julilili42/papers huggingface dataset:
Severe T-System Remodeling in Pediatric Viral Myocarditis
2021-01-18

Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca 2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 ± 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 ± 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 ± 2.3% in AVSD and 12.2 ± 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 ± 0.05 μm, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 ± 0.02 μm 2 ) when compared with AVSD (0.90 ± 0.02 μm, p &amp;lt; 0.001; 0.52 ± 0.02 μm 2 , n = 61, p &amp;lt; 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 ± 1.4%) than in AVSD samples (24.4 ± 0.8%, p &amp;lt; 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 ± 0.04 μm 2 vs. 0.72 ± 0.05 μm 2 , p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 ± 0.02 μm −3 vs. 0.05 ± 0.01 μm −3 , n = 9/10, p &amp;lt; 0.001), approaching values of AVSD (0.13 ± 0.05 μm −3 , n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 ± 5.0% vs. 6.8 ± 2.2%, p &amp;lt; 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.
Research data management in clinical neuroscience: the national research data infrastructure initiative
2021-01-18

Abstract In clinical neuroscience, there are considerable difficulties in translating basic research into clinical applications such as diagnostic tools or therapeutic interventions. This gap, known as the “valley of death,” was mainly attributed to the problem of “small numbers” in clinical neuroscience research, i.e. sample sizes that are too small (Hutson et al., 2017). As a possible solution, it has been repeatedly suggested to systematically manage research data to provide long-term storage, accessibility, and federate data. This goal is supported by a current call of the DFG for a national research data infrastructure (NFDI). This article will review current challenges and possible solutions specific to clinical neuroscience and discuss them in the context of other national and international health data initiatives. A successful NFDI consortium will help to overcome not only the “valley of death” but also promises a path to individualized medicine by enabling big data to produce generalizable results based on artificial intelligence and other methods.
Invited perspectives: Building sustainable and resilient communities – recommended actions for natural hazard scientists
2021-01-19

Abstract. Reducing disaster risk is critical to securing the ambitions of the Sustainable Development Goals (SDGs), and natural hazard scientists make a key contribution to achieving this aim. Understanding Earth processes and dynamics underpins hazard analysis, which (alongside analysis of other disaster risk drivers) informs the actions required to manage and reduce disaster risk. Here we suggest how natural hazard research scientists can better contribute to the planning and development of sustainable and resilient communities through improved engagement in disaster risk reduction (DRR). Building on existing good practice, this perspective piece aims to provoke discussion in the natural hazard science community about how we can strengthen our engagement in DRR. We set out seven recommendations for enhancing the integration of natural hazard science into DRR: (i) characterise multi-hazard environments; (ii) prioritise effective, positive, long-term partnerships; (iii) understand and listen to your stakeholders; (iv) embed cultural understanding into natural hazard research; (v) ensure improved and equitable access to hazard information; (vi) champion people-centred DRR (leaving no one behind); and (vii) improve links between DRR and sustainable development. We then proceed to synthesise key actions that natural hazard scientists and research funders should consider taking to improve education, training, and research design and to strengthen institutional, financial, and policy actions. We suggest that these actions should help to strengthen the effective application of natural hazard science to reduce disaster risk. By recognising and taking steps to address the issues raised in these recommendations, we propose that the natural hazard science community can more effectively contribute to the inter-/transdisciplinary, integrated work required to improve DRR.
An integrated study discloses chopping tools use from Late Acheulean Revadim (Israel)
2021-01-19

Chopping tools/choppers provide one of the earliest and most persistent examples of stone tools produced and used by early humans. These artifacts appeared for the first time ~2.5 million years ago in Africa and are characteristic of the Oldowan and Acheulean cultural complexes throughout the Old World. Chopping tools were manufactured and used by early humans for more than two million years regardless of differences in geography, climate, resource availability, or major transformations in human cultural and biological evolution. Despite their widespread distribution through time and space in Africa and Eurasia, little attention has been paid to the function of these items, while scholars still debate whether they are tools or cores. In this paper, we wish to draw attention to these prominent and ubiquitous early lithic artifacts through the investigation of 53 chopping tools retrieved from a specific context at Late Acheulean Revadim (Israel). We combined typo-technological and functional studies with a residue analysis aimed at shedding light on their functional role within the tool-kits of the inhabitants of the site. Here we show that most of the chopping tools were used to chop hard and medium materials, such as bone, most probably for marrow extraction. A few of the tools were also used for cutting and scraping activities, while some also served as cores for further flake detachment. The chopping tools exhibit extraordinarily well-preserved bone residues suggesting they were used mainly for bone-breaking and marrow acquisition. We discuss the data and explore the tool versus core debate also in light of a sample of 50 flake cores made on pebbles/cobbles retrieved from the same archeological layer. The results add further pieces to the puzzle of activities carried out at Revadim and add to our knowledge of the production and use of these enigmatic tools and their role in human evolutionary history.
Gut Commensal-Induced IκBζ Expression in Dendritic Cells Influences the Th17 Response
2021-01-19

Intestinal commensal bacteria can have a large impact on the state of health and disease of the host. Regulation of Th17 cell development by gut commensals is known to contribute to their dichotomous role in promoting gut homeostasis and host defense, or development of autoimmune diseases. Yet, the underlying mechanisms remain to be fully elucidated. One candidate factor contributing to Th17 differentiation, and the expression of which could be influenced by commensals is the atypical nuclear IκB protein IκBζ. IκBζ acts as a transcriptional regulator of the expression of Th17-related secondary response genes in many cell types including dendritic cells (DCs). Insights into the regulation of IκBζ in DCs could shed light on how these immune sentinel cells at the interface between commensals, innate and adaptive immune system drive an immune-tolerogenic or inflammatory Th17 cell response. In this study, the influence of two gut commensals of low ( Bacteroides vulgatus ) or high ( Escherichia coli ) immunogenicity on IκBζ expression in DCs and its downstream effects was analyzed. We observed that the amount of IκBζ expression and secretion of Th17-inducing cytokines correlated with the immunogenicity of these commensals. However, under immune-balanced conditions, E. coli also strongly induced an IκBζ-dependent secretion of anti-inflammatory IL-10, facilitating a counter-regulative Treg response as assessed in in vitro CD4 + T cell polarization assays. Yet, in an in vivo mouse model of T cell-induced colitis, prone to inflammatory and autoimmune conditions, administration of E. coli promoted an expansion of rather pro-inflammatory T helper cell subsets whereas administration of B. vulgatus resulted in the induction of protective T helper cell subsets. These findings might contribute to the development of new therapeutic strategies for the treatment of autoimmune diseases using commensals or commensal-derived components.
Does non-invasive vagus nerve stimulation affect heart rate variability? A living and interactive Bayesian meta-analysis
2021-01-19

Abstract Non-invasive brain stimulation techniques, such as transcutaneous auricular vagus nerve stimulation (taVNS), have considerable potential for clinical use. Beneficial effects of taVNS have been demonstrated on symptoms in patients with mental or neurological disorders as well as transdiagnostic dimensions, including mood and motivation. However, since taVNS research is still an emerging field, the underlying neurophysiological processes are not yet fully understood, and the replicability of findings on biomarkers of taVNS effects has been questioned. Here, we perform a living Bayesian random effects meta-analysis to synthesize the current evidence concerning the effects of taVNS on heart rate variability (HRV), a candidate biomarker that has, so far, received most attention in the field. To keep the synthesis of evidence transparent and up to date as new studies are being published, we developed a Shiny web app that regularly incorporates new results and enables users to modify study selection criteria to evaluate the robustness of the inference across potential confounds. Our analysis focuses on 17 single-blind studies comparing taVNS versus sham in healthy participants. These newly synthesized results provide strong evidence for the null hypothesis ( g = 0.011, CI shortest = [−0.103, 0.125], BF 01 = 25.587), indicating that acute taVNS does not alter HRV compared to sham. To conclude, based on a synthesis of the available evidence to date, there is no support for the hypothesis that HRV is a robust biomarker for acute taVNS. By increasing transparency and timeliness, we believe that the concept of living meta-analyses can lead to transformational benefits in emerging fields such as non-invasive brain stimulation.
Durable Effects of iGlarLixi Up to 52 Weeks in Type 2 Diabetes: The LixiLan-G Extension Study
2021-01-19

OBJECTIVE In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes uncontrolled by GLP-1 RAs (glycated hemoglobin [HbA1c] 7–9% [53–75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary end point period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety. RESULTS Glycemic control achieved with iGlarLixi at week 26 (mean HbA1c 6.7% [50 mmol/mol]) was maintained at week 52 (mean HbA1c 6.7% [50 mmol/mol]; mean ± SD change from baseline at week 52: −1.0 ± 0.9% [11 ± 10 mmol/mol]). Proportions of participants reaching HbA1c &amp;lt;7% (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (&amp;lt;3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events. CONCLUSIONS The efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial.
Control over patch encounters changes foraging behaviour
2021-01-19

Summary Foraging is a common decision problem in natural environments. When new exploitable sites are always available, a simple optimal strategy is to leave a current site when its return falls below a single average reward rate. Here, we examined foraging in a more structured environment, with a limited number of sites that replenished at different rates and had to be revisited. When participants could choose sites, they visited fast-replenishing sites more often, left sites at higher levels of reward, and achieved a higher net reward rate. Decisions to exploit-or-leave a site were best explained with a computational model that included both the average reward rate for the environment and reward information about the unattended sites. This suggests that unattended sites influence leave decisions, in foraging environments where sites can be revisited. Highlights Being able to select sites during foraging increased visits to high value sites This visitation pattern was efficient, producing higher average reward rates Decisions to leave a site were influenced by information about alternative sites Graphical Abstract
Genetic analysis of primary renal cell carcinoma to determine treatment approaches
2021-01-19

Introduction To date, there is no validated predictive biomarker available that guides treatment selection between an immune-based or an anti-VEGF-based regimen in patients with metastatic renal cell carcinoma (mRCC). Here, valid biomarkers could increase the benefit of therapy and thereby safe unnecessary toxicity. Recently, phase II and III clinical trials have shown a correlation between molecular clusters and responses to targeted therapy with tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) or as combination of both in patients with clear-cell mRCC.Areas covered This review discusses recent advances in the discovery of predictive biomarkers, highlighting the growing role of genetic analysis for treatment selection and its potential impact on precision medicine in mRCC. In this context, we extensively analyzed the available literature from Pubmed's archives on this topic.Expert opinion Molecular subclassification which predicts responses to TKI, or ICI therapy is an exciting step toward personalized medicine in mRCC, but this still requires validation. However, intratumoral heterogeneity in relationship to the predictive power of molecular analysis of the primary tumor and circulating tumor DNA is challenging and requires further analysis.
Intrinsic Justifications for Large-Cardinal Axioms
2021-01-19

ABSTRACT We shall defend three philosophical theses about the extent of intrinsic justification based on various technical results. We shall present a set of theorems which indicate intriguing structural similarities between a family of “weak” reflection principles roughly at the level of those considered by Tait and Koellner and a family of “strong” reflection principles roughly at the level of those of Welch and Roberts, which we claim to lend support to the view that the stronger reflection principles are intrinsically justified as well as the weaker ones. We consider connections with earlier work of Marshall.
Spreading of correlations in Markovian open quantum systems
2021-01-20

Understanding the spreading of quantum correlations in out-of-equilibrium\\nmany-body systems is one of the major challenges in physics. For {\\\\it isolated}\\nsystems, a hydrodynamic theory explains the origin and spreading of\\nentanglement via the propagation of quasi-particle pairs. However, when systems\\ninteract with their surrounding much less has been established. Here we show\\nthat the quasi-particle picture remains valid for open quantum systems: while\\ninformation is still spread by quasiparticles, the environment modifies their\\ncorrelation and introduces incoherent and mixing effects. For free fermions\\nwith gain/loss dissipation we provide formulae fully describing incoherent and\\nquasiparticle contributions in the spreading of entropy and mutual information.\\nImportantly, the latter is not affected by incoherent correlations. The mutual\\ninformation is exponentially damped at short times and eventually vanishes\\nsignalling the onset of a classical limit. The behaviour of the logarithmic\\nnegativity is similar and this scenario is common to other dissipations. For\\nweak dissipation, the presence of quasiparticles underlies remarkable scaling\\nbehaviors.\\n
Plume‐Induced Sinking of Intracontinental Lithospheric Mantle: An Overlooked Mechanism of Subduction Initiation?
2021-01-20

Abstract Although many different mechanisms for subduction initiation have been proposed, only few of them are viable in terms of consistency with observations and reproducibility in numerical experiments. In particular, it has recently been demonstrated that intra‐oceanic subduction triggered by an upwelling mantle plume could greatly contribute to the onset and operation of plate tectonics in the early and, to a lesser degree, modern Earth. On the contrary, the initiation of intra‐continental subduction still remains underappreciated. Here we provide an overview of 1) observational evidence for upwelling of hot mantle material flanked by downgoing proto‐slabs of sinking continental mantle lithosphere, and 2) previously published and new numerical models of plume‐induced subduction initiation. Numerical modeling shows that under the condition of a sufficiently thick (&gt;100 km) continental plate, incipient downthrusting at the level of the lowermost lithospheric mantle can be triggered by plume anomalies of moderate temperatures and without significant strain‐ and/or melt‐related weakening of overlying rocks. This finding is in contrast with the requirements for plume‐induced subduction initiation within oceanic or thinner continental lithosphere. As a result, plume‐lithosphere interactions within continental interiors of Paleozoic‐Proterozoic‐(Archean) platforms are the least demanding (and thus potentially very common) mechanism for initiation of subduction‐like foundering in the Phanerozoic Earth. Our findings are supported by a growing body of new geophysical data collected in various intra‐continental areas. A better understanding of the role of intra‐continental mantle downthrusting and foundering in global plate tectonics and, particularly, in the initiation of “classic” ocean‐continent subduction will benefit from more detailed follow‐up investigations.
Spatial and temporal resolution of the photoreceptors rescue dynamics after treatment with voretigene neparvovec
2021-01-20

Background Voretigene neparvovec is a gene therapeutic agent for treatment of retinal dystrophies caused by bi-allelic RPE65 mutations. In this study, we report on a novel and objective evaluation of a retinotopic photoreceptor rescue. Methods Seven eyes of five patients (14, 21, 23, 24, 36 years, 1 male, 4 females) with bi-allelic RPE65 mutations have been treated with voretigene neparvovec. The clinical examinations included visual acuity testing, dark-adapted full-field stimulus threshold (FST), dark-adapted chromatic perimeter (DAC) with a 30-degree grid, and a 30 degrees grid scotopic and photopic chromatic pupil campimetry (CPC). All evaluations and spectral domain optical coherence tomography were performed at baseline, 1 month and 3 months. Results All except the oldest patient had a measurable improvement of the rod function assessed via FST, DAC or scotopic CPC at 1 month. The visual acuity improved slightly or remained stable in all eyes. A cone function improvement as measured by photopic CPC was observed in three eyes. The gain of the dark-adapted threshold with blue FST and the DAC stimuli (cyan) average correlated strongly with age (R 2 &gt;0.7). The pupil response improvement in the scotopic CPC correlated with the baseline local retinal volume (R 2 =0.5). Conclusions The presented protocols allow evaluating the individual spatial and temporal effects of gene therapy effects. Additionally, we explored parameters that correlated with the success of the therapy. CPC and DAC present new and fast ways to assess functional changes in retinotopic maps of rod and cone function, measuring complementary aspects of retinal function.
The EU and Global Climate Justice
2021-01-20

This book examines the European Union (EU)'s contribution to the development of the global climate regime within the broader framework of global justice. It argues that the procedural dimension of justice has been largely overlooked so far in the assessment of EU climate policy and reveals that the EU has significantly contributed to the development of the climate regime within its broader efforts to 'solidarise' international society. At the same time, the book identifies deficits of the climate regime and limits to the EU's impact, and explains why the EU policy towards global climate change has shifted over time. Finally, it argues that these policies should not be assessed in terms of being wholly positive or wholly negative, but that they are shot through with ambiguities. This book will be of key interest to scholars, students, and practitioners of climate change, climate politics, and environmental and climate justice studies, and more broadly to EU Studies and International Relations.
Dynamical Density Functional Theory for the Drying and Stratification of Binary Colloidal Dispersions
2021-01-20

We develop a dynamical density functional theory based model for the drying of colloidal films on planar surfaces. We consider mixtures of two different sizes of hard-sphere colloids. Depending on the solvent evaporation rate and the initial concentrations of the two species, we observe varying degrees of stratification in the final dried films. Our model predicts the various structures described in the literature previously from experiments and computer simulations, in particular the small-on-top stratified films. Our model also includes the influence of adsorption of particles to the interfaces.