Miracle-dz/UniFAR-FTUs huggingface dataset:
Stored Fas Ligand, a Mediator of Rapid CTL-Mediated Killing, Has a Lower Threshold for Response Than Degranulation or Newly Synthesized Fas Ligand

CTL lyse target cells through the release of cytolytic granule mediators and expression of the death receptor ligand Fas ligand (FasL). We previously demonstrated that FasL is stored in vesicles distinct from cytolytic granules and is translocated to the cell surface within 15 min of TCR stimulation, followed by a later wave of newly synthesized FasL cell surface expression at 2 h poststimulation. Initial studies suggested that the two FasL responses had different signaling thresholds. To test this possibility directly, we titrated Ag presented to murine CTL to measure FasL and degranulation response thresholds. Stored FasL translocation to the cell surface required substantially lower concentrations of peptide than was required for de novo expression of FasL and degranulation. Furthermore, a low-affinity agonist peptide stimulated strong stored FasL translocation but only limited de novo FasL expression and degranulation. These data imply that the two FasL populations may have distinct functions. We examined bystander killing and found that the rapidly expressed FasL triggered highly specific lysis of target cells, as did degranulation. In contrast, the newly synthesized later wave of FasL mediated extensive Fas-dependent bystander killing. Our data indicate that stored FasL is mobilized in response to low concentrations of Ag to mediate rapid, highly specific lysis of target cells, whereas the later, newly synthesized FasL requires higher concentrations of Ag and mediates indiscriminate lysis. These findings suggest that early and late FasL and degranulation represent nonredundant lytic mechanisms that have been selected for distinct situations, possibly for optimal pathogen clearance.
New Infestin-4 Mutants with Increased Selectivity against Factor XIIa

Factor XIIa (fXIIa) is a serine protease that triggers the coagulation contact pathway and plays a role in thrombosis. Because it interferes with coagulation testing, the need to inhibit fXIIa exists in many cases. Infestin-4 (Inf4) is a Kazal-type inhibitor of fXIIa. Its specificity for fXIIa can be enhanced by point mutations in the protease-binding loop. We attempted to adapt Inf4 for the selective repression of the contact pathway under various in vitro conditions, e.g., during blood collection and in ‘global’ assays of tissue factor (TF)-dependent coagulation. First, we designed a set of new Inf4 mutants that, in contrast to wt-Inf4, had stabilized canonical conformations during molecular dynamics simulation. Off-target activities against factor Xa (fXa), plasmin, and other coagulation proteases were either reduced or eliminated in these recombinant mutants, as demonstrated by chromogenic assays. Interactions with fXIIa and fXa were also analyzed using protein-protein docking. Next, Mutant B, one of the most potent mutants (its K i for fXIIa is 0.7 nM) was tested in plasma. At concentrations 5–20 μM, this mutant delayed the contact-activated generation of thrombin, as well as clotting in thromboelastography and thrombodynamics assays. In these assays, Mutant B did not affect coagulation initiated by TF, thus demonstrating sufficient selectivity and its potential practical significance as a reagent for coagulation diagnostics.
Peste des petits ruminants: a suitable candidate for eradication?

This year will see the final announcement, accompanied by much justifiable celebration, of the eradication from the wild of rinderpest, the ‘cattle plague’ that has been with us for so many centuries. The only known rinderpest virus (RPV) remaining is in a relatively small number of laboratories around the world, and in the stockpiles of vaccine held on a precautionary basis. As we mark this achievement, only the second virus ever eradicated through human intervention, it seems a good time to look at rinderpest's less famous cousin, peste des petits ruminants (‘the plague of small ruminants’) and assess if it should, and could, also be targeted for global eradication.
Toxicity to Melita plumulosa from intermittent and continuous exposures to dissolved copper

The concentrations of metal contaminants often fluctuate in estuarine waters; yet we have limited knowledge about the effects of intermittent exposures on estuarine organisms. Using 10‐d lethality bioassays with the epibenthic amphipod Melita plumulosa, different combinations of intermittent (pulsed) dissolved Cu exposure were investigated, varying Cu concentration, pulse duration, and time between pulses. Negligible organism mortality was observed immediately after single 12‐ to 62‐h duration pulsed exposures of 100 to 900 µg/L dissolved Cu. However, delayed mortality was observed in the subsequent 96‐h nonexposure period, after which negligible additional mortality occurred during the remainder of the 240‐h tests. For multiple pulsed exposures, increasing the time between pulses from 0 to 144 h did not result in significantly different mortality rates for 300 and 400 µg/L dissolved copper, indicating that the organisms did not recover between pulses. Organism mortality exhibited a strong relationship with the time‐averaged concentration (TAC) resulting from the combination of exposure concentration and duration. The lethal concentration to 50 (LC50), 20 (LC20), and 10% (LC10) (95% confidence interval) of the test population for the combined TAC exposure–survival data were 86 (71–103), 44 (30–64), and 30 (18–49) µg Cu/L, respectively, which were similar to the respective values of 100 (87–114), 55 (43–70), and 39 (28–54) µg Cu/L determined for continuous exposure. The results from the current study support the use of analytical techniques capable of determining the time‐averaged concentration of metals, because they will more accurately predict the effects of toxiciants on organisms than single time‐point measurements. Environ. Toxicol. Chem. 2010;29:2823–2830. © 2010 SETAC
An electronic health record based model predicts statin adherence, LDL cholesterol, and cardiovascular disease in the United States Military Health System

HMG-CoA reductase inhibitors (or “statins”) are important and commonly used medications to lower cholesterol and prevent cardiovascular disease. Nearly half of patients stop taking statin medications one year after they are prescribed leading to higher cholesterol, increased cardiovascular risk, and costs due to excess hospitalizations. Identifying which patients are at highest risk for not adhering to long-term statin therapy is an important step towards individualizing interventions to improve adherence. Electronic health records (EHR) are an increasingly common source of data that are challenging to analyze but have potential for generating more accurate predictions of disease risk. The aim of this study was to build an EHR based model for statin adherence and link this model to biologic and clinical outcomes in patients receiving statin therapy. We gathered EHR data from the Military Health System which maintains administrative data for active duty, retirees, and dependents of the United States armed forces military that receive health care benefits. Data were gathered from patients prescribed their first statin prescription in 2005 and 2006. Baseline billing, laboratory, and pharmacy claims data were collected from the two years leading up to the first statin prescription and summarized using non-negative matrix factorization. Follow up statin prescription refill data was used to define the adherence outcome (> 80 percent days covered). The subsequent factors to emerge from this model were then used to build cross-validated, predictive models of 1) overall disease risk using coalescent regression and 2) statin adherence (using random forest regression). The predicted statin adherence for each patient was subsequently used to correlate with cholesterol lowering and hospitalizations for cardiovascular disease during the 5 year follow up period using Cox regression. The analytical dataset included 138 731 individuals and 1840 potential baseline predictors that were reduced to 30 independent EHR “factors”. A random forest predictive model taking patient, statin prescription, predicted disease risk, and the EHR factors as potential inputs produced a cross-validated c-statistic of 0.736 for classifying statin non-adherence. The addition of the first refill to the model increased the c-statistic to 0.81. The predicted statin adherence was independently associated with greater cholesterol lowering (correlation = 0.14, p < 1e-20) and lower hospitalization for myocardial infarction, coronary artery disease, and stroke (hazard ratio = 0.84, p = 1.87E-06). Electronic health records data can be used to build a predictive model of statin adherence that also correlates with statins’ cardiovascular benefits.
The Impact of Disability on the Lives of Children; Cross-Sectional Data Including 8,900 Children with Disabilities and 898,834 Children without Disabilities across 30 Countries

Background Children with disabilities are widely believed to be less likely to attend school or access health care, and more vulnerable to poverty. There is currently little large-scale or internationally comparable evidence to support these claims. The aim of this study was to investigate the impact of disability on the lives of children sponsored by Plan International across 30 countries. Methods and Findings We conducted a cross-sectional survey including 907,734 children aged 0–17 participating in the Plan International Sponsorship Programme across 30 countries in 2012. Parents/guardians were interviewed using standardised questionnaires including information on: age, sex, health, education, poverty, and water and sanitation facilities. Disability was assessed through a single question and information was collected on type of impairment. The dataset included 8,900 children with reported disabilities across 30 countries. The prevalence of disability ranged from 0.4%–3.0% and was higher in boys than girls in 22 of the 30 countries assessed – generally in the range of 1.3–1.4 fold higher. Children with disabilities were much less likely to attend formal education in comparison to children without disabilities in each of the 30 countries, with age-sex adjusted odds ratios exceeding 10 for nearly half of the countries. This relationship varied by impairment type. Among those attending school, children with disabilities were at a lower level of schooling for their age compared to children without disabilities. Children with disabilities were more likely to report experiencing a serious illness in the last 12 months, except in Niger. There was no clear relationship between disability and poverty. Conclusions Children with disabilities are at risk of not fulfilling their educational potential and are more vulnerable to serious illness. This exclusion is likely to have a long-term deleterious impact on their lives unless services are adapted to promote their inclusion.
Microstructure and mechanical properties of Zn-Mg alloys as implant materials manufactured by powder metallurgy method

Currently some biomaterials, especially Zn and Mg alloys and related manufacturing methods are among important research topics due to their suitable biocompatibility, mechanical and corrosion properties. Zn Mg alloy has been processed by Mechanical Alloying method. Hot sintering was conducted at 410°C under argon atmosphere. Resulting microstructures densities and hardness test behaviors of the Zn-based alloys were studied.Visual inspection using SEM (Scanning Electron Microscope) analyses indicates that the microstructure of the composite is also greatly effected by these parameters. In addition, EDS (Energy Dispersive X-Ray Spectroscopy analyses were performed for reliable determination of the chemical composition.
Synchronization from Second Order Network Connectivity Statistics

We investigate how network structure can influence the tendency for a neuronal network to synchronize, or its synchronizability, independent of the dynamical model for each neuron. The synchrony analysis takes advantage of the framework of second order networks, which defines four second order connectivity statistics based on the relative frequency of two-connection network motifs. The analysis identifies two of these statistics, convergent connections, and chain connections, as highly influencing the synchrony. Simulations verify that synchrony decreases with the frequency of convergent connections and increases with the frequency of chain connections. These trends persist with simulations of multiple models for the neuron dynamics and for different types of networks. Surprisingly, divergent connections, which determine the fraction of shared inputs, do not strongly influence the synchrony. The critical role of chains, rather than divergent connections, in influencing synchrony can be explained by their increasing the effective coupling strength. The decrease of synchrony with convergent connections is primarily due to the resulting heterogeneity in firing rates.
c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells

During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-κB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel−/− mice, thymic T reg cell numbers are markedly reduced as a result of a T cell–intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-β conversion of peripheral CD4+CD25− T cells into CD4+Foxp3+ cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel−/− mice, the residual peripheral c-rel−/− T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.
Tracking the extent of the South Pacific Convergence Zone since the early 1600s

The South Pacific Convergence Zone (SPCZ) is the largest and most persistent spur of the Intertropical Convergence Zone. At the southeastern edge of the SPCZ near 170°W and 15°–20°S a surface ocean salinity frontal zone exists that separates fresher Western Pacific Warm Pool water from saltier and cooler waters in the east. This salinity front is known to shift east and west with the phase of the El Niño Southern Oscillation. We have generated subannually resolved and replicated coral oxygen isotopic time series from Fiji (17°S, 179°E) and Rarotonga (21.5°S, 160°W) that have recorded interannual displacements of the salinity front over the last 380 years and also indicate that at lower frequencies the decadal mean position of the salinity front, and eastern extent of the SPCZ, has shifted east‐west through 10° to 20° of longitude three times during this interval. The most recent and largest shift began in the mid 1800s as the salinity front progressively moved eastward and salinity decreased at both sites. Our results suggest that sea surface salinity at these sites is now at the lowest levels recorded and is evidence for an unprecedented expansion of the SPCZ since the mid 1800s. The expansion of the SPCZ implies a gradual change in the South Pacific to more La Niña‐like long‐term mean conditions. This observation is consistent with the ocean thermostat mechanism for the Pacific coupled ocean‐atmosphere system, whereby exogenous heating of the atmosphere would result in greater warming in the western Pacific and a greater east‐west surface temperature gradient.
A scalable modular convex solver for regularized risk minimization

A wide variety of machine learning problems can be described as minimizing a regularized risk functional, with different algorithms using different notions of risk and different regularizers. Examples include linear Support Vector Machines (SVMs), Logistic Regression, Conditional Random Fields (CRFs), and Lasso amongst others. This paper describes the theory and implementation of a highly scalable and modular convex solver which solves all these estimation problems. It can be parallelized on a cluster of workstations, allows for data-locality, and can deal with regularizers such as l1 and l2 penalties. At present, our solver implements 20 different estimation problems, can be easily extended, scales to millions of observations, and is up to 10 times faster than specialized solvers for many applications. The open source code is freely available as part of the ELEFANT toolbox.
Replication-Defective Adenovirus Serotype 5 Vectors Elicit Durable Cellular and Humoral Immune Responses in Nonhuman Primates

ABSTRACT The magnitude and durability of immune responses induced by replication-defective adenovirus serotype 5 (ADV5) vector-based vaccines were evaluated in the simian-human immunodeficiency virus/rhesus monkey model. A single inoculation of recombinant ADV5 vector constructs induced cellular and humoral immunity, but the rapid generation of neutralizing anti-Ad5 antibodies limited the immunity induced by repeated vector administration. The magnitude and durability of the immune responses elicited by these vaccines were greater when they were delivered as boosting immunogens in plasmid DNA-primed monkeys than when they were used as single-modality immunogens. Therefore, administration of ADV5-based vectors in DNA-primed subjects may be a preferred use of this vaccine modality for generating long-term immune protection.
Treatment failure and dietary habits in women with breast cancer.

BACKGROUND Epidemiological and experimental evidence suggests that breast cancer risk can be reduced by dietary measures. Study of the relationships between dietary habits and prognosis in patients with breast cancer is essential to the design of diet intervention trials. PURPOSE Our purpose was to determine whether dietary habits are associated with disease-free survival in patients with breast cancer who have undergone treatment. METHODS We interviewed 240 women about their dietary histories. These women were 50-65 years old and had pathological stage I-II breast cancer with subsequent follow-up for 4 years; 209 of these women were postmenopausal. Differences in dietary variables between groups of patients were analyzed with bivariate and multivariate statistical methods. RESULTS Cancers were classified as estrogen receptor (ER) rich (> or = 0.10 fmol/micrograms of DNA) in 149 patients and as ER poor (< 0.10 fmol/micrograms of DNA) in 71 patients. Fifty-two patients had treatment failure during follow-up. The 30 patients with ER-rich tumors who had treatment failure reported higher intakes of total fat, saturated fatty acids, and polyunsaturated fatty acids than did the 119 patients with ER-rich tumors who did not have treatment failure. The multiple-odds ratio (OR) for treatment failure in these women was 1.08 for each 1% increment in percentage of total energy (E%) from total fat. For treatment failure within the first 2 years, the OR was 1.19 for each 1-mg increase in vitamin E intake per 10 megajoules of energy. In women with treatment failure 2-4 years after diagnosis, ORs were 1.13 and 1.23 for each E% increment in total fat or saturated fatty acids, respectively. No association between dietary habits and treatment failure was found for women with ER-poor cancers. There was a tendency to a dose-response relationship (in quartiles) between intake of saturated fatty acids and disease-free survival, but the observed differences were not statistically significant. CONCLUSIONS Dietary habits at the time of diagnosis may affect prognosis, at least for patients with ER-rich breast cancers. Dietary fat may have an effect on growth or spread of breast cancer, both of which may vary according to type of fat. Total fat and saturated fatty acids were the dietary parameters most strongly associated with risk for treatment failure. IMPLICATIONS Dietary intervention might serve as an adjuvant treatment to improve breast cancer prognosis.
A Genotype-Dependent Intermediate ECG Phenotype in Patients With Persistent Lone Atrial Fibrillation: Genotype ECG-Phenotype Correlation in Atrial Fibrillation

Background—Atrial fibrillation (AF) is heterogeneous at the clinical and molecular levels. Association studies have reported that common single-nucleotide polymorphisms in KCNE1 and SCN5A may predispose to AF. In this study, we tested the hypothesis that specific AF-associated genotypes confer variation on the appearance of AF assessed by analysis of fibrillatory rate of the atria. Methods and Results—Twenty-six nonrelated patients (21 males, mean age 55±12 years) with persistent lone AF (median AF duration 5 weeks) not taking class I or III antiarrhythmic drugs were studied. Fibrillatory rate was obtained by spatiotemporal QRST cancellation and time-frequency analysis of the index surface ECG. Genotypes at the AF-associated loci in KCNE1 (S38G) and SCN5A (H558R) were determined by direct DNA sequencing. The atrial fibrillatory rate was 418±50 fibrillations per minute (range, 336 to 521) in the study cohort. Carriers of the 38GG KCNE1 genotype (n=13) had significantly lower fibrillatory rates (392±36 versus 443±49 fibrillations per minute, P=0.006) compared to those with GS or SS genotype (n=13). Six patients (23%) with fibrillatory rates >450 fibrillations per minute, all had either the GS or SS genotype (&khgr;2 P=0.008). In contrast, both the heterozygeous and homozygeous SCN5A H558R polymorphism had no effect on fibrillatory rate. There were no significant associations between fibrillatory rate and clinical (age, gender, AF duration, drug treatment) or echocardiographic (left atrial diameter, left ventricular ejection fraction) variables. In multivariable regression analysis, the KCNE1 S38G genotype (SS/GS coded 0, GG coded 1) was the only independent predictor of fibrillatory rate (β=−0.437, P=0.006) with a SE of the estimate of 44 fibrillations per minute. Conclusions—This study suggests that atrial fibrillatory rate obtained from the surface ECG is at least in part determined by KCNE1 (S38G) genotype, implying that this variant exerts functional effects on atrial electrophysiology. This intermediate ECG phenotype may be useful for elaborating genetic influences on AF mechanisms and identifying subsets of patients for variability in AF susceptibility or response to therapies.
Velocity of Rolling Bed Load Particles

AbstractExperimental measurements of the reach-averaged bed-load particle velocity Vp on smooth and rough plane surfaces were analyzed for particles of different shape, size ds, and density G. Particle types included natural quartz particles (1.2 mm<ds<13.6 mm at G=2.65), spherical glass marbles (14.5 mm<ds<29.3 mm at G=2.6), and spherical steel ball bearings (1.6 mm<ds<19 mm at G=8.02). The velocity of 9,739 individual bed load particles continuously rolling on aluminum plates coated with a layer of sand/gravel (roughness 0<ks<3.4 mm) was measured for 356 different conditions. For each flow condition, the reach-averaged particle velocity measurements over a 2 m test reach were repeated at least 15 times to provide mean values and standard deviations. For bed load particles rolling on smooth surfaces (ks=0), it was concluded that (1) Vp is within ±30% of the calculated flow velocity from the vertical velocity profile at the top of the particle; (2) Vp for spheres does not vary much with particle de.