Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptotagmin 7 functions as a Ca2+-sensor for synaptic vesicle replenishment

Synaptotagmin (syt) 7 is one of three syt isoforms found in all metazoans; it is ubiquitously expressed, yet its function in neurons remains obscure. Here, we resolved Ca2+-dependent and Ca2+-independent synaptic vesicle (SV) replenishment pathways, and found that syt 7 plays a selective and critical role in the Ca2+-dependent pathway. Mutations that disrupt Ca2+-binding to syt 7 abolish this function, suggesting that syt 7 functions as a Ca2+-sensor for replenishment. The Ca2+-binding protein calmodulin (CaM) has also been implicated in SV replenishment, and we found that loss of syt 7 was phenocopied by a CaM antagonist. Moreover, we discovered that syt 7 binds to CaM in a highly specific and Ca2+-dependent manner; this interaction requires intact Ca2+-binding sites within syt 7. Together, these data indicate that a complex of two conserved Ca2+-binding proteins, syt 7 and CaM, serve as a key regulator of SV replenishment in presynaptic nerve terminals. DOI: http://dx.doi. org/10.7554/eLife.01524. 001
A PAC-Bayesian Tutorial with A Dropout Bound

This tutorial gives a concise overview of existing PAC-Bayesian theory focusing on three generalization bounds. The first is an Occam bound which handles rules with finite precision parameters and which states that generalization loss is near training loss when the number of bits needed to write the rule is small compared to the sample size. The second is a PAC-Bayesian bound providing a generalization guarantee for posterior distributions rather than for individual rules. The PAC-Bayesian bound naturally handles infinite precision rule parameters, $L_2$ regularization, {\em provides a bound for dropout training}, and defines a natural notion of a single distinguished PAC-Bayesian posterior distribution. The third bound is a training-variance bound --- a kind of bias-variance analysis but with bias replaced by expected training loss. The training-variance bound dominates the other bounds but is more difficult to interpret. It seems to suggest variance reduction methods such as bagging and may ultimately provide a more meaningful analysis of dropouts.
In-Network Cache Coherence

With the trend towards increasing number of processor cores in future chip architectures, scalable directory-based protocols for maintaining cache coherence will be needed. However, directory-based protocols face well-known problems in delay and scalability. Most current protocol optimizations targeting these problems maintain a firm abstraction of the interconnection network fabric as a communication medium: protocol optimizations consist of end-to-end messages between requestor, directory and sharer nodes, while network optimizations separately target lowering communication latency for coherence messages. In this paper, we propose an implementation of the cache coherence protocol within the network, embedding directories within each router node that manage and steer requests towards nearby data copies, enabling in-transit optimization of memory access delay. Simulation results across a range of SPLASH-2 benchmarks demonstrate significant performance improvement and good system scalability, with up to 44.5% and 56% savings in average memory access latency for 16 and 64-node systems, respectively, when compared against the baseline directory cache coherence protocol. Detailed micro architecture and implementation characterization affirms the low area and delay impact of in-network coherence
Suppression of Angiotensin II Release by Prostaglandin Synthesis Inhibitors in Hind Legs

Previously we reported that immunoreactive angiotensin II (Ang II) release from isolated perfused rat mesenteric arteries was mediated by β-adrenergic receptor activation. However, the precise mechanism of regulation of vascular renin-angiotensin is not completely understood. In this study, we examined the effect of indomethacin and medofenamate on immunoreactive angiotensin I (Ang I) and Immunoreactive Ang II release from perfused rat hind leg vasculature to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. We also examined the effects of isoproterenol and propranolol on the immunoreactive Ang I and II release. Isolated rat hind legs were perfused with Krebs-Ringer solution, and immunoreactive Ang I and II released into the perfusate were measured directly by using a Sep-Pak CSs18 cartridge connected to the perfusion system. Indomethacin and meclofenamate (10−8 to 2 × 10−6 M) added to the perfusion medium suppressed immunoreactive Ang I and II release to similar extents in a dose-dependent manner (p < 0.001); the maximal percent inhibition of immunoreactive Ang II release evoked by these Inhibitors (2 × 10−6 M) was 60 ± 6% {p < 0.001) for indomethacin and 50 ± 4% (p < 0.001) for meclofenamate. Isoproterenol (10−6 M) failed to cause a change in the release of both pep tides, but propranolol (10−6 M) slightly decreased the release of immunoreactive Ang I and II by 28 ± 4% (p < 0.001) and 32 ± 4% (p < 0.001), respectively. There was a highly significant positive correlation between the released amount of immunoreactive Ang I and that of immunoreactive Ang II altered by indomethacin (r = 0.91), meclofenamate (r = 0.94), or propranolol administration (r = 0.90). These results suggest that the renin-angiotensin in the hind legs is modulated by prostaglandins and that a difference exists in the β-adrenergk receptor-mediated release of Ang II among diverse vascular beds.
Interconnect electromagnetic modeling using conduction modes as global basis functions

A new method is formulated for modeling current distributions inside conductors for a quasi-static or a full-wave electromagnetic field simulator. In our method, we model current distributions inside interconnects using a small number of conduction modes as global basis functions for discretization of the mixed potential integral equation. A very simple example is presented to illustrate the potential of our method.
Loss of Local Astrocyte Support Disrupts Action Potential Propagation and Glutamate Release Synchrony from Unmyelinated Hippocampal Axon Terminals In Vitro

Neuron–astrocyte interactions are critical for proper CNS development and function. Astrocytes secrete factors that are pivotal for synaptic development and function, neuronal metabolism, and neuronal survival. Our understanding of this relationship, however, remains incomplete due to technical hurdles that have prevented the removal of astrocytes from neuronal circuits without changing other important conditions. Here we overcame this obstacle by growing solitary rat hippocampal neurons on microcultures that were comprised of either an astrocyte bed (+astrocyte) or a collagen bed (−astrocyte) within the same culture dish. −Astrocyte autaptic evoked EPSCs, but not IPSCs, displayed an altered temporal profile, which included increased synaptic delay, increased time to peak, and severe glutamate release asynchrony, distinct from previously described quantal asynchrony. Although we observed minimal alteration of the somatically recorded action potential waveform, action potential propagation was altered. We observed a longer latency between somatic initiation and arrival at distal locations, which likely explains asynchronous EPSC peaks, and we observed broadening of the axonal spike, which likely underlies changes to evoked EPSC onset. No apparent changes in axon structure were observed, suggesting altered axonal excitability. In conclusion, we propose that local astrocyte support has an unappreciated role in maintaining glutamate release synchrony by disturbing axonal signal propagation. SIGNIFICANCE STATEMENT Certain glial cell types (oligodendrocytes, Schwann cells) facilitate the propagation of neuronal electrical signals, but a role for astrocytes has not been identified despite many other functions of astrocytes in supporting and modulating neuronal signaling. Under identical global conditions, we cultured neurons with or without local astrocyte support. Without local astrocytes, glutamate transmission was desynchronized by an alteration of the waveform and arrival time of axonal action potentials to synaptic terminals. GABA transmission was not disrupted. The disruption did not involve detectable morphological changes to axons of glutamate neurons. Our work identifies a developmental role for astrocytes in the temporal precision of excitatory signals.
18F-EF5 PET Imaging as an Early Response Biomarker for the Hypoxia-Activated Prodrug SN30000 Combined with Radiation Treatment in a Non–Small Cell Lung Cancer Xenograft Model

Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-18F-pentafluoropropyl)-acetamide (18F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). Methods: Human non–small cell lung cancer xenografts (H460) in athymic rats were imaged with 18F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo γ-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by 18F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. Results: The uptake of 18F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 ± 0.08 vs. 0.56 ± 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in 18F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased 18F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased 18F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in 18F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. Conclusion: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of 18F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug.
Cost Effectiveness of Interventions to Promote Screening for Colorectal Cancer: A Randomized Trial

Objectives Screening for colorectal cancer is considered cost effective, but is underutilized in the U.S. Information on the efficiency of "tailored interventions" to promote colorectal cancer screening in primary care settings is limited. The paper reports the results of a cost effectiveness analysis that compared a survey-only control group to a Centers for Disease Control (CDC) web-based intervention (screen for life) and to a tailored interactive computer-based intervention. Methods A randomized controlled trial of people 50 and over, was conducted to test the interventions. The sample was 1224 partcipants 50-70 years of age, recruited from Kelsey-Seybold Clinic, a large multi-specialty clinic in Houston, Texas. Screening status was obtained by medical chart review after a 12-month follow-up period. An "intention to treat" analysis and micro costing from the patient and provider perspectives were used to estimate the costs and effects. Analysis of statistical uncertainty was conducted using nonparametric bootstrapping. Results The estimated cost of implementing the web-based intervention was $40 per person and the cost of the tailored intervention was $45 per person. The additional cost per person screened for the web-based intervention compared to no intervention was $2602 and the tailored intervention was no more effective than the web-based strategy. Conclusions The tailored intervention was less cost-effective than the web-based intervention for colorectal cancer screening promotion. The web-based intervention was less cost-effective than previous studies of in-reach colorectal cancer screening promotion. Researchers need to continue developing and evaluating the effectiveness and cost-effectiveness of interventions to increase colorectal cancer screening.
PAPILLOMAVIRUS ANTIBODY PREVALENCE IN FREE-RANGING AND CAPTIVE BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS)

Genital epithelial tumors of Atlantic bottlenose dolphins (Tursiops truncatus [Tt]) and Burmeister's porpoises (Phocoena spinipinnis) were formerly shown to be associated with papillomavirus (PV) infection. Papillomaviruses are highly prevalent viruses involved in the development of various tumor types in a wide range of animals, and so-called high-risk PVs contribute to malignant progression. In marine mammals, the incidence and prevalence of PV infection, transmission pathways, and persistence of infection are largely unknown. Using virus-like particles of bottlenose dolphin PV type 1 (TtPV1) as the antigen, enzyme-linked immunosorbent assay (ELISA) studies were conducted to evaluate PV antibody prevalence in bottlenose dolphins. In total, sera obtained from 115 dolphins were examined. Fifty-one percent of captive dolphins (n=18 of 35) and 90% of free-ranging dolphins (n=72 of 80) were antibody positive. Higher ELISA reactivity was observed among males compared with females. Sexually immature dolphins appeared more likely to seroconvert with age. Besides determining their PV antibody prevalence, each animal was also assessed for the presence of orogenital tumors. Interestingly, the mean age of free-ranging dolphins with tumors (n=21) was 11.2 yr compared with 29.9 yr in captive dolphins with tumors (n=9). Results from the current study suggest PV infection in bottlenose dolphins is common, that the main route of PV transmission among them may be horizontal, and that orogenital neoplasia may develop in early life stages of certain free-ranging bottlenose dolphins.
The accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder

We investigated sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-fluorodeoxyglucose-positron emission tomography in 170 cases with suspected or biopsy-proven posttransplant lymphoproliferative disorder. All solid organ and hematopoietic stem cell transplant recipients who underwent an 18F-fluorodeoxyglucose-positron emission tomography scan between 2003 and 2010 in our center for the indication posttransplant lymphoproliferative disorder, were retrospectively reviewed and results were compared with tissue biopsy whenever possible. One hundred and seventy positron emission tomography scans in 150 patients were eligible for evaluation. In 45 cases, the patient had a biopsy-confirmed posttransplant lymphoproliferative disorder before positron emission tomography scanning and positron emission tomography was performed for staging purposes. In the remaining 125 cases, positron emission tomography was performed to differentiate between posttransplant lymphoproliferative disorder and other diseases. 18F-fluorodeoxyglucose-uptake was quantitatively expressed by calculation of maximum and mean standardized uptake value in the most intense lesion or, in the absence of attenuation corrected positron emission tomography scans, by comparing uptake in target lesion to liver and mediastinal uptake. We found an overall sensitivity of 89%, specificity of 89%, positive predictive value of 91% and negative predictive value of 87% for posttransplant lymphoproliferative disorder detection by 18F-fluorodeoxyglucose-positron emission tomography. In a subanalysis of the 125 scans performed for differentiating posttransplant lymphoproliferative disorder from other diseases, sensitivity, specificity, positive predictive value and negative predictive value were 90%, 89%, 85% and 93%, respectively. 18F-fluorodeoxyglucose-uptake in posttransplant lymphoproliferative disorder was generally high with a median mean and maximum standardized uptake value of 9.0 (range 2.0–18.6) and 17.4 (range 2.6–26.4). Posttransplant lymphoproliferative disorder often had an atypical presentation on positron emission tomography with high incidence of extranodal involvement. In conclusion, from these data, we can conclude that 18F-fluorodeoxyglucose-positron emission tomography is highly sensitive for detecting posttransplant lymphoproliferative disorder and has an excellent ability to differentiate posttransplant lymphoproliferative disorder from non-malignant diseases.
Nuclear Localization and Formation of β-Catenin–Lymphoid Enhancer Factor 1 Complexes Are Not Sufficient for Activation of Gene Expression

ABSTRACT In response to activation of the Wnt signaling pathway, β-catenin accumulates in the nucleus, where it cooperates with LEF/TCF (for lymphoid enhancer factor and T-cell factor) transcription factors to activate gene expression. The mechanisms by which β-catenin undergoes this shift in location and participates in activation of gene transcription are unknown. We demonstrate here that β-catenin can be imported into the nucleus independently of LEF/TCF binding, and it may also be exported from nuclei. We have introduced a small deletion within β-catenin (Δ19) that disrupts binding to LEF-1, E-cadherin, and APC but not axin. This Δ19 β-catenin mutant localizes to the nucleus because it may not be efficiently sequestered in the cytoplasm. The nuclear localization of Δ19 definitively demonstrates that the mechanisms by which β-catenin localizes in the nucleus are completely independent of LEF/TCF factors. β-Catenin and LEF-1 complexes can activate reporter gene expression in a transformed T-lymphocyte cell line (Jurkat) but not in normal T lymphocytes, even though both factors are nuclear. Thus, localization of both factors to the nucleus is not sufficient for activation of gene expression. Excess β-catenin can squelch reporter gene activation by LEF-1–β-catenin complexes but not activation by the transcription factor VP16. Taken together, these data suggest that a third component is necessary for gene activation and that this third component may vary with cell type.
Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation

Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.
Isolation and characterization of antimicrobial-resistant Escherichia coli from national horse racetracks and private horse-riding courses in Korea

Limited information is available regarding horse-associated antimicrobial resistant (AR) Escherichia (E.) coli. This study was designed to evaluate the frequency and characterize the pattern of AR E. coli from healthy horse-associated samples. A total of 143 E. coli (4.6%) were isolated from 3,078 samples collected from three national racetracks and 14 private horse-riding courses in Korea. Thirty of the E. coli isolates (21%) showed antimicrobial resistance to at least one antimicrobial agent, and four of the AR E. coli (13.3%) were defined as multi-drug resistance. Most of the AR E. coli harbored AR genes corresponding to their antimicrobial resistance phenotypes. Four of the AR E. coli carried class 1 integrase gene (intI1), a gene associated with multi-drug resistance. Pulsed-field gel electrophoretic analysis showed no genetic relatedness among AR E. coli isolated from different facilities; however, cross-transmissions between horses or horses and environments were detected in two facilities. Although cross-transmission of AR E. coli in horses and their environments was generally low, our study suggests a risk of transmission of AR bacteria between horses and humans. Further studies are needed to evaluate the risk of possible transmission of horse-associated AR bacteria to human communities through horse riders and horse-care workers.
A Prospective Study of Nutritional Factors and Hypertension Among US Men

BackgroundAn effect of diet in determining blood pressure is suggested by epidemiological studies, but the role of specific nutrients is still unsettled. Methods and ResultsThe relation of various nutritional factors with hypertension was examined prospectively among 30,681 predominantly white US male health professionals, 40–75 years old, without diagnosed hypertension. During 4 years of follow-up, 1,248 men reported a diagnosis of hypertension. Age, relative weight, and alcohol consumption were the strongest predictors for the development of hypertension. Dietary fiber, potassium, and magnesium were each significantly associated with lower risk of hypertension when considered individually and after adjustment for age, relative weight, alcohol consumption, and energy intake. When these nutrients were considered simultaneously, only dietary fiber had an independent inverse association with hypertension. For men with a fiber intake of <12 g/day, the relative risk of hypertension was 1.57 (95% confidence interval, 1.20–2.05) compared with an intake of >24 g/day. Calcium was significantly associated with lower risk of hypertension only in lean men. Dietary fiber, potassium, and magnesium were also inversely related to baseline systolic and diastolic blood pressure and to change in blood pressure during the follow-up among men who did not develop hypertension. Calcium was inversely associated with baseline blood pressure but not with change in blood pressure. No significant associations with hypertension were observed for sodium, total fat, or saturated, transunsaturated, and polyunsaturated fatty acids. Fruit fiber but not vegetable or cereal fiber was inversely associated with incidence of hypertension. ConclusionsThese results support hypotheses that an increased intake of fiber and magnesium may contribute to the prevention of hypertension.