julilili42/papers huggingface dataset:
Direct and Indirect Protection with Pediatric Quadrivalent Live-Attenuated Influenza Vaccination in Europe Estimated by a Dynamic Transmission Model
2017-07-28

Objectives: To estimate the public health impact of annual vaccination of children with a quadrivalent live-attenuated influenza vaccine (QLAIV) across Europe. Methods: A deterministic, age-structured, dynamic model was used to simulate influenza transmission across 14 European countries, comparing current vaccination coverage using a quadrivalent inactivated vaccine (QIV) to a scenario whereby vaccination coverage was extended to 50% of 2–17 year-old children, using QLAIV. Differential equations described demographic changes, exposure to infectious individuals, recovery and immunity dynamics. For each country, the basic reproduction number (R0) was calibrated to published influenza incidence statistics. Assumed vaccine efficacy for children was 80% (QLAIV) and 59% (QIV). Symptomatic cases cumulated over 10 years were calculated per 100 000 person-years. One-way sensitivity analyses were conducted on QLAIV efficacy in 7–17 year-olds (59% instead of 80%), durations of natural (±3 years; base case: 6, 12 years for influenza A, B respectively) and QLAIV vaccine-induced immunity (100% immunity loss after 1 season; base case: 30%), and R0 (+/-10% around all-year average value). Results: Across countries, annual QLAIV vaccination additionally prevents 1366–3604 symptomatic cases per 100 000 population (average 2495 /100 000, ie, a reduction of 47.6% of the cases which occur in the reference scenario with QIV vaccination only). Among children (2–17 years), QLAIV prevents 551–1555 cases per 100 000 population (average 990 /100 000, ie, 67.2% of current cases). Among adults, QLAIV indirectly prevents 726-2047 cases per 100 000 population (average 1466 /100 000, ie, 40.0% of current cases). The most impactful drivers of total protection were duration of natural immunity against influenza A, R0 and QLAIV immunity duration and efficacy. In all evaluated scenarios, there was a large direct and even larger indirect protection compared with the reference scenario. Conclusions: The model highlights direct and indirect protection benefits when vaccinating healthy children with QLAIV in Europe, across a range of demographic structures, contact patterns and vaccination coverage rates.
Bax, Bak and beyond — mitochondrial performance in apoptosis
2017-07-29

Bax and Bak are members of the Bcl‐2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerize at the mitochondrial outer membrane (MOM) to mediate its permeabilization, which is considered a key step in apoptosis. However, the molecular mechanism underlying Bax and Bak function has remained a key question in the field. Here, we review recent structural and biophysical evidence that has changed our understanding of how Bax and Bak promote MOM permeabilization. We also discuss how the spatial regulation of Bcl‐2 family preference for binding partners contributes to regulate Bax and Bak activation. Finally, we consider the contribution of mitochondrial composition, dynamics and interaction with other organelles to apoptosis commitment. A new perspective is emerging, in which the control of apoptosis by Bax and Bak goes beyond them and is highly influenced by additional mitochondrial components.
Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies
2017-07-29

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10 −6 ,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10 −12 , OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10 −3 ,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known ( NRXN1 , RBFOX1 and PCDH7 ) and novel ( LOC102723362 ) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.
Freeze‐Drying as a Novel Biofabrication Method for Achieving a Controlled Microarchitecture within Large, Complex Natural Biomaterial Scaffolds
2017-07-31

Abstract The biofabrication of large natural biomaterial scaffolds into complex 3D shapes which have a controlled microarchitecture remains a major challenge. Freeze‐drying (or lyophilization) is a technique used to generate scaffolds in planar 3D geometries. Here we report the development of a new biofabrication process to form a collagen‐based scaffold into a large, complex geometry which has a large height to width ratio, and a controlled porous microarchitecture. This biofabrication process is validated through the successful development of a heart valve shaped scaffold, fabricated from a collagen‐glycosaminoglycan co‐polymer. Notably, despite the significant challenges in using freeze‐drying to create such a structure, the resultant scaffold has a uniform, homogenous pore architecture throughout. This is achieved through optimization of the freeze‐drying mold and the freezing parameters. We believe this to be the first demonstration of using freeze‐drying to create a large, complex scaffold geometry with a controlled, porous architecture for natural biomaterials. This study validates the potential of using freeze‐drying for development of organ‐specific scaffold geometries for tissue engineering applications, which up until now might not have been considered feasible.
Nocturnal Oximetry–based Evaluation of Habitually Snoring Children
2017-07-31

Neural network-based automated analyses of nSp<sub>O<sub>2</sub></sub> recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.
Social networking for scientists: an analysis on how and why academics use ResearchGate
2017-07-31

Purpose The purpose of this paper is to examine the usage and utility of ResearchGate (RG), which is a social networking site where scientists disseminate their work and build their reputations. In a sample consisting largely of American and European academics, the authors analyzed the ways they use the site, what they thought about the site’s utility, and the effects of usage on career outcomes. Design/methodology/approach The authors employed an online survey approach to target scientists who have an active RG account. Scientists who were not users were also recruited in order to get a better idea of the reasons for their nonuse. Findings Most academics who have an RG account did not use it very heavily. Users did not perceive many benefits from using the site, and RG use was not related to career satisfaction or informational benefits, but was related to productivity and stress. Research limitations/implications Systematic research is needed to explore positive and negative consequences of using professional social media in academia, especially productivity and stress. Findings also suggest that RG needs to increase user engagement. Originality/value This study is one of the first to closely examine how and why people in academia use professional social media sites and whether usage leads to perceived benefits and effects on more general career outcomes.
Inactivation of Ascaris Eggs in Human Fecal Material Through In Situ Production of Carboxylic Acids
2017-07-31

Discovering new ways to inactivate pathogens in human waste is critical for the improvement of worldwide access to sanitation and for the reduction of the environmental impact of conventional waste treatment processes. Here, we utilized the carboxylate platform and chain elongation to produce n-butyric acid and n-caproic acid via the anaerobic fermentation of human fecal material. Then, we inactivated Ascaris eggs through exposure to these carboxylic acids. Using batch experiments with human fecal material as substrate, we accumulated n-butyric acid and n-caproic acid at total concentrations (uncharged acid plus conjugate base) of 257 and 27.1 mM, respectively. We then showed that carboxylic acids at these concentrations inactivated Ascaris eggs when the pH was below the pK<sub>a</sub> for the acids, causing them to exist primarily in the uncharged forms. We observed that uncharged carboxylic acids affected viability rather than the pH itself or conjugate bases. In addition, we modeled the viability of Ascaris eggs as a function of uncharged carboxylic acid concentration for n-butyric acid and n-caproic acid at exposure times of 2, 6, 12, and 20 days. The results presented here indicate that in situ biological production of carboxylic acids in HFM provides a promising method of pathogen inactivation and may lead to new developments in sanitation technology and treatment of fecal sludge.
11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice
2017-07-31

Abstract 11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.
A Gutzwiller trace formula for large hermitian matrices
2017-07-31

We develop a semiclassical approximation for the dynamics of quantum systems in finite-dimensional Hilbert spaces whose classical counterparts are defined on a toroidal phase space. In contrast to previous models of quantum maps, the time evolution is in continuous time and, hence, is generated by a Schrödinger equation. In the framework of Weyl quantization, we construct discrete, semiclassical Fourier integral operators approximating the unitary time evolution and use these to prove a Gutzwiller trace formula. We briefly discuss a semiclassical quantization condition for eigenvalues as well as some simple examples.
Cultural Continuity and Social Resistance: The Chronology of Megalithic Funerary Practices in Southern Iberia
2017-07-31

Inspired by the biographical approach to the study of material culture, a radiocarbon dating programme was undertaken to explore the chronology and temporality of the megalithic monuments in south-eastern Iberia. Instead of one or two dates per tomb, the normal way of approaching this complex issue, we carried out a complete radiocarbon dating series of single tombs based on human remains. We focused our attention on four tholos-type tombs in the cemetery of El Barranquete (Almería, Spain). According to the new radiocarbon series modelled in a Bayesian framework, four main conclusions can be drawn: that the cemetery shows a very long period of funerary activity, which began in the late fourth millennium and ended in the last centuries of the second millennium cal bc ; that continuity of ritual practices attained an unexpected importance during the Bronze Age; that interments, which fall into cultural periods that would be unthinkable if only the typological properties of the grave goods were considered, occurred; and that each tomb had a complex and very different biography.
Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer
2017-08-01

Abstract Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer. Experimental Design: We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease. Results: The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%–72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A. Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1. A novel FGFR3 gene fusion was identified in consecutive samples from one patient. Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. Clin Cancer Res; 23(21); 6487–97. ©2017 AACR.
Assessment of Gully Erosion Susceptibility Using Multivariate Adaptive Regression Splines and Accounting for Terrain Connectivity
2017-08-01

Abstract In this work, we assessed gully erosion susceptibility in two adjacent cultivated catchments of Sicily (Italy) by employing multivariate adaptive regression splines and a set of geo‐environmental variables. To explore the influence of hydrological connectivity on gully occurrence, we measured the changes of performance occurred when adding one by one nine predictors reflecting terrain connectivity to a base model that included contributing area and slope gradient. Receiver operating characteristic (ROC) curves and the area under the ROC curve were used to evaluate model performance. Gully predictive models were trained in both the catchments and submitted to internal (in the calibration catchment) and external (in the adjacent one) validation, using samples extracted both from all cells of the catchments and only from cells located along flow concentration axes. Model evaluation on the entire catchments shows outstanding predictive performance of models that either include or do not include the predictors selected to reflect potential hydrological connectivity. Conversely, area under the ROC curve values measured on flow concentration axes reveals that almost all the additional predictors improve the performance of the base model, but the most enhanced increase of accuracy occurs when upstream drainage density of each landscape position is included as predictor of gully occurrence. Copyright © 2017 John Wiley &amp; Sons, Ltd.
Polymorphonuclear Neutrophil Functions are Differentially Altered in Amnestic Mild Cognitive Impairment and Mild Alzheimer’s Disease Patients
2017-08-01

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.
Enzymatic characterization of novel arylsulfatase A variants using human arylsulfatase A‐deficient immortalized mesenchymal stromal cells
2017-08-01

Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T > C, c.195delC, c.229G > C, c.545C > G, c.674A > G, c.852T > A, and c.1274A > G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSA<sup>-/-</sup> cell system, the seven ARSA mutants showed ARSA activity of less than 10% when compared with wild type, which is evidence for the pathogenicity of all seven variants. In conclusion, the system of ARSA<sup>-/-</sup> -immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants.
Non-classical Protein Excretion Is Boosted by PSMα-Induced Cell Leakage
2017-08-01

Release of cytoplasmic proteins into the supernatant occurs both in bacteria and eukaryotes. Because the underlying mechanism remains unclear, the excretion of cytoplasmic proteins (ECP) has been referred to as "non-classical protein secretion." We show that none of the known specific protein transport systems of Gram-positive bacteria are involved in ECP. However, the expression of the cationic and amphipathic α-type phenol-soluble modulins (PSMs), particularly of PSMα2, significantly increase ECP, while PSMβ peptides or δ-toxin have no effect on ECP. Because psm expression is strictly controlled by the accessory gene regulator (agr), ECP is also reduced in agr-negative mutants. PSMα peptides damage the cytoplasmic membrane, as indicated by the release of not only CPs but also lipids, nucleic acids, and ATP. Thus, our results show that in Staphylococcus aureus, PSMα peptides non-specifically boost the translocation of CPs by their membrane-damaging activity.
Entry, Intracellular Survival, and Multinucleated-Giant-Cell-Forming Activity of Burkholderia pseudomallei in Human Primary Phagocytic and Nonphagocytic Cells
2017-08-01

ABSTRACT The human pathogen Burkholderia pseudomallei and the related species Burkholderia thailandensis are facultative intracellular bacteria characterized by the ability to escape into the cytosol of the host cell and to stimulate the formation of multinucleated giant cells (MNGCs). MNGC formation is induced via an unknown mechanism by bacterial type VI secretion system 5 (T6SS-5), which is an essential virulence factor in both species. Despite the vital role of the intracellular life cycle in the pathogenesis of the bacteria, the range of host cell types permissive for initiation and completion of the intracellular cycle is poorly defined. In the present study, we used several different types of human primary cells to evaluate bacterial entry, intracellular survival, and MNGC formation. We report the capacity of B. pseudomallei to enter, efficiently replicate in, and mediate MNGC formation of vein endothelial and bronchial epithelial cells, indicating that the T6SS-5 is important in the host-pathogen interaction in these cells. Furthermore, we show that B. pseudomallei invades fibroblasts and keratinocytes and survives inside these cells as well as in monocyte-derived macrophages and neutrophils for at least 17 h postinfection; however, MNGC formation is not induced in these cells. In contrast, infection of mixed neutrophils and RAW264.7 macrophages with B. thailandensis stimulated the formation of heterotypic MNGCs in a T6SS-5-dependent manner. In summary, the ability of the bacteria to enter and survive as well as induce MNGC formation in certain host cells may contribute to the pathogenesis observed in B. pseudomallei infection.
Rock climbing and acute emotion regulation in patients with major depressive disorder in the context of a psychological inpatient treatment: a controlled pilot trial
2017-08-01

The results show that rock climbing is associated with acute emotion regulatory effects. These findings have to be replicated with a randomized design, and future research should pay attention to possible mechanisms of rock climbing in regard to emotion regulation.