide—decorated with H2A.Z. Those “Z loci” are predominantly found within specific nucleosomes in the promoter of inactive genes all across the genome. Furthermore, we have shown that H2A.Z can regulate nucleosome positioning at the GAL1 promoter. Within HZAD domains, the regions where H2A.Z shows an antisilencing function, H2A.Z is localized in a wider pattern, suggesting that the variant histone regulates a silencing and transcriptional activation via different mechanisms. Our data suggest that the incorporation of H2A.Z into specific promoter-bound nucleosomes configures chromatin structure to poise genes for transcriptional activation. The relevance of these findings to higher eukaryotes is discussed. | Variant Histone H2A.Z Is Globally Localized to the Promoters of Inactive Yeast Genes and Regulates Nucleosome Positioning |
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Complex situations that follow war and natural disasters have a psychosocial impact on not only the individual but also on the family, community and society. Just as the mental health effects on the individual psyche can result in non pathological distress as well as a variety of psychiatric disorders; massive and widespread trauma and loss can impact on family and social processes causing changes at the family, community and societal levels. METHOD This qualitative, ecological study is a naturalistic, psychosocial ethnography in Northern Sri Lanka, while actively involved in psychosocial and community mental health programmes among the Tamil community. Participatory observation, key informant interviews and focus group discussion with community level relief and rehabilitation workers and government and non-governmental officials were used to gather data. The effects on the community of the chronic, man-made disaster, war, in Northern Sri Lanka were compared with the contexts found before the war and after the tsunami. RESULTS Fundamental changes in the functioning of the family and the community were observed. While the changes after the tsunami were not so prominent, the chronic war situation caused more fundamental social transformations. At the family level, the dynamics of single parent families, lack of trust among members, and changes in significant relationships, and child rearing practices were seen. Communities tended to be more dependent, passive, silent, without leadership, mistrustful, and suspicious. Additional adverse effects included the breakdown in traditional structures, institutions and familiar ways of life, and deterioration in social norms and ethics. A variety of community level interventions were tried. CONCLUSION Exposure to conflict, war and disaster situations impact on fundamental family and community dynamics resulting in changes at a collective level. Relief, rehabilitation and development programmes to be effective will need to address the problem of collective trauma, particularly using integrated multi-level approaches. | Collective trauma in northern Sri Lanka: a qualitative psychosocial-ecological study |
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"28848": 0.6689305305480957, "28976": 0.3777405619621277, "29290": 0.5844172835350037} | 15790930 | In the present study, the relationship between short interfering RNA (siRNA) sequence and RNA interference (RNAi) effect was extensively analyzed using 62 targets of four exogenous and two endogenous genes and three mammalian and Drosophila cells. We present the rules that may govern siRNA sequence preference and in accordance with which highly effective siRNAs essential for systematic mammalian functional genomics can be readily designed. These rules indicate that siRNAs which simultaneously satisfy all four of the following sequence conditions are capable of inducing highly effective gene silencing in mammalian cells: (i) A/U at the 5' end of the antisense strand; (ii) G/C at the 5' end of the sense strand; (iii) at least five A/U residues in the 5' terminal one-third of the antisense strand; and (iv) the absence of any GC stretch of more than 9 nt in length. siRNAs opposite in features with respect to the first three conditions give rise to little or no gene silencing in mammalian cells. Essentially the same rules for siRNA sequence preference were found applicable to DNA-based RNAi in mammalian cells and in ovo RNAi using chick embryos. In contrast to mammalian and chick cells, little siRNA sequence preference could be detected in Drosophila in vivo RNAi. | Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference. |
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suite is a collection of programs and associated data and software libraries which can be used for macromolecular structure determination by X-ray crystallography. The suite is designed to be flexible, allowing users a number of methods of achieving their aims. The programs are from a wide variety of sources but are connected by a common infrastructure provided by standard file formats, data objects and graphical interfaces. Structure solution by macromolecular crystallography is becoming increasingly automated and the CCP4 suite includes several automation pipelines. After giving a brief description of the evolution of CCP4 over the last 30 years, an overview of the current suite is given. While detailed descriptions are given in the accompanying articles, here it is shown how the individual programs contribute to a complete software package. | Overview of the CCP4 suite and current developments |
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"29217": 0.2516399025917053, "29280": 0.9162907600402832} | 15803282 | The extremely low efficiency of human embryonic stem cell (hESC) derivation using somatic cell nuclear transfer (SCNT) limits its potential application. Blastocyst formation from human SCNT embryos occurs at a low rate and with only some oocyte donors. We previously showed in mice that reduction of histone H3 lysine 9 trimethylation (H3K9me3) through ectopic expression of the H3K9me3 demethylase Kdm4d greatly improves SCNT embryo development. Here we show that overexpression of a related H3K9me3 demethylase KDM4A improves human SCNT, and that, as in mice, H3K9me3 in the human somatic cell genome is an SCNT reprogramming barrier. Overexpression of KDM4A significantly improves the blastocyst formation rate in human SCNT embryos by facilitating transcriptional reprogramming, allowing efficient derivation of SCNT-derived ESCs using adult Age-related Macular Degeneration (AMD) patient somatic nuclei donors. This conserved mechanistic insight has potential applications for improving SCNT in a variety of contexts, including regenerative medicine. | Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells. |
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to suppress the occurrence of aberrant cells in epithelia. We find that ectopic expression of transcription factors that specify cell fates causes abnormal epithelial cysts in Drosophila imaginal discs. Cysts do not form cell autonomously but result from the juxtaposition of two cell populations with divergent fates. Juxtaposition of wild-type and aberrantly specified cells induces enrichment of actomyosin at their entire shared interface, both at adherens junctions as well as along basolateral interfaces. Experimental validation of 3D vertex model simulations demonstrates that enhanced interface contractility is sufficient to explain many morphogenetic behaviors, which depend on cell cluster size. These range from cyst formation by intermediate-sized clusters to segregation of large cell populations by formation of smooth boundaries or apical constriction in small groups of cells. In addition, we find that single cells experiencing lateral interface contractility are eliminated from tissues by apoptosis. Cysts, which disrupt epithelial continuity, form when elimination of single, aberrantly specified cells fails and cells proliferate to intermediate cell cluster sizes. Thus, increased interface contractility functions as error correction mechanism eliminating single aberrant cells from tissues, but failure leads to the formation of large, potentially disease-promoting cysts. Our results provide a novel perspective on morphogenetic mechanisms, which arise from cell-fate heterogeneities within tissues and maintain or disrupt epithelial homeostasis. | Interface Contractility between Differently Fated Cells Drives Cell Elimination and Cyst Formation |
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"26282": 0.4932899475097656, "26462": 0.8298473954200745, "26591": 0.3416208028793335, "26835": 0.07250232994556427, "26906": 1.0305955410003662, "27184": 0.2145126610994339, "27749": 0.06795065850019455, "27862": 0.3526630103588104, "28018": 0.2741633653640747, "28297": 0.06429435312747955, "28488": 0.09495500475168228, "28561": 0.3910386264324188, "28591": 0.11430477350950241, "28696": 0.015504186972975731, "29206": 0.007782140281051397, "29486": 0.02412080205976963} | 15830352 | In some organisms longevity, growth, and developmental rate are improved when they are maintained on a light/dark cycle, the period of which "resonates" optimally with the period of the endogenous circadian clock. However, to our knowledge no studies have demonstrated that reproductive fitness per se is improved by resonance between the endogenous clock and the environmental cycle. We tested the adaptive significance of circadian programming by measuring the relative fitness under competition between various strains of cyanobacteria expressing different circadian periods. Strains that had a circadian period similar to that of the light/dark cycle were favored under competition in a manner that indicates the action of soft selection. | Resonating circadian clocks enhance fitness in cyanobacteria. |
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0.03266380727291107} | 15832146 | Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1. | Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion |
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The location of B1 cells determines the types of OB neurons they generate. Here we show that the majority of mouse B1 cell precursors are produced between embryonic days (E) 13.5 and 15.5 and remain largely quiescent until they become reactivated postnatally. Using a retroviral library carrying over 100,000 genetic tags, we found that B1 cells share a common progenitor with embryonic cells of the cortex, striatum, and septum, but this lineage relationship is lost before E15.5. The regional specification of B1 cells is evident as early as E11.5 and is spatially linked to the production of neurons that populate different areas of the forebrain. This study reveals an early embryonic regional specification of postnatal neural stem cells and the lineage relationship between them and embryonic progenitor cells. | Embryonic Origin of Postnatal Neural Stem Cells |
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"29477": 0.06520967930555344} | 15836115 | Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo. | The Opa1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, and Ischemic Tissue Damage |
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0.06612417846918106, "28293": 0.02316705882549286, "28603": 0.15943801403045654, "28648": 0.6882523894309998, "28727": 0.440646231174469, "28758": 0.08692999184131622, "29080": 0.0009760859538801014, "29490": 0.638455867767334} | 15856466 | : Advances in stem cell research have triggered scores of studies in regenerative medicine in a large number of institutions and companies around the world. However, reproducibility and data exchange among laboratories or cell banks are constrained by the lack of a standardized format for experiments. To enhance information flow in stem cell and derivative cell research, here we propose a minimum information standard to describe cellular assay data to facilitate practical regenerative medicine. Based on the existing Minimum Information About a Cellular Assay, we developed Minimum Information About a Cellular Assay for Regenerative Medicine (MIACARM), which allows for the description of advanced cellular experiments with defined taxonomy of human cell types. By using controlled terms, such as ontologies, MIACARM will provide a platform for cellular assay data exchange among cell banks or registries that have been established at more than 20 sites in the world. SIGNIFICANCE Currently, there are more than 20 human cell information storage sites around the world. However, reproducibility and data exchange among different laboratories or cell information providers are usually inadequate or nonexistent because of the lack of a standardized format for experiments. This study, which is the fruit of collaborative work by scientists at stem cell banks and cellular information registries worldwide, including those in the U.S., the U.K., Europe, and Japan, proposes new minimum information guidelines, Minimum Information About a Cellular Assay for Regenerative Medicine (MIACARM), for cellular assay data deposition. MIACARM is intended to promote data exchange and facilitation of practical regenerative medicine. | First Proposal of Minimum Information About a Cellular Assay for Regenerative Medicine |
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Some of the PAR proteins are localized asymmetrically and form physical complexes with one another. Strikingly, the PAR proteins have been found to regulate cell polarization in many different contexts in diverse animals, suggesting they form part of an ancient and fundamental mechanism for cell polarization. Although the picture of how the PAR proteins function remains incomplete, cell biology and biochemistry are beginning to explain how PAR proteins polarize cells. | The PAR proteins: fundamental players in animal cell polarization. |
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"26210": 0.9929623603820801, "26282": 0.0058422754518687725, "26475": 0.020300358533859253, "26770": 0.9944084882736206, "26835": 0.7057625651359558, "26927": 1.4469189643859863, "26972": 0.0009760859538801014, "27152": 0.28963330388069153, "27226": 0.029824240133166313, "27764": 0.6270449161529541, "28023": 0.5364705324172974, "28170": 0.1677299439907074, "28263": 0.15777134895324707, "28297": 0.1619328260421753, "28691": 1.2829933166503906, "28822": 0.11081436276435852, "29090": 0.05694137513637543, "29495": 0.2561853528022766, "29543": 0.21765978634357452} | 15879544 | An unidentified environmental reservoir of infectivity contributes to the natural transmission of prion diseases (transmissible spongiform encephalopathies [TSEs]) in sheep, deer, and elk. Prion infectivity may enter soil environments via shedding from diseased animals and decomposition of infected carcasses. Burial of TSE-infected cattle, sheep, and deer as a means of disposal has resulted in unintentional introduction of prions into subsurface environments. We examined the potential for soil to serve as a TSE reservoir by studying the interaction of the disease-associated prion protein (PrPSc) with common soil minerals. In this study, we demonstrated substantial PrPSc adsorption to two clay minerals, quartz, and four whole soil samples. We quantified the PrPSc-binding capacities of each mineral. Furthermore, we observed that PrPSc desorbed from montmorillonite clay was cleaved at an N-terminal site and the interaction between PrPSc and Mte was strong, making desorption of the protein difficult. Despite cleavage and avid binding, PrPSc bound to Mte remained infectious. Results from our study suggest that PrPSc released into soil environments may be preserved in a bioavailable form, perpetuating prion disease epizootics and exposing other species to the infectious agent. | Prions Adhere to Soil Minerals and Remain Infectious |
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"25524": 0.3870677351951599, "25543": 0.2247048318386078, "25710": 0.22392450273036957, "25714": 0.026025565341114998, "25742": 0.14179791510105133, "25761": 0.16110190749168396, "26261": 0.06977381557226181, "26305": 0.7674643993377686, "26402": 0.5707147121429443, "26632": 1.2605451345443726, "26651": 0.20421554148197174, "26773": 0.33953672647476196, "27036": 0.05046287178993225, "27295": 0.11168810725212097, "27321": 0.2409527748823166, "27598": 0.6512666940689087, "27833": 1.3123366832733154, "28041": 0.13157635927200317, "28156": 0.3269403576850891, "28487": 0.04207121208310127, "28517": 0.055094651877880096, "28522": 0.045809537172317505, "28696": 1.0375399589538574, "28788": 0.3127557039260864, "28915": 0.6441128253936768, "29166": 0.4831010699272156, "29290": 0.040196798741817474} | 15879931 | Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol. | Regulated Accumulation of Desmosterol Integrates Macrophage Lipid Metabolism and Inflammatory Responses |
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0.9553611874580383, "27777": 0.19541899859905243, "27781": 0.27564704418182373, "27854": 0.12642613053321838, "27895": 0.12728634476661682, "28177": 0.28963330388069153, "28228": 0.5893046259880066, "28625": 0.9232974052429199, "28696": 0.1808556467294693, "28788": 0.3416208028793335, "28873": 0.10203468054533005, "28896": 0.18004031479358673, "29076": 0.11951763927936554, "29170": 0.38308101892471313, "29290": 0.34922540187835693} | 15889329 | Brain glial cells, five times more prevalent than neurons, have recently received attention for their potential involvement in epileptic seizures. Microglia and astrocytes, associated with inflammatory innate immune responses, are responsible for surveillance of brain damage that frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures may be facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence strongly implicates innate immune responses in lowering seizure threshold in experimental models of epilepsy, yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we show that cortical innate immune responses alone produce profound increases of brain excitability resulting in focal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4 (TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effects are prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury. These results suggest an important role of innate immunity in epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and the pro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders in humans. | A JOURNAL OF NEUROLOGY |
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Here, we provide functional insights into how successive structural re-arrangements in ribosomal protein S3 promote maturation of the 40S ribosomal subunit. We show that S3 dimerizes and is imported into the nucleus with its N-domain in a rotated conformation and associated with the chaperone Yar1. Initial assembly of S3 with 40S precursors occurs via its C-domain, while the N-domain protrudes from the 40S surface. Yar1 is replaced by the assembly factor Ltv1, thereby fixing the S3 N-domain in the rotated orientation and preventing its 40S association. Finally, Ltv1 release, triggered by phosphorylation, and flipping of the S3 N-domain into its final position results in the stable integration of S3. Such a stepwise assembly may represent a new paradigm for the incorporation of ribosomal proteins. | Sequential domain assembly of ribosomal protein S3 drives 40S subunit maturation. |
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"27152": 1.2358801364898682, "27226": 0.5290185213088989, "27295": 0.1011524572968483, "27321": 0.9849710464477539, "27343": 0.03831886500120163, "27354": 0.11430477350950241, "27528": 0.255429208278656, "27815": 0.6619023680686951, "27969": 0.02412080205976963, "28024": 0.32270604372024536, "28086": 0.14264501631259918, "28156": 0.7047978043556213, "28406": 0.012615402229130268, "28667": 0.7942996621131897, "28788": 0.39367714524269104, "28901": 0.07250232994556427, "29139": 0.016465263441205025, "29290": 0.7314660549163818, "29490": 0.46117570996284485} | 15907458 | In this protocol, we describe how to isolate keratinocytes from adult mouse epidermis, fractionate them into different sub-populations on the basis of cell surface markers and examine their function in an in vivo skin reconstitution assay with disaggregated neonatal dermal cells. We also describe how the isolated keratinocytes can be subjected to clonal analysis in vitro and in vivo and how to enrich for hair follicle-inducing dermal papilla cells in the dermal preparation. Using these approaches, it is possible to compare the capacity of different populations of adult epidermal stem cells to proliferate and to generate progeny that differentiate along the different epidermal lineages. Isolating, fractionating and grafting cells for the skin reconstitution assay is normally spread over 2 d. Clonal growth in culture is assessed after 14 d, while evaluation of the grafts is carried out after 4–5 weeks. | Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis |
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"25468": 1.310758113861084, "25746": 0.6907027959823608, "26305": 0.06886265426874161, "26796": 0.09317722171545029, "26835": 0.36426326632499695, "26874": 0.19622190296649933, "27144": 0.056018441915512085, "27321": 0.5186077356338501, "27881": 0.07159364968538284, "28024": 0.371698260307312, "28667": 0.37907835841178894, "28696": 0.7629209756851196, "28788": 0.2105647772550583, "28828": 0.02412080205976963, "28873": 0.5261374711990356} | 15913433 | Telomerase-negative immortalized human cells maintain their telomeres by a mechanism known as alternative lengthening of telomeres (ALT). We report here that ALT cells contain a novel promyelocytic leukemia (PML) body (ALT-associated PML body, APB). APBs are large donut-shaped nuclear structures containing PML protein, telomeric DNA, and the telomere binding proteins human telomere repeat binding factors 1 and 2. Immunostaining showed that APBs also contain replication factor A, RAD51, and RAD52, proteins involved in DNA synthesis and recombination. During immortalization, APBs appeared at exactly the same time as activation of ALT. APBs were found in ALT tumors and cell lines but not in mortal cell strains or in telomerase-positive cell lines or tumors. | Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. |
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"29166": 1.0492360591888428, "29299": 0.4926934838294983, "29378": 0.10026945173740387, "29458": 0.8715548515319824} | 15925931 | BACKGROUND Whole-body magnetic resonance angiography (WB-MRA) has shown its potential for the non-invasive assessment of nearly the entire arterial vasculature within one examination. Since the presence of extra-cardiac atherosclerosis is associated with an increased risk of coronary events, our goal was to establish the relationship between WB-MRA findings, including a systemic atherosclerosis score index, and the presence of significant coronary artery disease (CAD). METHODS WB-MRA was performed on a 1.5T scanner in 50 patients scheduled to undergo elective cardiac catheterization for suspected CAD. In each patient, 40 extra-cardiac vessel segments were evaluated and assigned scores according to their luminal narrowing. The atherosclerosis score index (ASI) was generated as the ratio of summed scores to analyzable segments. RESULTS ASI was higher in patients with significant (> 50% stenosis) CAD (n = 27) vs. patients without CAD (n = 22; 1.56 vs. 1.28, p = 0.004). ASI correlated with PROCAM (R = 0.57, p < 0.001) and Framingham (R = 0.36, p = 0.01) risk scores as estimates of the 10-year risk of coronary events. A ROC derived ASI of > 1.54 predicted significant CAD with a sensitivity of 59%, specificity of 86% and a positive predictive value of 84%. Logistic regression revealed ASI > 1.54 as the strongest independent predictor for CAD with a 11-fold increase in likelihood to suffer from significant coronary disease. On the contrary, while 15/27 (55%) of patients with CAD exhibited at least one extra-cardiac stenosis > 50%, only 3/22 (14%) of those patients without CAD did (p = 0.003). The likelihood for an extra-cardiac stenosis when CAD is present differed between vascular territories and ranged from 15% for a carotid stenosis to 44% for a stenosis in the lower extremities. CONCLUSION This study provides important new evidence for the close association of extra-cardiac and coronary atherosclerosis. The novel findings that a WB-MRA derived systemic atherosclerosis score index is not only associated with established cardiovascular risk scores but is also predictive of significant CAD suggest its potential prognostic implications and underline the importance to screen for coronary disease in patients with extra-cardiac manifestations of atherosclerosis. | Prediction of coronary artery disease by a systemic atherosclerosis score index derived from whole-body MR angiography |
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0.0317181795835495, "27788": 0.7018978595733643, "27790": 0.05694137513637543, "28024": 1.360575795173645, "28424": 0.11256109178066254, "28522": 0.8925741910934448, "28667": 0.5696102976799011, "29021": 1.0409941673278809, "29107": 0.07341018319129944, "29172": 0.07341018319129944, "29206": 0.9084475636482239, "29264": 0.26820653676986694, "29461": 0.11343330889940262} | 15926408 | A major challenge each human cell-division cycle is to ensure that DNA replication origins do not initiate more than once, a phenomenon known as re-replication. Acute deregulation of replication control ultimately causes extensive DNA damage, cell-cycle checkpoint activation and cell death whereas moderate deregulation promotes genome instability and tumorigenesis. In the absence of detectable increases in cellular DNA content however, it has been difficult to directly demonstrate re-replication or to determine if the ability to re-replicate is restricted to a particular cell-cycle phase. Using an adaptation of DNA fiber spreading we report the direct detection of re-replication on single DNA molecules from human chromosomes. Using this method we demonstrate substantial re-replication within 1 h of S phase entry in cells overproducing the replication factor, Cdt1. Moreover, a comparison of the HeLa cancer cell line to untransformed fibroblasts suggests that HeLa cells produce replication signals consistent with low-level re-replication in otherwise unperturbed cell cycles. Re-replication after depletion of the Cdt1 inhibitor, geminin, in an untransformed fibroblast cell line is undetectable by standard assays but readily quantifiable by DNA fiber spreading analysis. Direct evaluation of re-replicated DNA molecules will promote increased understanding of events that promote or perturb genome stability. | Analysis of re-replication from deregulated origin licensing by DNA fiber spreading |
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factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy. | Liver receptor homolog-1 is essential for pregnancy |
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However, it is still unclear how similar human iPSCs are to human Embryonic Stem Cells (hESCs). Here, we describe the transcriptional profile of human iPSCs generated without viral vectors or genomic insertions, revealing that these cells are in general similar to hESCs but with significant differences. For the generation of human iPSCs without viral vectors or genomic insertions, pluripotent factors Oct4 and Nanog were cloned in episomal vectors and transfected into human fetal neural progenitor cells. The transient expression of these two factors, or from Oct4 alone, resulted in efficient generation of human iPSCs. The reprogramming strategy described here revealed a potential transcriptional signature for human iPSCs yet retaining the gene expression of donor cells in human reprogrammed cells free of viral and transgene interference. Moreover, the episomal reprogramming strategy represents a safe way to generate human iPSCs for clinical purposes and basic research. | Transcriptional Signature and Memory Retention of Human-Induced Pluripotent Stem Cells |
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0.026976587250828743, "25086": 0.06520967930555344, "25409": 0.9724938273429871, "25456": 0.11865071207284927, "25468": 0.33605360984802246, "25502": 0.09850110858678818, "25714": 0.010684899985790253, "25761": 0.9673105478286743, "25778": 0.5063233375549316, "26243": 0.13071982562541962, "26402": 0.19782574474811554, "26520": 0.3241194784641266, "26534": 0.0174254160374403, "26775": 0.9776504039764404, "26897": 1.2510874271392822, "26944": 0.18978065252304077, "26986": 0.40481385588645935, "27099": 0.554580807685852, "27144": 1.2516462802886963, "27295": 0.02887592278420925, "27854": 0.38574060797691345, "27881": 0.21372433006763458, "28286": 1.0023250579833984, "28309": 0.04113444685935974, "28633": 0.011650617234408855, "28696": 0.0019512200960889459, "28987": 0.0029254043474793434, "29170": 0.056018441915512085, "29248": 0.025073638185858727, "29290": 0.15610189735889435} | 15946643 | Metastasis and chemoresistance in cancer are linked phenomena, but the molecular basis for this link is unknown. We uncovered a network of paracrine signals between carcinoma, myeloid, and endothelial cells that drives both processes in breast cancer. Cancer cells that overexpress CXCL1 and 2 by transcriptional hyperactivation or 4q21 amplification are primed for survival in metastatic sites. CXCL1/2 attract CD11b(+)Gr1(+) myeloid cells into the tumor, which produce chemokines including S100A8/9 that enhance cancer cell survival. Although chemotherapeutic agents kill cancer cells, these treatments trigger a parallel stromal reaction leading to TNF-α production by endothelial and other stromal cells. TNF-α via NF-kB heightens the CXCL1/2 expression in cancer cells, thus amplifying the CXCL1/2-S100A8/9 loop and causing chemoresistance. CXCR2 blockers break this cycle, augmenting the efficacy of chemotherapy against breast tumors and particularly against metastasis. This network of endothelial-carcinoma-myeloid signaling interactions provides a mechanism linking chemoresistance and metastasis, with opportunities for intervention. | A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis |
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1.2980393171310425, "24895": 0.16276304423809052, "25002": 0.960606575012207, "25022": 0.6043586730957031, "25311": 0.841701865196228, "25344": 0.3870677351951599, "25456": 0.27934664487838745, "25688": 0.7510106563568115, "25711": 0.09672962874174118, "25918": 1.1413075923919678, "26013": 0.09584271162748337, "26237": 0.8281423449516296, "26261": 0.12814582884311676, "26402": 0.151916041970253, "26455": 1.325913906097412, "26461": 0.2184450328350067, "26591": 0.10467668622732162, "26651": 0.1064341589808464, "26708": 0.24248650670051575, "26927": 0.05694137513637543, "26942": 0.03925827145576477, "26989": 0.6389714479446411, "27042": 0.08244366943836212, "27144": 0.4113073945045471, "27211": 0.9710156321525574, "27417": 0.06703783571720123, "28212": 0.14264501631259918, "28282": 0.12038381397724152, "28804": 0.9287132620811462, "29031": 0.17267228662967682, "29110": 0.1751343309879303, "29598": 0.9440274834632874} | 15948830 | Postoperative vomiting (POV) remains one of the commonest causes of significant morbidity after tonsillectomy in children. A variety of prophylactic anti-emetic interventions have been reported, but there has only been a limited systematic review in this patient group. A systematic search was performed by using Cochrane Controlled Trials Register, MEDLINE and EMBASE to identify double-blind, randomized, placebo-controlled trials of prophylactic anti-emetic interventions in children undergoing tonsillectomy, with or without adenoidectomy. The outcome of interest was POV in the first 24 h. Summary estimates of the effect of each prophylactic anti-emetic strategy were derived using fixed effect meta-analysis. Where appropriate, dose-response effects were estimated using logistic regression and 22 articles were identified. Good evidence was found for the prophylactic anti-emetic effect of dexamethasone [odds ratio (OR) 0.23, 95% CI 0.16-0.33], and the serotinergic antagonists ondansetron (OR 0.36, 95% CI 0.29-0.46), granisetron (OR 0.11, 95% CI 0.06-0.19), tropisetron (OR 0.15, 95% CI 0.06-0.35) and dolasetron (OR 0.25, 95% CI 0.1-0.59). Metoclopramide was also found to be efficacious (OR 0.51, 95% CI 0.34-0.77). There is not sufficient evidence to suggest that dimenhydrinate, perphenazine or droperidol, in the doses studied, are efficacious, nor were gastric aspiration or acupuncture. In conclusion, dexamethasone and the anti-serotinergic agents appear to be the most effective agents for the prophylaxis for POV in children undergoing tonsillectomy. | Prophylaxis of postoperative vomiting in children undergoing tonsillectomy: a systematic review and meta-analysis. |
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"26886": 0.11081436276435852, "26914": 0.1930064558982849, "27011": 0.5528968572616577, "27045": 0.036437395960092545, "27197": 0.1064341589808464, "27263": 0.14518201351165771, "27354": 0.2223619967699051, "28093": 0.8500841856002808, "28167": 0.25694093108177185, "28436": 0.5347557663917542, "28549": 0.15526613593101501, "29280": 0.08692999184131622} | 15953181 | Receiver operating characteristic (ROC) curves are used to describe and compare the performance of diagnostic technology and diagnostic algorithms. This paper refines the statistical comparison of the areas under two ROC curves derived from the same set of patients by taking into account the correlation between the areas that is induced by the paired nature of the data. The correspondence between the area under an ROC curve and the Wilcoxon statistic is used and underlying Gaussian distributions (binormal) are assumed to provide a table that converts the observed correlations in paired ratings of images into a correlation between the two ROC areas. This between-area correlation can be used to reduce the standard error (uncertainty) about the observed difference in areas. This correction for pairing, analogous to that used in the paired t-test, can produce a considerable increase in the statistical sensitivity (power) of the comparison. For studies involving multiple readers, this method provides a measure of a component of the sampling variation that is otherwise difficult to obtain. | A method of comparing the areas under receiver operating characteristic curves derived from the same cases. |
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limited, whereas urodele amphibians and teleost fish regenerate major structures, largely by cell cycle reentry. Upon inactivation of Rb, proliferation of postmitotic urodele skeletal muscle is induced, whereas in mammalian muscle this mechanism does not exist. We postulated that a tumor suppressor present in mammals but absent in regenerative vertebrates, the Ink4a product ARF (alternative reading frame), is a regeneration suppressor. Concomitant inactivation of Arf and Rb led to mammalian muscle cell cycle reentry, loss of differentiation properties, and upregulation of cytokinetic machinery. Single postmitotic myocytes were isolated by laser micro-dissection-catapulting, and transient suppression of Arf and Rb yielded myoblast colonies that retained the ability to differentiate and fuse into myofibers upon transplantation in vivo. These results show that differentiation of mammalian cells is reversed by inactivation of Arf and Rb and support the hypothesis that Arf evolved at the expense of regeneration. | Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. |
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However, the mechanism by which the centromere assembles and stabilizes at a specific genomic region is not clear. The de novo formation of a human/mammalian artificial chromosome (HAC/MAC) with a functional centromere assembly requires the presence of alpha-satellite DNA containing binding motifs for the centromeric CENP-B protein. We demonstrate here that de novo centromere assembly on HAC/MAC is dependent on CENP-B. In contrast, centromere formation is suppressed in cells expressing CENP-B when alpha-satellite DNA was integrated into a chromosomal site. Remarkably, on those integration sites CENP-B enhances histone H3-K9 trimethylation and DNA methylation, thereby stimulating heterochromatin formation. Thus, we propose that CENP-B plays a dual role in centromere formation, ensuring de novo formation on DNA lacking a functional centromere but preventing the formation of excess centromeres on chromosomes. | CENP-B Controls Centromere Formation Depending on the Chromatin Context |
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They can be used to search sequence data bases, evaluate similarity scores, and identify periodic structures based on local sequence similarity. The FASTA program is a more sensitive derivative of the FASTP program, which can be used to search protein or DNA sequence data bases and can compare a protein sequence to a DNA sequence data base by translating the DNA data base as it is searched. FASTA includes an additional step in the calculation of the initial pairwise similarity score that allows multiple regions of similarity to be joined to increase the score of related sequences. The RDF2 program can be used to evaluate the significance of similarity scores using a shuffling method that preserves local sequence composition. The LFASTA program can display all the regions of local similarity between two sequences with scores greater than a threshold, using the same scoring parameters and a similar alignment algorithm; these local similarities can be displayed as a "graphic matrix" plot or as individual alignments. In addition, these programs have been generalized to allow comparison of DNA or protein sequences based on a variety of alternative scoring matrices. | Improved tools for biological sequence comparison. |
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METHOD Using data from the National Health and Aging Trends Study (NHATS), a representative survey of the older Medicare population, we calculated the prevalence of disability-related need for assistance with self-care, household tasks, and mobility activities and the prevalence of adverse consequences of unmet need by dually eligible and Medicare only status. RESULTS Over 2 million community-dwelling older persons experienced an adverse consequence due to unmet need for assistance with self-care (e.g., soiled their clothes), over 2 million experienced adverse consequences due to unmet need for assistance with household tasks (e.g., went without groceries), and over 3 million persons experienced at least one adverse consequence of unmet need for assistance with mobility-related activities (e.g., had to stay in bed) in the month prior to the NHATS interview. Dually eligible persons experienced higher rates of 6 of the 11 adverse consequences studied and were more likely to have at least one adverse consequence in all 3 domains than others. DISCUSSION Several care models are emerging with the goal of integrating medical care, behavioral health, and long-term services for the dual eligible population. Indicators of adverse consequences of unmet need could be used to monitor the quality and adequacy of such care systems. | The adverse consequences of unmet need among older persons living in the community: dual-eligible versus Medicare-only beneficiaries. |
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"27663": 0.1889725625514984, "27776": 0.13414156436920166, "27955": 0.014542185701429844, "27965": 0.05139094591140747, "28003": 1.2477279901504517, "28105": 0.565735399723053, "28426": 0.11778303235769272, "28516": 0.0174254160374403, "28616": 0.19862671196460724, "29278": 0.6128603219985962} | 15969637 | UNLABELLED MesoRD is a tool for stochastic simulation of chemical reactions and diffusion. In particular, it is an implementation of the next subvolume method, which is an exact method to simulate the Markov process corresponding to the reaction-diffusion master equation. AVAILABILITY MesoRD is free software, written in C++ and licensed under the GNU general public license (GPL). MesoRD runs on Linux, Mac OS X, NetBSD, Solaris and Windows XP. It can be downloaded from http://mesord.sourceforge.net. CONTACT [email protected]; [email protected] SUPPLEMENTARY INFORMATION 'MesoRD User's Guide' and other documents are available at http://mesord.sourceforge.net. | Supplementary information: ‘MesoRD User’s Guide ’ and other |
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"27011": 0.1477125883102417, "27099": 0.045809537172317505, "27169": 1.3377727270126343, "27295": 0.10993985831737518, "27325": 0.02412080205976963, "27448": 0.17431432008743286, "27777": 0.16276304423809052, "27781": 0.37974658608436584, "27854": 0.9680526852607727, "28041": 0.058784693479537964, "28352": 0.0317181795835495, "28696": 0.036437395960092545, "28788": 0.0019512200960889459, "28789": 0.20102575421333313, "28873": 1.1115491390228271, "29083": 0.006812678650021553, "29290": 0.3930181860923767, "29610": 0.06977381557226181} | 15972906 | T cell activation and function require a structured engagement of antigen-presenting cells. These cell contacts are characterized by two distinct dynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapses or prolonged contacts from stable junctions called immunological synapses. Kinapses operate in the steady state to allow referencing to self-peptide-MHC (pMHC) and searching for pathogen-derived pMHC. Synapses are induced by T cell receptor (TCR) interactions with agonist pMHC under specific conditions and correlate with robust immune responses that generate effector and memory T cells. High-resolution imaging has revealed that the synapse is highly coordinated, integrating cell adhesion, TCR recognition of pMHC complexes, and an array of activating and inhibitory ligands to promote or prevent T cell signaling. In this review, we examine the molecular components, geometry, and timing underlying kinapses and synapses. We integrate recent molecular and physiological data to provide a synthesis and suggest ways forward. | Functional anatomy of T cell activation and synapse formation. |
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"29722": 0.3339579105377197} | 15975146 | The fungal pathogen, Cryptococcus neoformans, has been shown to undergo replicative aging. Old cells are characterized by advanced generational age and phenotypic changes that appear to mediate enhanced resistance to host and antifungal-based killing. As a consequence of this age-associated resilience, old cells accumulate during chronic infection. Based on these findings, we hypothesized that shifting the generational age of a pathogenic yeast population would alter its vulnerability to the host and affect its virulence. SIR2 is a well-conserved histone deacetylase, and a pivotal target for the development of anti-aging drugs. We tested its effect on C. neoformans' replicative lifespan (RLS). First, a mutant C. neoformans strain (sir2Δ) was generated, and confirmed a predicted shortened RLS in sir2Δ cells consistent with its known role in aging. Next, RLS analysis showed that treatment of C. neoformans with Sir2p-agonists resulted in a significantly prolonged RLS, whereas treatment with a Sir2p-antagonist shortened RLS. RLS modulating effects were dependent on SIR2 and not observed in sir2Δ cells. Because SIR2 loss resulted in a slightly impaired fitness, effects of genetic RLS modulation on virulence could not be compared with wild type cells. Instead we chose to chemically modulate RLS, and investigated the effect of Sir2p modulating drugs on C. neoformans cells in a Galleria mellonella infection model. Consistent with our hypothesis that shifts in the generational age of the infecting yeast population alters its vulnerability to host cells, we observed decreased virulence of C. neoformans in the Galleria host when RLS was prolonged by treatment with Sir2p agonists. In contrast, treatment with a Sir2p antagonist, which shortens RLS enhanced virulence in Galleria. In addition, combination of Sir2p agonists with antifungal therapy enhanced the antifungal's effect. Importantly, no difference in virulence was observed with drug treatment when sir2Δ cells were used for infection, which confirmed target specificity and ruled out non-specific effects of the drugs on the Galleria host. Thus, this study suggests that RLS modulating drugs, such as Sir2p agonists, shift lifespan and vulnerability of the fungal population, and should be further investigated as a potential class of novel antifungal drug targets that can enhance antifungal efficacy. | Modulation of Replicative Lifespan in Cryptococcus neoformans: Implications for Virulence |
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0.6149744987487793, "28290": 0.12814582884311676, "28472": 0.9029204845428467, "28667": 0.9944084882736206, "28848": 0.0174254160374403, "29206": 0.27044451236724854, "29226": 0.12470348179340363, "29248": 0.11256109178066254} | 15981174 | To generate transgenic mice that express Cre-recombinase exclusively in the megakaryocytic lineage, we modified a mouse bacterial artificial chromosome (BAC) clone by homologous recombination and replaced the first exon of the platelet factor 4 (Pf4), also called CXCL4, with a codon-improved Cre cDNA. Several strains expressing the transgene were obtained and one strain, Q3, was studied in detail. Crossing Q3 mice with the ROSA26-lacZ reporter strain showed that Cre-recombinase activity was confined to megakaryocytes. These results were further verified by crossing the Q3 mice with a strain containing loxP-flanked integrin beta1. Excision of this conditional allele in megakaryocytes was complete at the DNA level, and platelets were virtually devoid of the integrin beta1 protein. The Pf4-Cre transgenic strain will be a valuable tool to study megakaryopoiesis, platelet formation, and platelet function. | Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo. |
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Although both these domains are equally important for signal transmission, our understanding of dendrite development remains relatively poor. Here, we show that in C. elegans the Wnt ligand, LIN-44, and its Frizzled receptor, LIN-17, regulate dendrite development of the PQR oxygen sensory neuron. In lin-44 and lin-17 mutants, PQR dendrites fail to form, display stunted growth, or are misrouted. Manipulation of temporal and spatial expression of LIN-44, combined with cell-ablation experiments, indicates that this molecule is patterned during embryogenesis and acts as an attractive cue to define the site from which the dendrite emerges. Genetic interaction between lin-44 and lin-17 suggests that the LIN-44 signal is transmitted through the LIN-17 receptor, which acts cell autonomously in PQR. Furthermore, we provide evidence that LIN-17 interacts with another Wnt molecule, EGL-20, and functions in parallel to MIG-1/Frizzled in this process. Taken together, our results reveal a crucial role for Wnt and Frizzled molecules in regulating dendrite development in vivo. | LIN-44/Wnt Directs Dendrite Outgrowth through LIN-17/Frizzled in C. elegans Neurons |
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"29235": 0.11256109178066254, "29336": 0.012615402229130268, "29525": 0.6892333030700684, "29598": 0.20102575421333313} | 15983982 | OBJECTIVES To describe the role patient expectations play in general practitioners (GPs) antibiotic prescribing for upper respiratory tract infections (URTI). METHODS Concurrent explanatory mixed methods approach using a cross-sectional survey and semistructured interviews. SETTINGS Primary care GPs in Australia. PARTICIPANTS 584 GPs (response rate of 23.6%) completed the cross-sectional survey. 32 GPs were interviewed individually. OUTCOME MEASURE Prescribing of antibiotics for URTI. RESULTS More than half the GP respondents to the survey in Australia self-reported that they would prescribe antibiotics for an URTI to meet patient expectations. Our qualitative findings suggest that 'patient expectations' may be the main reason given for inappropriate prescribing, but it is an all-encompassing phrase that includes other reasons. These include limited time, poor doctor-patient communication and diagnostic uncertainty. We have identified three role archetypes to explain the behaviour of GPs in reference to antibiotic prescribing for URTIs. The main themes emerging from the qualitative component was that many GPs did not think that antibiotic prescribing in primary care was responsible for the development of antibiotic resistance nor that their individual prescribing would make any difference in light of other bigger issues like hospital prescribing or veterinary use. For them, there were negligible negative consequences from their inappropriate prescribing. CONCLUSIONS There is a need to increase awareness of the scope and magnitude of antibiotic resistance and the role primary care prescribing plays, and of the contribution of individual prescribing decisions to the problem of antibiotic resistance. | Why do general practitioners prescribe antibiotics for upper respiratory tract infections to meet patient expectations: a mixed methods study |
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0.5069117546081543, "27354": 0.083342544734478, "27794": 0.9907892942428589, "27833": 0.1011524572968483, "28027": 0.0019512200960889459, "28093": 0.6522845029830933, "28102": 0.026025565341114998, "28246": 0.021256839856505394, "28353": 0.4624064862728119, "28687": 0.841701865196228, "28697": 0.1970241367816925, "29048": 0.034552380442619324, "29166": 0.1229778528213501, "29212": 0.3622259199619293, "29278": 0.030771657824516296, "29477": 0.3423145115375519} | 15984735 | OBJECTIVE To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. DESIGN Systematic review and meta-analysis. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. DATA EXTRACTION Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. RESULTS Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. CONCLUSION Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations. | Migraine and cardiovascular disease: systematic review and meta-analysis. |
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0.36494144797325134, "23260": 0.9455460906028748, "23852": 1.3433949947357178, "24191": 0.3554046154022217, "24479": 0.6664261221885681, "24590": 0.47766464948654175, "24710": 0.03266380727291107, "24806": 0.4450363218784332, "24964": 0.319873183965683, "25223": 0.04767346754670143, "25228": 0.6149744987487793, "25354": 0.4356052577495575, "25370": 0.31204116344451904, "25582": 0.0174254160374403, "25775": 0.10818854719400406, "25808": 0.036437395960092545, "26163": 0.4002431631088257, "26237": 0.9680526852607727, "26243": 0.14095009863376617, "26282": 0.10291612148284912, "26419": 1.3233171701431274, "26591": 0.41195443272590637, "26721": 0.011650617234408855, "26835": 0.24325250089168549, "26989": 0.09228714555501938, "27144": 0.4734157919883728, "28297": 0.0019512200960889459, "28648": 0.2607102394104004, "28965": 0.07612881064414978, "29234": 0.0317181795835495, "29235": 0.1693800985813141, "29251": 0.8212929964065552} | 15997009 | BACKGROUND Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes. METHODS AND FINDINGS PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1-2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy. CONCLUSIONS TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy. | Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis |
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"29295": 0.045809537172317505, "29490": 0.034552380442619324, "29598": 0.841701865196228} | 16016673 | PURPOSE This study aims to provide a better set of DNA methylation markers in urine sediments for sensitive and specific detection of bladder cancer. EXPERIMENTAL DESIGN Fifty-nine tumor-associated genes were profiled in three bladder cancer cell lines, a small cohort of cancer biopsies and urine sediments by methylation-specific PCR. Twenty-one candidate genes were then profiled in urine sediments from 132 bladder cancer patients (8 cases for stage 0a; 68 cases for stage I; 50 cases for stage II; 4 cases for stages III; and 2 cases for stage IV), 23 age-matched patients with noncancerous urinary lesions, 6 neurologic diseases, and 7 healthy volunteers. RESULTS Despite six incidences of four genes reported in 3 of 23 noncancerous urinary lesion patients analyzed, cancer-specific hypermethylation in urine sediments were reported for 15 genes (P < 0.05). Methylation assessment of an 11-gene set (SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1, DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1) confirmed the existing diagnosis of 121 among 132 bladder cancer cases (sensitivity, 91.7%) with 87% accuracy. Significantly, more than 75% of stage 0a and 88% of stage I disease were detected, indicating its value in the early diagnosis of bladder cancer. Interestingly, the cluster of reported methylation markers used in the U.S. bladder cancers is distinctly different from that identified in this study, suggesting a possible epigenetic disparity between the American and Chinese cases. CONCLUSIONS Methylation profiling of an 11-gene set in urine sediments provides a sensitive and specific detection of bladder cancer. | A novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer. |
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1.1102628707885742, "27164": 0.19622190296649933, "27169": 0.011650617234408855, "27211": 1.0874829292297363, "27216": 0.956112265586853, "27570": 0.31204116344451904, "27697": 0.22157983481884003, "27777": 0.24554696679115295, "27790": 0.41001203656196594, "27854": 0.21765978634357452, "28251": 1.4794715642929077, "28433": 0.03925827145576477, "28691": 0.22157983481884003, "28723": 0.03360854089260101, "28828": 0.010684899985790253, "29060": 0.7995813488960266, "29533": 1.1381834745407104, "29720": 0.2539152204990387} | 16056410 | BACKGROUND Microtubules are built from linear polymers of α-β tubulin dimers (protofilaments) that form a tubular quinary structure. Microtubules assembled from purified tubulin in vitro contain between 10 and 16 protofilaments; however, such structural polymorphisms are not found in cells. This discrepancy implies that factors other than tubulin constrain microtubule protofilament number, but the nature of these constraints is unknown. RESULTS Here, we show that acetylation of MEC-12 α-tubulin constrains protofilament number in C. elegans touch receptor neurons (TRNs). Whereas the sensory dendrite of wild-type TRNs is packed with a cross-linked bundle of long, 15-protofilament microtubules, mec-17;atat-2 mutants lacking α-tubulin acetyltransferase activity have short microtubules, rampant lattice defects, and variable protofilament number both between and within microtubules. All-atom molecular dynamics simulations suggest a model in which acetylation of lysine 40 promotes the formation of interprotofilament salt bridges, stabilizing lateral interactions between protofilaments and constraining quinary structure to produce stable, structurally uniform microtubules in vivo. CONCLUSIONS Acetylation of α-tubulin is an essential constraint on protofilament number in vivo. We propose a structural model in which this posttranslational modification promotes the formation of lateral salt bridges that fine-tune the association between adjacent protofilaments and enable the formation of uniform microtubule populations in vivo. | Posttranslational Acetylation of α-Tubulin Constrains Protofilament Number in Native Microtubules |
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debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder. | A KEY ROLE FOR OREXIN IN PANIC ANXIETY |
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"27998": 1.2215901613235474, "28086": 0.23247487843036652, "28375": 0.7258110046386719, "28424": 0.11517547070980072, "28568": 0.10026945173740387, "28820": 0.06886265426874161, "28892": 0.09850110858678818, "29083": 0.24248650670051575, "29458": 0.04113444685935974} | 16057926 | Mechanical forces play important roles during tissue organization in developing animals. Many tissues are organized into adjacent, nonmixing groups of cells termed compartments. Boundaries between compartments display a straight morphology and are associated with signaling centers that are important for tissue growth and patterning. Local increases in mechanical tension at cell junctions along compartment boundaries have recently been shown to prevent cell mixing and to maintain straight boundaries. The cellular mechanisms by which local increases in mechanical tension prevent cell mixing at compartment boundaries, however, remain poorly understood. Here, we have used live imaging and quantitative image analysis to determine cellular dynamics at and near the anteroposterior compartment boundaries of the Drosophila pupal abdominal epidermis. We show that cell mixing within compartments involves multiple cell intercalations. Frequency and orientation of cell intercalations are unchanged along the compartment boundaries; rather, an asymmetry in the shrinkage of junctions during intercalation is biased, resulting in cell rearrangements that suppress cell mixing. Simulations of tissue growth show that local increases in mechanical tension can account for this bias in junctional shrinkage. We conclude that local increases in mechanical tension maintain cell populations separate by influencing junctional rearrangements during cell intercalation. | Local Increases in Mechanical Tension Shape Compartment Boundaries by Biasing Cell Intercalations |
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"26721": 0.5968599319458008, "26773": 0.6410312056541443, "26835": 0.22859740257263184, "26972": 0.04767346754670143, "27099": 0.42608439922332764, "27144": 0.5811457633972168, "27263": 1.200646996498108, "28173": 0.8289952278137207, "28406": 0.2763880789279938, "28424": 0.34577593207359314, "28848": 0.6734226942062378, "28976": 0.14179791510105133, "29170": 0.22079704701900482, "29226": 0.4419025182723999, "29290": 0.34508460760116577, "29490": 0.1970241367816925, "29545": 0.014542185701429844} | 16058322 | beta-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a 'dialog' between beta-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic beta-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic-polycitidilic acid-PIC). Real-time RT-PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate beta-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic beta-cell level. | MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA |
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1.4874467849731445, "28344": 0.4512746334075928, "28728": 0.4041621685028076, "28788": 0.06886265426874161, "28873": 0.15860503911972046, "29090": 0.13925230503082275, "29145": 1.2791962623596191, "29166": 1.2192846536636353, "29278": 0.2822965085506439, "29461": 0.13071982562541962, "29494": 0.4831010699272156, "29516": 0.20818853378295898} | 16066726 | Tumor necrosis factor (TNF), a key effector in controlling tuberculosis, is thought to exert protection by directing formation of granulomas, organized aggregates of macrophages and other immune cells. Loss of TNF signaling causes progression of tuberculosis in humans, and the increased mortality of Mycobacterium tuberculosis-infected mice is associated with disorganized necrotic granulomas, although the precise roles of TNF signaling preceding this endpoint remain undefined. We monitored transparent Mycobacterium marinum-infected zebrafish live to conduct a stepwise dissection of how TNF signaling operates in mycobacterial pathogenesis. We found that loss of TNF signaling caused increased mortality even when only innate immunity was operant. In the absence of TNF, intracellular bacterial growth and granuloma formation were accelerated and was followed by necrotic death of overladen macrophages and granuloma breakdown. Thus, TNF is not required for tuberculous granuloma formation, but maintains granuloma integrity indirectly by restricting mycobacterial growth within macrophages and preventing their necrosis. | Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. |
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Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in ∼50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis. | Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis |
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spindle positioning during embryonic cell division and centrosome positioning during fibroblast migration. To investigate how cortical dynein interacts with microtubule ends to generate force and how this functional association impacts positioning, we have reconstituted the 'cortical' interaction between dynein and dynamic microtubule ends in an in vitro system using microfabricated barriers. We show that barrier-attached dynein captures microtubule ends, inhibits growth, and triggers microtubule catastrophes, thereby controlling microtubule length. The subsequent interaction with shrinking microtubule ends generates pulling forces up to several pN. By combining experiments in microchambers with a theoretical description of aster mechanics, we show that dynein-mediated pulling forces lead to the reliable centering of microtubule asters in simple confining geometries. Our results demonstrate the intrinsic ability of cortical microtubule-dynein interactions to regulate microtubule dynamics and drive positioning processes in living cells. | Cortical Dynein Controls Microtubule Dynamics to Generate Pulling Forces that Position Microtubule Asters |
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"26786": 0.14264501631259918, "27162": 0.0058422754518687725, "27295": 0.10467668622732162, "27312": 0.17431432008743286, "27354": 0.0009760859538801014, "27794": 0.06246116757392883, "28309": 0.4624064862728119, "28321": 0.21687394380569458, "28436": 0.04113444685935974, "28847": 0.06703783571720123, "29107": 0.045809537172317505, "29299": 0.5133614540100098, "29458": 0.25845035910606384, "29477": 0.8143964409828186} | 16098747 | Evaluate known breast cancer risk factors in relation to breast density. We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires. Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer. The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more. | Breast cancer risk factors in relation to breast density (United States) |
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0.18492233753204346, "28593": 0.05970508232712746, "28732": 0.007782140281051397, "28973": 0.03925827145576477, "29068": 0.0317181795835495, "29206": 0.13755162060260773, "29273": 0.0174254160374403, "29374": 0.037378571927547455, "29458": 0.02792670577764511} | 16108876 | Repression of competition within groups joins kin selection as the second major force in the history of life shaping the evolution of cooperation. When opportunities for competition against neighbors are limited within groups, individuals can increase their own success only by enhancing the efficiency and productivity of their group. Thus, characters that repress competition within groups promote cooperation and enhance group success. Leigh first expressed this idea in the context of fair meiosis, in which each chromosome has an equal chance of transmission via gametes. Randomized success means that each part of the genome can increase its own success only by enhancing the total number of progeny and thus increasing the success of the group. Alexander used this insight about repression of competition in fair meiosis to develop his theories for the evolution of human sociality. Alexander argued that human social structures spread when they repress competition within groups and promote successful group-against-group competition. Buss introduced a new example with his suggestion that metazoan success depended on repression of competition between cellular lineages. Maynard Smith synthesized different lines of thought on repression of competition. In this paper, I develop simple mathematical models to illustrate the main processes by which repression of competition evolves. With the concepts made clear, I then explain the history of the idea. I finish by summarizing many new developments in this subject and the most promising lines for future study. | Perspective: repression of competition and the evolution of cooperation. |
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0.1332872211933136, "27325": 0.10379679501056671, "27441": 1.3799264430999756, "27641": 0.29036402702331543, "27781": 0.26446542143821716, "27854": 1.1255888938903809, "28156": 0.6086184978485107, "28227": 0.39893341064453125, "28286": 0.8600510358810425, "28389": 0.42799583077430725, "28483": 0.07793712615966797, "28696": 0.3027053773403168, "28775": 0.06977381557226181, "28788": 0.1994270235300064, "28873": 0.255429208278656, "29110": 0.014542185701429844, "29290": 0.22079704701900482, "29461": 1.0437490940093994, "29490": 0.03925827145576477} | 16119973 | IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 as the antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment. | Article |
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0.42926809191703796, "27598": 0.7565253376960754, "27642": 0.3963087201118469, "28032": 0.7201237678527832, "28227": 0.49030399322509766, "28327": 0.8869584798812866, "28696": 1.2035820484161377, "28848": 1.346956491470337, "29090": 0.6139179468154907, "29300": 1.4459995031356812, "29516": 0.1064341589808464} | 16120395 | Tight regulation of the expression of mRNAs encoding iron uptake proteins is essential to control iron homeostasis and avoid intracellular iron toxicity. We show that many mRNAs encoding iron uptake or iron mobilization proteins are expressed in iron-replete conditions in the absence of the S. cerevisiae RNase III ortholog Rnt1p or of the nuclear exosome component Rrp6p. Extended forms of these mRNAs accumulate in the absence of Rnt1p or of the 5'-->3' exonucleases Xrn1p and Rat1p, showing that multiple degradative pathways contribute to the surveillance of aberrant forms of these transcripts. RNase III-deficient cells are hypersensitive to high iron concentrations, suggesting that Rnt1p-mediated RNA surveillance is required to prevent iron toxicity. These results show that RNA surveillance through multiple ribonucleolytic pathways plays a role in iron homeostasis in yeast to avoid the potentially toxic effects of the expression of the iron starvation response in iron-replete conditions. | Multiple RNA surveillance pathways limit aberrant expression of iron uptake mRNAs and prevent iron toxicity in S. cerevisiae. |
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1.2905446290969849, "29235": 0.6613984704017639, "29490": 0.40546512603759766, "29494": 0.14179791510105133} | 16128711 | Adherens junctions (AJs) in epithelial cells are constantly turning over to modulate adhesion properties under various physiological and developmental contexts, but how such AJ dynamics are regulated during the apical-basal polarization of primary epithelia remains unclear. Here, we used new and genetically validated GFP markers of Drosophila E-cadherin (DE-cadherin, hereafter referred to as DE-Cad) and β-catenin (Armadillo, Arm) to quantitatively assay the in vivo dynamics of biosynthetic turnover and membrane redistribution by fluorescence recovery after photobleaching (FRAP) assays. Our data showed that membrane DE-Cad and Arm in AJs of polarizing epithelial cells had much faster biosynthetic turnover than in polarized cells. Fast biosynthetic turnover of membrane DE-Cad is independent of actin- and dynamin-based trafficking, but is microtubule-dependent. Furthermore, Arm in AJs of polarizing cells showed a faster and diffusion-based membrane redistribution that was both quantitatively and qualitatively different from the slower and exchange-based DE-Cad membrane distribution, indicating that the association of Arm with DE-Cad is more dynamic in polarizing cells, and only becomes stable in polarized epithelial cells. Consistently, biochemical assays showed that the binding of Arm to DE-Cad is weaker in polarizing cells than in polarized cells. Our data revealed that the molecular interaction between DE-Cad and Arm is modulated during apical-basal polarization, suggesting a new mechanism that might be crucial for establishing apical-basal polarity through regulating the AJ dynamics. | Differential regulation of adherens junction dynamics during apical-basal polarization. |
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"25761": 0.14686977863311768, "26189": 0.19541899859905243, "26524": 0.02792670577764511, "26534": 0.03925827145576477, "26572": 1.4132709503173828, "26601": 0.5174443125724792, "26775": 0.20818853378295898, "26786": 0.07341018319129944, "26994": 0.13670019805431366, "27226": 0.01934296265244484, "27405": 0.19381128251552582, "27749": 0.1401015669107437, "28086": 0.23324857652187347, "28156": 0.35677260160446167, "28314": 0.20501139760017395, "28603": 0.08692999184131622, "28691": 0.11081436276435852, "28790": 0.46853771805763245, "28848": 1.341354250907898, "29206": 0.151916041970253, "29226": 0.01934296265244484} | 16167746 | mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs, and is tightly coupled with termination of transcription in defining the 3'-end of genes. Large numbers of human and mouse genes harbor alternative polyadenylation sites [poly(A) sites] that lead to mRNA variants containing different 3'-untranslated regions (UTRs) and/or encoding distinct protein sequences. Here, we examined the conservation and divergence of different types of alternative poly(A) sites across human, mouse, rat and chicken. We found that the 3'-most poly(A) sites tend to be more conserved than upstream ones, whereas poly(A) sites located upstream of the 3'-most exon, also termed intronic poly(A) sites, tend to be much less conserved. Genes with longer evolutionary history are more likely to have alternative polyadenylation, suggesting gain of poly(A) sites through evolution. We also found that nonconserved poly(A) sites are associated with transposable elements (TEs) to a much greater extent than conserved ones, albeit less frequently utilized. Different classes of TEs have different characteristics in their association with poly(A) sites via exaptation of TE sequences into polyadenylation elements. Our results establish a conservation pattern for alternative poly(A) sites in several vertebrate species, and indicate that the 3'-end of genes can be dynamically modified by TEs through evolution. | Phylogenetic analysis of mRNA polyadenylation sites reveals a role of transposable elements in evolution of the 3′-end of genes |
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1.20182204246521, "26835": 1.117316484451294, "26957": 1.2797396183013916, "27000": 0.05786345899105072, "27152": 0.8550800085067749, "27216": 0.2561853528022766, "27399": 0.15275461971759796, "27642": 0.06612417846918106, "27928": 0.11343330889940262, "28024": 0.5381823778152466, "28389": 0.36697331070899963, "28436": 1.1894142627716064, "28498": 0.1401015669107437, "28848": 0.40546512603759766, "29458": 0.014542185701429844} | 16172576 | BACKGROUND High genetic diversity at both inter- and intra-host level are hallmarks of RNA viruses due to the error-prone nature of their genome replication. Several groups have evaluated the extent of viral variability using different RNA virus deep sequencing methods. Although much of this effort has been dedicated to pathogens that cause chronic infections in humans, few studies investigated arthropod-borne, acute viral infections. METHODS AND PRINCIPAL FINDINGS We deep sequenced the complete genome of ten DENV2 isolates from representative classical and severe cases sampled in a large outbreak in Brazil using two different approaches. Analysis of the consensus genomes confirmed the larger extent of the 2010 epidemic in comparison to a previous epidemic caused by the same viruses in another city two years before (genetic distance = 0.002 and 0.0008 respectively). Analysis of viral populations within the host revealed a high level of conservation. After excluding homopolymer regions of 454/Roche generated sequences, we found 10 to 44 variable sites per genome population at a frequency of >1%, resulting in very low intra-host genetic diversity. While up to 60% of all variable sites at intra-host level were non-synonymous changes, only 10% of inter-host variability resulted from non-synonymous mutations, indicative of purifying selection at the population level. CONCLUSIONS AND SIGNIFICANCE Despite the error-prone nature of RNA-dependent RNA-polymerase, dengue viruses maintain low levels of intra-host variability. | Inter- and Intra-Host Viral Diversity in a Large Seasonal DENV2 Outbreak |
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"26163": 0.8433839678764343, "26237": 1.1610734462738037, "26287": 0.20660123229026794, "26305": 0.08064348995685577, "26427": 0.06337817758321762, "26445": 0.0029254043474793434, "26745": 0.8715548515319824, "27108": 0.2763880789279938, "27196": 0.10731173306703568, "27204": 0.029824240133166313, "27339": 0.7951818704605103, "27354": 0.1229778528213501, "28093": 0.15359249711036682, "28155": 0.20421554148197174, "28227": 0.5116065740585327, "28353": 0.18978065252304077, "28741": 0.004870930220931768, "28774": 0.66441810131073, "29048": 0.5336109399795532, "29215": 0.0752234235405922, "29458": 0.6075552701950073} | 16180601 | OBJECTIVE Serum soluble corin has been associated with stroke. However, whether it is associated with stroke prognosis has not yet been studied. Therefore, we aimed to study the association of serum soluble corin with risk of poor outcomes within 3 months after stroke. METHODS We followed 522 stroke patients for 3 months to identify major disability, death and vascular events. Serum soluble corin was measured at baseline for all participants. Logistic regression was used to examine the associations of baseline serum soluble corin with outcomes of stroke, adjusting for age, sex, baseline NIHSS score, hours from onset to hospitalization, smoking, drinking, hypertension, diabetes, coronary heart disease, atrial fibrillation, family history of stroke, and stroke subtype. RESULTS Patients with high corin had a significantly lower crude risk for the composite outcome of major disability or death (OR = 0.64, 95%CI: 0.43-0.96) than patients with low corin (the lowest tertile). After adjustment for age and baseline NIHSS score, patients with high corin still had a significantly lower risk for the composite outcome of major disability or death (OR = 0.60, 95%CI: 0.36-0.99). This association became bottom line significant after additionally adjusting for other conventional factors (OR = 0.61, P = 0.058). No association was found between serum soluble corin and other composite outcomes. CONCLUSION Serum soluble corin deficiency predicted risk for major disability within 3 months after stroke, independent of baseline neurological deficient. Our results may indicate a probable role of corin in stroke prognosis. | Serum Soluble Corin Deficiency Predicts Major Disability within 3 Months after Acute Stroke |
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"29206": 0.05786345899105072, "29295": 0.040196798741817474, "29610": 0.255429208278656} | 16201748 | BACKGROUND Different molecular alterations have been described in endometrioid endometrial carcinoma (EECA). Among them the most frequently altered is loss of the PTEN protein, a tumor suppressor gene. The purpose of this study was to evaluate the expression pattern of PTEN gene in normal, hyperplastic and neoplastic endometrium. METHODS In a study in a referral gynecologic hospital in Tehran, Iran, immunohistochemical (IHC) evaluation of PTEN was performed on 87 consecutive specimens to the following three groups; group A- normal proliferative endometrium(n = 29); group B- hyperplastic endometrium [including simple hyperplasia without atypia(n = 21) and complex hyperplasia with atypia (n = 8)] and group C- EECA(n = 29). Immunostaining of cells was analyzed by arbitrary quantitative methods according to both slide's area staining and intensity of color reaction. RESULTS PTEN immunoreactivity was present in all normal proliferative endometrium, all simple hyperplasia, 75% of atypical complex hyperplasia and in 48% of EECA (P < 0.001). The intensity of PTEN reaction was significantly higher in group with proliferative endometrium than hyperplastic endometrium and EECA (P < 0.001). CONCLUSION PTEN expression was significantly higher in cyclical endometrium than in atypical hyperplasia and endometrioid carcinoma. | Altered PTEN expression; a diagnostic marker for differentiating normal, hyperplastic and neoplastic endometrium |
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0.13499516248703003, "25430": 0.10026945173740387, "25969": 0.34508460760116577, "26125": 0.13755162060260773, "26163": 0.05694137513637543, "26319": 0.16276304423809052, "26462": 0.13925230503082275, "26708": 0.11865071207284927, "26835": 0.0174254160374403, "27162": 0.037378571927547455, "27480": 0.21687394380569458, "27815": 0.8366385698318481, "27839": 0.08692999184131622, "27969": 0.6118015646934509, "27974": 0.3560888469219208, "28321": 0.07159364968538284, "28821": 0.08513788133859634, "29025": 0.9294845461845398, "29073": 0.12470348179340363, "29444": 0.7445381283760071} | 16204011 | BACKGROUND Despite recent achievements to reduce child mortality, neonatal deaths continue to remain high, accounting for 41% of all deaths in children under five years of age worldwide, of which over 90% occur in low- and middle-income countries (LMICs). Infections are a leading cause of death and limitations in care seeking for ill neonates contribute to high mortality rates. As estimates for care-seeking behaviors in LMICs have not been studied, this review describes care seeking for neonatal illnesses in LMICs, with particular attention to type of care sought. METHODS AND FINDINGS We conducted a systematic literature review of studies that reported the proportion of caregivers that sought care for ill or suspected ill neonates in LMICs. The initial search yielded 784 studies, of which 22 studies described relevant data from community household surveys, facility-based surveys, and intervention trials. The majority of studies were from South Asia (n = 17/22), set in rural areas (n = 17/22), and published within the last 4 years (n = 18/22). Of the 9,098 neonates who were ill or suspected to be ill, 4,320 caregivers sought some type of care, including care from a health facility (n = 370) or provider (n = 1,813). Care seeking ranged between 10% and 100% among caregivers with a median of 59%. Care seeking from a health care provider yielded a similar range and median, while care seeking at a health care facility ranged between 1% and 100%, with a median of 20%. Care-seeking estimates were limited by the few studies conducted in urban settings and regions other than South Asia. There was a lack of consistency regarding illness, care-seeking, and care provider definitions. CONCLUSIONS There is a paucity of data regarding newborn care-seeking behaviors; in South Asia, care seeking is low for newborn illness, especially in terms of care sought from health care facilities and medically trained providers. There is a need for representative data to describe care-seeking patterns in different geographic regions and better understand mechanisms to enhance care seeking during this vulnerable time period. | Care Seeking for Neonatal Illness in Low- and Middle-Income Countries: A Systematic Review |
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"26402": 0.34023189544677734, "26468": 0.1384023278951645, "26534": 0.009718249551951885, "26773": 0.12986256182193756, "26986": 0.2493593990802765, "27099": 0.5267143249511719, "27159": 0.09672962874174118, "27169": 0.013579257763922215, "27574": 0.25694093108177185, "27777": 0.23710809648036957, "27854": 0.5104349255561829, "28177": 0.18248429894447327, "28282": 0.22782009840011597, "28517": 0.07159364968538284, "28633": 0.04487626627087593, "29170": 0.1332872211933136, "29226": 0.11168810725212097, "29290": 0.1221139207482338, "29441": 0.0038986403960734606} | 16208091 | Incorporation of GluR1-containing AMPA receptors into synapses is essential to several forms of neural plasticity, including long-term potentiation (LTP). Numerous signaling pathways that trigger this process have been identified, but the direct modifications of GluR1 that control its incorporation into synapses are unclear. Here, we show that phosphorylation of GluR1 by PKC at a highly conserved serine 818 residue is increased during LTP and critical for LTP expression. GluR1 is phosphorylated by PKC at this site in vitro and in vivo. In addition, acute phosphorylation at GluR1 S818 by PKC, as well as a phosphomimetic mutation, promotes GluR1 synaptic incorporation. Conversely, preventing GluR1 S818 phosphorylation reduces LTP and blocks PKC-driven synaptic incorporation of GluR1. We conclude that the phosphorylation of GluR1 S818 by PKC is a critical event in the plasticity-driven synaptic incorporation of AMPA receptors. | Synaptic Incorporation of AMPA Receptors during LTP Is Controlled by a PKC Phosphorylation Site on GluR1 |
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