Miracle-dz/UniFAR-FTUs huggingface dataset:
Validation of 3D EM Reconstructions: The Phantom in the Noise

Validation is a necessity to trust the structures solved by electron microscopy by single particle techniques. The impressive achievements in single particle reconstruction fuel its expansion beyond a small community of image processing experts. This poses the risk of inappropriate data processing with dubious results. Nowhere is it more clearly illustrated than in the recovery of a reference density map from pure noise aligned to that map—a phantom in the noise. Appropriate use of existing validating methods such as resolution-limited alignment and the processing of independent data sets (“gold standard”) avoid this pitfall. However, these methods can be undermined by biases introduced in various subtle ways. How can we test that a map is a coherent structure present in the images selected from the micrographs? In stead of viewing the phantom emerging from noise as a cautionary tale, it should be used as a defining baseline. Any map is always recoverable from noise images, provided a sufficient number of images are aligned and used in reconstruction. However, with smaller numbers of images, the expected coherence in the real particle images should yield better reconstructions than equivalent numbers of noise or background images, even without masking or imposing resolution limits as potential biases. The validation test proposed is therefore a simple alignment of a limited number of micrograph and noise images against the final reconstruction as reference, demonstrating that the micrograph images yield a better reconstruction. I examine synthetic cases to relate the resolution of a reconstruction to the alignment error as a function of the signal-to-noise ratio. I also administered the test to real cases of publicly available data. Adopting such a test can aid the microscopist in assessing the usefulness of the micrographs taken before committing to lengthy processing with questionable outcomes.
Histone Modifications at the ABCG2 Promoter following Treatment with Histone Deacetylase Inhibitor Mirror Those in Multidrug-Resistant Cells

ABCG2 is a ubiquitous ATP-binding cassette transmembrane protein that is important in pharmacology and may play a role in stem cell biology and clinical drug resistance. To study the mechanism(s) regulating ABCG2 expression, we used ChIP to investigate the levels of acetylated histone H3, histone deacetylases (HDAC), histone acetyltransferases, and other transcription regulatory proteins associated with the ABCG2 promoter. Following selection for drug resistance and the subsequent overexpression of ABCG2, an increase in acetylated histone H3 but a decrease in class I HDACs associated with the ABCG2 promoter was observed. Permissive histone modifications, including an increase in histone H3 lysine 4 trimethylation (Me3-K4 H3) and histone H3 serine 10 phosphorylation (P-S10 H3), were observed accompanying development of the resistance phenotype. These changes mirrored those in some cell lines treated with a HDAC inhibitor, romidepsin. A repressive histone mark, trimethylated histone H3 lysine 9 (Me3-K9 H3), was found in untreated parental cells and cells that did not respond to HDAC inhibition with ABCG2 up-regulation. Interestingly, although all five studied cell lines showed global histone acetylation and MDR1 up-regulation upon HDAC inhibition, only those cells with removal of the repressive mark, and recruitment of RNA polymerase II and a chromatin remodeling factor Brg-1 from the ABCG2 promoter, showed increased ABCG2 expression. In the remaining cell lines, HDAC1 binding in association with the repressive Me3-K9 H3 mark apparently constrains the effect of HDAC inhibition on ABCG2 expression. These studies begin to address the differential effect of HDAC inhibitors widely observed in gene expression studies. (Mol Cancer Res 2008;6(1):151–64)
The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains

Abstract Objectives: Angiogenesis promotes neurobehavioral recovery after cerebral ischemic stroke. 15(S)-hydroxyeicosatetraenoic acid (15-HETE) is one of the major metabolites of arachidonic acid by 15-lipoxygenase (15-LO) and stimulates the production of vascular endothelial growth factor (VEGF), thus, inducing autocrine-mediated angiogenesis. The present study aimed to investigate the role of 15-LO/15-HETE system on VEGF expression and angiogenesis in brain ischemia. Methods: Rat cerebral arterial vascular endothelial cells were used to set up a cell injury model of oxygen-glucose deprivation and reoxygenation (OGD/R), mimicking a condition of brain ischemia. A mouse model of middle cerebral artery occlusion (MCAO) was established. Results: Oxygen-glucose deprivation increased cellular expression of 15-LO-1 and VEGF. Transfection of 15-LO-1 siRNA depleted cells of 15-LO-1, and sequentially induced downregulation of VEGF expression; while, incubation of 15-HETE increased the expression of VEGF. Incubation of 15-HETE attenuated the reduction in cell viability induced by oxygen-glucose deprivation, and promoted cell migration, while transfection of 15-LO-1 siRNA showed an opposite effect. In animal experiments, the density of microvessels in hypoxic regions of brains was significantly increased after MCAO, while intracerebroventricular delivery of 15-LO-1 siRNA significantly reduced the density of microvessels, and downregulates VEGF expression. Discussion: The results indicate that the 15-LO-1/15-HETE system promotes angiogenesis in ischemic brains by upregulation of VEGF, representing a potential target for improving neurobehavioral recovery after cerebral ischemic stroke.
Assessing potentially time‐dependent treatment effect from clinical trials and observational studies for survival data, with applications to the Women's Health Initiative combined hormone therapy trial

For risk and benefit assessment in clinical trials and observational studies with time‐to‐event data, the Cox model has usually been the model of choice. When the hazards are possibly non‐proportional, a piece‐wise Cox model over a partition of the time axis may be considered. Here, we propose to analyze clinical trials or observational studies with time‐to‐event data using a certain semiparametric model. The model allows for a time‐dependent treatment effect. It includes the important proportional hazards model as a sub‐model and can accommodate various patterns of time‐dependence of the hazard ratio. After estimation of the model parameters using a pseudo‐likelihood approach, simultaneous confidence intervals for the hazard ratio function are established using a Monte Carlo method to assess the time‐varying pattern of the treatment effect. To assess the overall treatment effect, estimated average hazard ratio and its confidence intervals are also obtained. The proposed methods are applied to data from the Women's Health Initiative. To compare the Women's Health Initiative clinical trial and observational study, we use the propensity score in building the regression model. Compared with the piece‐wise Cox model, the proposed model yields a better model fit and does not require partitioning of the time axis. Copyright © 2015 John Wiley & Sons, Ltd.
Dynamic Choice of State Abstraction in Q-Learning

Q-learning associates states and actions of a Markov Decision Process to expected future reward through online learning. In practice, however, when the state space is large and experience is still limited, the algorithm will not find a match between current state and experience unless some details describing states are ignored. On the other hand, reducing state information affects long term performance because decisions will need to be made on less informative inputs. We propose a variation of Q-learning that gradually enriches state descriptions, after enough experience is accumulated. This is coupled with an ad-hoc exploration strategy that aims at collecting key information that allows the algorithm to enrich state descriptions earlier. Experimental results obtained by applying our algorithm to the arcade game Pac-Man show that our approach significantly outperforms Q-learning during the learning process while not penalizing long-term performance.
Computational Statistics and Data Analysis

We present a Bayesian variable selection method for the setting in which the number of independentvariablesorpredictorsinaparticulardatasetismuchlargerthantheavailable sample size. While most of the existing methods allow some degree of correlations among predictors but do not consider these correlations for variable selection, our method accounts for correlations among the predictors in variable selection. Our correlation-based stochastic search (CBS) method, the hybrid-CBS algorithm, extends a popular search algorithm for high-dimensional data, the stochastic search variable selection (SSVS) method. Similar to SSVS, we search the space of all possible models using variable addition, deletion or swap moves. However, our moves through the model space are designed to accommodate correlations among the variables. We describe our approach for continuous, binary, ordinal, and count outcome data. The impact of choices of prior distributions and hyperparameters is assessed in simulation studies. We also examined the performance of variable selection and prediction as the correlation structure of the predictors varies. We found that the hybrid-CBS resulted in lower prediction errors and identified better the true outcome associated predictors than SSVS when predictors were moderately to highly correlated.Weillustratethemethodondatafromaproteomicprofilingstudyofmelanoma
Class B Scavenger Receptor Types I and II and CD36 Mediate Bacterial Recognition and Proinflammatory Signaling Induced by Escherichia coli, Lipopolysaccharide, and Cytosolic Chaperonin 60

Class B scavenger receptors (SR-B) are lipoprotein receptors that also mediate pathogen recognition, phagocytosis, and clearance as well as pathogen-induced signaling. In this study we report that three members of the SR-B family, namely, CLA-1, CLA-2, and CD36, mediate recognition of bacteria not only through interaction with cell wall LPS but also with cytosolic chaperonin 60. HeLa cells stably transfected with any of these SR-Bs demonstrated markedly (3- to 5-fold) increased binding and endocytosis of Escherichia coli, LPS, and chaperonin 60 (GroEL) as revealed by both FACS analysis and confocal microscopy imaging. Increased pathogen (E. coli, LPS, and GroEL) binding to SR-Bs was also associated with the dose-dependent stimulation of cytokine secretion in the order of CD36 > CLA-2 > CLA-1 in HEK293 cells. Pathogen-induced IL-6-secretion was reduced in macrophages from CD36- and SR-BI/II–null mice by 40–50 and 30–40%, respectively. Intravenous GroEL administration increased plasma IL-6 and CXCL1 levels in mice. The cytokine responses were 40–60% lower in CD36−/− relative to wild-type mice, whereas increased cytokine responses were found in SR-BI/II−/− mice. While investigating the discrepancy of in vitro versus in vivo data in SR-BI/II deficiency, SR-BI/II−/− mice were found to respond to GroEL administration without increases in either plasma corticosterone or aldosterone as normally seen in wild-type mice. SR-BI/II−/− mice with mineralocorticoid replacement demonstrated an ∼40–50% reduction in CXCL1 and IL-6 responses. These results demonstrate that, by recognizing and mediating inflammatory signaling of both bacterial cell wall LPS and cytosolic GroEL, all three SR-B family members play important roles in innate immunity and host defense.
Liver Simulated Allocation Modeling: Were the Predictions Accurate for Share 35?

Background The liver simulated allocation model (LSAM) can be used to study likely effects of liver transplant allocation policy changes on organ offers, acceptance, waitlist survival, and posttransplant survival. Implementation of Share 35 in June 2013 allowed for testing how well LSAM predicted actual changes. Methods LSAM projections for 1 year of liver transplants before and after the Share 35 policy change were compared with observed data during the same period. Numbers of organs recovered, organ sharing, transplant rates, and waitlist mortality rates (per 100 waitlist years) were evaluated by LSAM and compared with observed data. Results Candidate, recipient, and donor characteristics in the LSAM cohorts were similar to those in the observed population before and after Share 35. LSAM correctly predicted more accepted organs and fewer discarded organs with Share 35. LSAM also predicted increased regional and national sharing, consistent with observed data, although the magnitude was overestimated. Transplant rates were correctly projected to increase and waitlist death rates to decrease. Conclusions Although the absolute number of transplants was underestimated and waitlist deaths overestimated, the direction of change was consistent with observed data. LSAM correctly predicted change in discarded organs, regional and national sharing, waitlist mortality, and transplants after Share 35 implementation.
Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2

Background and Purpose— Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. Methods— The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10−6 and performed in silico association analyses in an independent sample of ⩽1003 cases and 7745 controls. Results— One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10−9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII–activating protease levels, a product of HABP2. Conclusions— HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
Modulation of Presynaptic Ca2+ Entry by AMPA Receptors at Individual GABAergic Synapses in the Cerebellum

Cerebellar Purkinje cells (PCs) receive GABAergic input that undergoes powerful retrograde modulation by presynaptic cannabinoid and glutamate receptors. Here we examine a distinct modulatory mechanism at these synapses, which does not require postsynaptic depolarization and acts via presynaptic AMPA receptors. We find that this mechanism operates mainly in the somatic vicinity of PCs in which large boutons of basket cell axons form synapses on the PC soma. We use fast confocal microscopy and detailed kinetic modeling to estimate that, in these boutons, an action potential opens 100-200 Ca2+ channels, eliciting a brief 3-5 μm transient, followed by a longer-term, 15-30 nm rise of free Ca2+ (above the resting level of ∼100 nm). Brief activation of local AMPA receptors suppresses Ca2+ entry (probably by silencing 20-40 P/Q-type channels) in a subgroup of terminals that tend to show a higher dynamic range of Ca2+ signaling. The results provide the first quantitative description of presynaptic Ca2+ kinetics and its modulation by AMPA receptor activation (most likely via a glutamate spillover-mediated mechanism) at identified GABAergic synapses.
AP‐1A Controls Secretory Granule Biogenesis and Trafficking of Membrane Secretory Granule Proteins

The adaptor protein 1A complex (AP‐1A) transports cargo between the trans‐Golgi network (TGN) and endosomes. In professional secretory cells, AP‐1A also retrieves material from immature secretory granules (SGs). The role of AP‐1A in SG biogenesis was explored using AtT‐20 corticotrope tumor cells expressing reduced levels of the AP‐1A μ1A subunit. A twofold reduction in μ1A resulted in a decrease in TGN cisternae and immature SGs and the appearance of regulated secretory pathway components in non‐condensing SGs. Although basal secretion of endogenous SG proteins was unaffected, secretagogue‐stimulated release was halved. The reduced μ1A levels interfered with the normal trafficking of carboxypeptidase D (CPD) and peptidylglycine α‐amidating monooxygenase‐1 (PAM‐1), integral membrane enzymes that enter immature SGs. The non‐condensing SGs contained POMC products and PAM‐1, but not CPD. Based on metabolic labeling and secretion experiments, the cleavage of newly synthesized PAM‐1 into PHM was unaltered, but PHM basal secretion was increased in sh‐μ1A PAM‐1 cells. Despite lacking a canonical AP‐1A binding motif, yeast two‐hybrid studies demonstrated an interaction between the PAM‐1 cytosolic domain and AP‐1A. Coimmunoprecipitation experiments with PAM‐1 mutants revealed an influence of the luminal domains of PAM‐1 on this interaction. Thus, AP‐1A is crucial for normal SG biogenesis, function and composition.
The Role of Perceived Discrimination and Other Psychosocial Factors in Explaining Diabetes Distress Among Older African American and White Adults

Background: Diabetes distress, also referred to as diabetes-related emotional distress, has been shown to contribute to worsening diabetes status over time as well as increased depressive symptoms. Other psychosocial factors, including perceived discrimination, are also related to poorer diabetes outcomes. This study explores the relationships between diabetes distress and several psychosocial variables relevant to health disparities (i.e., race, cognition, social support, physician trust, and perceived discrimination) among older adults with type 2 diabetes mellitus. Design and Method: Structured telephone interviews were conducted with 148 African American and White adults (age ≥65) with type 2 diabetes mellitus. Results: Perceived discrimination and physician trust partially explain the relationship between African American race and diabetes distress. Younger age, less satisfaction with social support, and lower physician trust were associated with higher levels of diabetes distress. Conclusion: These results highlight the need to address unique stressors, such as perceived discrimination, among racial/ethnic minorities to improve diabetes-related outcomes.
Are meat and heme iron intake associated with pancreatic cancer? Results from the NIH‐AARP diet and health cohort

Several studies on pancreatic cancer have reported significant positive associations for intake of red meat but null associations for heme iron. We assessed total, red, white and processed meat intake, meat cooking methods and doneness and heme iron and mutagen intake in relation to pancreatic cancer in the NIH‐AARP Diet and Health Study cohort. A total of 322,846 participants (187,265 men and 135,581 women) successfully completed and returned the food frequency questionnaire between 1995 and 1996. After a mean follow‐up of 9.2 years (up to 10.17 years), 1,417 individuals (895 men and 522 women) developed exocrine pancreatic cancer. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), and trends were calculated using the median value of each quantile. Models incorporated age as the time metric and were adjusted for smoking history, body mass index, self‐reported diabetes and energy‐adjusted saturated fat. Pancreatic cancer risk significantly increased with intake of total meat (Q5 vs. Q1: HR = 1.20, 95% CI 1.02–1.42, p‐trend = 0.03), red meat (HR = 1.22, 95% CI 1.01–1.48, p‐trend = 0.02), high‐temperature cooked meat (HR = 1.21, 95% CI 1.00–1.45, p‐trend = 0.02), grilled/barbequed meat (HR = 1.24, 95% CI 1.03–1.50, p‐trend = 0.007), well/very well done meat (HR = 1.32, 95% CI 1.10–1.58, p‐trend = 0.005) and heme iron from red meat (Q4 vs. Q1: HR = 1.21, 95% CI 1.01–1.45, p‐trend = 0.04). When stratified by sex, these associations remained significant in men but not women except for white meat intake in women (HR = 1.33, 95% CI 1.02–1.74, p‐trend = 0.04). Additional studies should confirm our findings that consuming heme iron from red meat increases pancreatic cancer risk.
Estimating Length of Stay by Patient Type in the Neonatal Intensive Care Unit

Abstract Objective Develop length of stay prediction models for neonatal intensive care unit patients. Study Design We used data from 2008 to 2010 to construct length of stay models for neonates admitted within 1 day of age to neonatal intensive care units and surviving to discharge home. Results Our sample included 23,551 patients. Median length of stay was 79 days when birth weight was < 1,000 g, 46 days for 1,000 to 1,500 g, 21 days for 1,500 to 2,500 g, and 8 days for ≥2,500 g. Risk factors for longer length of stay varied by weight. Units with shorter length of stay for one weight group had shorter lengths of stay for other groups. Conclusion Risk models for comparative assessments of length of stay need to appropriately account for weight, particularly considering the cutoff of 1,500 g. Refining prediction may benefit counseling of families and health care systems to efficiently allocate resources.
A brief survey of program slicing

Program slicing is a technique to extract program parts with respect to some special computation. Since Weiser first proposed the notion of slicing in 1979, hundreds of papers have been presented in this area. Tens of variants of slicing have been studied, as well as algorithms to compute them. Different notions of slicing have different properties and different applications. These notions vary from Weiser's syntax-preserving static slicing to amorphous slicing which is not syntax-preserving, and the algorithms can be based on dataflow equations, information-flow relations or dependence graphs.Slicing was first-developed to facilitate debugging, but it is then found helpful in many aspects of the software development life cycle, including program debugging, software testing, software measurement, program comprehension, software maintenance, program parallelization and so on.Over the last two decades, several surveys on program slicing have been presented. However, most of them only reviewed parts of researches on program slicing or have now been out of date. People who are interested in program slicing need more information about the up to date researches. Our survey fills this gap. In this paper, we briefly review most of existing slicing techniques including static slicing, dynamic slicing and the latest slicing techniques. We also discuss the contribution of each work and compare the major difference between them. Researches on slicing are classified by the research hot spots such that people can be kept informed of the overall program slicing researches.
Initial testing of lenalidomide by the pediatric preclinical testing program

Lenalidomide, a novel immunomodulatory agent, is reported to modulate stem cell differentiation, and have direct antiproliferative activity as well as inhibit inflammation and hyperalgesia. On the basis of this varied pharmacological profile, lenalidomide is under investigation as a treatment for a range of oncologic indications.
Non-Visually Performing Analytical Tasks on Statistical Charts

This article proposes a natural language-based approach to accessibility of charts. Formal underpinnings are used to semantically annotate the constituent elements of a vector graphic to support accessing and modifying the content by natural language queries in a web interface. A prototype which lets blind users perform a number of analytical activities on bar charts is introduced.