julilili42/papers huggingface dataset:
Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials
2020-09-18

Abstract Background Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Results Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I 2 =0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I 2 =0%; 4 trials; 307 patients). We identified no subgroup effects. Conclusions We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
Lipoproteins in Gram-Positive Bacteria: Abundance, Function, Fitness
2020-09-18

When one thinks of the Gram+ cell wall, the peptidoglycan (PG) scaffold in particular comes to mind. However, the cell wall also consists of many other components, for example those that are covalently linked to the PG: the wall teichoic acid and the cell wall proteins tethered by the sortase. In addition, there are completely different molecules that are anchored in the cytoplasmic membrane and span the cell wall. These are lipoteichoic acids and bacterial lipoproteins (Lpp). The latter are in the focus of this review. Lpp are present in almost all bacteria. They fulfill a wealth of different tasks. They represent the window to the outside world by recognizing nutrients and incorporating them into the bacterial cell via special transport systems. Furthermore, they perform very diverse and special tasks such as acting as chaperonin, as cyclomodulin, contributing to invasion of host cells or uptake of plasmids via conjugation. All these functions are taken over by the protein part. Nevertheless, the lipid part of the Lpp plays an as important role as the protein part. It is the released lipoproteins and derived lipopeptides that massively modulate our immune system and ultimately play an important role in immune tolerance or non-tolerance. All these varied activities of the Lpp are considered in this review article.
Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology
2020-09-18

Abstract Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
Considering Insulin Secretory Capacity as Measured by a Fasting C-Peptide/Glucose Ratio in Selecting Glucose-Lowering Medications
2020-09-18

Abstract Type 2 diabetes mellitus is a heterogeneous disease. Recently introduced new subclassifications promise more efficacious, tailored treatments which could complement current guidelines. In the differentiation of the new diabetes subphenotypes, assessment of insulin secretion is one of the essential components. Based on a large number of insulin secretion measurements, we propose fasting C-peptide/glucose ratio (CGR) as an adequate and practicable estimate of insulin secretion. CGR discriminates insulin deficiency from insulin hypersecretion. We suggest using insulin secretion, determined from CGR, as an essential input for therapeutic decisions at the beginning or modification of diabetes treatment. Furthermore, we propose 3 practical steps to guide decisions in the subtype-specific therapy of diabetes mellitus. The first step consists of detecting insulin deficiency indicated by a low CGR with the need for immediate insulin therapy. The second step is related to high CGR and aims at lowering cardiovascular risk associated with diabetes. The third step is the consideration of a de-escalation of glucose-lowering therapy in individuals with mild diabetes subphenotypes.
Small Alarmone Synthetases RelP and RelQ of Staphylococcus aureus Are Involved in Biofilm Formation and Maintenance Under Cell Wall Stress Conditions
2020-09-18

The stringent response is characterized by the synthesis of the alarmone (p)ppGpp. The phenotypic consequences resulting from (p)ppGpp accumulation vary among species, and for several pathogenic bacteria, it has been shown that the activation of the stringent response strongly affects biofilm formation and maintenance. In <i>Staphylococcus aureus</i>, (p)ppGpp can be synthesized by the RelA/SpoT homolog Rel upon amino acid deprivation or by the two small alarmone synthetases RelP and RelQ under cell wall stress. We found that <i>relP</i> and <i>relQ</i> increase biofilm formation under cell wall stress conditions induced by a subinhibitory vancomycin concentration. However, the effect of (p)ppGpp on biofilm formation is independent of the regulators CodY and Agr. Biofilms formed by the strain HG001 or its (p)ppGpp-defective mutants are mainly composed of extracellular DNA and proteins. Furthermore, the induction of the RelPQ-mediated stringent response contributes to biofilm-related antibiotic tolerance. The proposed (p)ppGpp-inhibiting peptide DJK-5 shows bactericidal and biofilm-inhibitory activity. However, a non-(p)ppGpp-producing strain is even more vulnerable to DJK-5. This strongly argues against the assumption that DJK-5 acts via (p)ppGpp inhibition. In summary, RelP and RelQ play a major role in biofilm formation and maintenance under cell wall stress conditions.
Nano‐Magnetite Aggregates in Red Soil on Low Magnetic Bedrock, Their Changes During Source‐Sink Transfer, and Implications for Paleoclimate Studies
2020-09-18

Abstract Soil and lake sediments are important paleoclimate archives often forming a source‐sink setting. To better understand magnetic properties in such settings, we studied red soil on low‐magnetic bedrock and subrecent sediments of Caohai Lake (CL) in Heqing Basin, China. Red soil is the only important source material for the CL sediments, it is highly magnetic with susceptibilities (χ) of ~10 −5 m 3 /kg. The red soil is dominated by pedogenic nano‐magnetite (~10–15 nm) arranged in aggregates of ~100 nm, with particle interaction that causes a wide effective grain size distribution in the superparamagnetic (SP) range tailing into stable single‐domain behavior. Transmission electron microscopy and broadband frequency χ(f) suggest partial disintegration of the aggregates and increased alteration of the nanoparticles to hematite during transfer of red soil material to CL. This shifts the domain state behavior to smaller effective magnetic grain sizes, resulting in lower χ fd % and χ values, and a characteristic change of χ(f). The SP‐stable single‐domain distribution of the aggregates in red soil could be climate dependent, and the ratio of saturation remanence to χ is a potential bedrock‐specific paleoclimate proxy reflecting it. Magnetic properties of the CL sediments are controlled by an assemblage of nanoparticle aggregates and larger‐sized bedrock‐derived magnetite. The results challenge the validity of the previous paleoclimate interpretation from the 168‐m‐long Core‐HQ (900–30 ka) in Heqing Basin. Disintegration of aggregates could lead to SP behavior with low χ fd % without extinction of individual magnetite nanoparticles, and the χ fd %‐based assumption of SP magnetite dissolution may be wrong.
Subcortical Atlas of the Rhesus Macaque (SARM) for Magnetic Resonance Imaging
2020-09-18

Abstract Digitized neuroanatomical atlases are crucial for localizing brain structures and analyzing functional networks identified by magnetic resonance imaging (MRI). To aid in MRI data analysis, we have created a comprehensive parcellation of the rhesus macaque subcortex using a high-resolution ex vivo structural imaging scan. The structural scan and its parcellation were warped to the updated NIMH Macaque Template (NMT v2), an in vivo population template, where the parcellation was refined to produce the Subcortical Atlas of the Rhesus Macaque (SARM). The subcortical parcellation and nomenclature reflect those of the 4 th edition of the Rhesus Monkey Brain in Stereotaxic Coordinates (RMBSC4; Paxinos et al., in preparation). The SARM features six parcellation levels, arranged hierarchically from fine regions-of-interest (ROIs) to broader composite regions, suited for fMRI studies. As a test, we ran a functional localizer for the dorsal lateral geniculate (DLG) nucleus in three macaques and found significant fMRI activation in this atlas region. The SARM has been made openly available to the neuroimaging community and can easily be used with common MR data processing software, such as AFNI, where the atlas can be embedded into the software alongside cortical macaque atlases. Highlights We present the Subcortical Atlas of the Rhesus Macaque (SARM). SARM provides a neuroanatomical reference frame for neuroimaging analysis. The entire subcortex is mapped, including the thalamus, basal ganglia, and brainstem. ROIs are grouped hierarchically, making SARM useful at multiple spatial resolutions. SARM is in the NMT v2 template space and complements the CHARM atlas for the cortex.
Low-Temperature Atomic Layer Deposited Oxide on Titanium Nitride Electrodes Enables Culture and Physiological Recording of Electrogenic Cells
2020-09-18

The performance of electrode arrays insulated by low-temperature atomic layer deposited (ALD) titanium dioxide (TiO<sub>2</sub>) or hafnium dioxide (HfO<sub>2</sub>) for culture of electrogenic cells and for recording of extracellular action potentials is investigated. If successful, such insulation may be considered to increase the stability of future neural implants. Here, insulation of titanium nitride electrodes of microelectrode arrays (MEAs) was performed using ALD of nanometer-sized TiO<sub>2</sub> or hafnium oxide at low temperatures (100-200°C). The electrode properties, impedance, and leakage current were measured and compared. Although electrode insulation using ALD oxides increased the electrode impedance, it did not prevent stable, physiological recordings of electrical activity from electrogenic cells (cardiomyocytes and neurons). The insulation quality, estimated from leakage current measurements, was less than 100 nA/cm<sup>2</sup> in a range of 3 V. Cardiomyocytes were successfully cultured and recorded after 5 days on the insulated MEAs with signal shapes similar to the recordings obtained using uncoated electrodes. Light-induced electrical activity of retinal ganglion cells was recorded using a complementary metal-oxide semiconductor-based MEA insulated with HfO<sub>2</sub> without driving the recording electrode into saturation. The presented results demonstrate that low-temperature ALD-deposited TiO<sub>2</sub> and hafnium oxide are biocompatible and biostable and enable physiological recordings. Our results indicate that nanometer-sized ALD insulation can be used to protect electrodes for long-term biological applications.
Longitudinal multi-omics analysis identifies responses of megakaryocytes, erythroid cells and plasmablasts as hallmarks of severe COVID-19 trajectories
2020-09-18

Abstract The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (&gt;358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.
Autophagy inhibition rescues structural and functional defects caused by the loss of mitochondrial chaperoneHsc70-5/mortalininDrosophila
2020-09-19

Abstract We investigate in larval and adult Drosophila models whether loss of the mitochondrial chaperone Hsc70-5 / mortalin is sufficient to cause pathological alterations commonly observed in Parkinson disease. At affected larval neuromuscular junctions, no effects on terminal size, bouton size or number, synapse size, or number were observed, suggesting that we study an early stage of pathogenesis. At this stage, we noted a loss of synaptic vesicle proteins and active zone components, delayed synapse maturation, reduced evoked and spontaneous excitatory junctional potentials, increased synaptic fatigue, and cytoskeleton rearrangements. The adult model displays ATP depletion, altered body posture, and susceptibility to heat-induced paralysis. Adult phenotypes could be suppressed by knockdown of DJ-1b, LRRK, p50, p150, Atg1, Atg101, Atg5, Atg7 , and Atg12 . The knockdown of components of the autophagy machinery or overexpression of human mortalin broadly rescued larval and adult phenotypes, while disease-associated HSPA9 variants did not. Overexpression of Pink1 or promotion of autophagy exacerbated defects.
A Comprehensive Safety Metric to Evaluate Perception in Autonomous Systems
2020-09-20

Complete perception of the environment and its correct interpretation is crucial for autonomous vehicles. Object perception is the main component of automotive surround sensing. Various metrics already exist for the evaluation of object perception. However, objects can be of different importance depending on their velocity, orientation, distance, size, or the potential damage that could be caused by a collision due to a missed detection. Thus, these additional parameters have to be considered for safety evaluation. We propose a new safety metric that incorporates all these parameters and returns a single easily interpretable safety assessment score for object perception. This new metric is evaluated with both real world and virtual data sets and compared to state of the art metrics.
Driver Intention Anticipation Based on In-Cabin and Driving Scene Monitoring
2020-09-20

Numerous car accidents are caused by improper driving maneuvers. Serious injuries are however avoidable, if such driving maneuvers are detected beforehand and the driver is assisted accordingly. In fact, various recent research has focused on the automated prediction of driving maneuver based on hand-crafted features extracted mainly from in-cabin driver videos. Since the outside view from the traffic scene may also contain informative features for driving maneuver prediction, we present a framework for the detection of the drivers' intention based on both in-cabin and traffic scene videos. More specifically, we (1) propose a Convolutional-LSTM (ConvLSTM)-based auto-encoder to extract motion features from the out-cabin traffic, (2) train a classifier which considers motions from both inand outside of the cabin jointly for maneuver intention anticipation, (3) experimentally prove that the inand outside image features have complementary information. Our evaluation based on the publicly available dataset Brain4cars shows that our framework achieves a prediction with the accuracy of 83.98% and F <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</sub> -score of 84.3%.
C‐Cbl regulates c‐MPL receptor trafficking and its internalization
2020-09-20

Abstract Thrombocyte formation from megakaryocyte and their progenitor cells is tightly regulated by thrombopoietin (TPO) and its receptor c‐MPL, thereby maintaining physiological functionality and numbers of circulating platelets. In patients, dysfunction of this regulation could cause thrombocytopenia or myeloproliferative syndromes. Since regulation of this pathway is still not completely understood, we investigated the role of the ubiquitin ligase c‐Cbl which was previously shown to negatively regulated c‐MPL signalling. We developed a new conditional mouse model using c‐Cbl fl/fl Pf4 Cre mice and demonstrated that platelet‐specific knockout of c‐Cbl led to severe microthrombocytosis and impaired uptake of TPO and c‐MPL receptor internalization. Furthermore, we characterized a constitutive STAT5 activation c‐Cbl KO platelets. This study identified c‐Cbl as a potential player in causing megakaryocytic and thrombocytic disorders.
Detection of hypofibrinogenemia during cardiac surgery: a comparison of resonance-based thrombelastography with the traditional Clauss method
2020-09-21

Bleeding after cardiac surgery is associated with significant morbidity and mortality. Hypofibrinogenemia is a crucial factor for bleeding in this setting and may be rapidly detected using point-of-care viscoelastic tests (POC-VET). However, the correlation of POC-VET with conventional coagulation assays is still unclear. The current study aimed to correlate resonance-based POC-VET assays (Haemonetics TEG 6s) with the traditional nonrapid Clauss method. Another aim was to identify a cut-off value for the detection of hypofibrinogenemia (fibrinogen plasma level below 150 mg/dl) focusing on the maximum amplitude of the TEG 6s citrated functional fibrinogen (CFF) assay. Adult patients undergoing cardiac surgery were screened for inclusion in this single-centre retrospective cohort study. Inclusion criteria were the availability of a TEG assay and timely corresponding laboratory results. Calculation of a CFF-maximum amplitude (CFF-MA) cut-off value was performed using receiver operating curve analysis in the baseline cohort and validated in the control cohort. The best correlation with the Clauss method was observed for the CFF-MA ( r = 0.77; P &lt; 0.0001) compared with the citrate kaolin maximum amplitude assay ( r = 0.57; P &lt; 0.0001) and the citrate kaolin heparinase maximum amplitude assay ( r = 0.67; P &lt; 0.0001). A cut-off value of 19.9 mm for the CFF-MA was calculated [area under the curve 0.87 (95% confidence interval: 0.82–0.92; P &lt; 0.0001)]. This cut-off value had a sensitivity of 81.8% and a specificity of 71.1% for identification of hypofibrinogenemia in the control cohort. The resonance-based thrombelastography analyser can identify hypofibrinogenemia. Future clinical studies should investigate whether cut-off value guided coagulation therapy with POC-VET may improve patient outcomes in patients who suffer from bleeding complications.
From Hair to iPSCs—A Guide on How to Reprogram Keratinocytes and Why
2020-09-21

Abstract Keratinocytes, as a primary somatic cell source, offer exceptional advantages compared to fibroblasts, which are commonly used for reprogramming. Keratinocytes can beat fibroblasts in reprogramming efficiency and reprogramming time and, in addition, can be easily and non‐invasively harvested from human hair roots. However, there is still much to know about acquiring keratinocytes and maintaining them in cell culture. In this article, we want to offer readers the profound knowledge that we have gained since our initial use of keratinocytes for reprogramming more than 10 years ago. Here, all hints and tricks, from plucking the hair roots to growing and maintaining keratinocytes, are described in detail. Additionally, an overview of the currently used reprogramming methods, viral and non‐viral, is included, with a special focus on their applicability to keratinocytes. This overview is intended to provide a brief but comprehensive insight into the field of keratinocytes and their use for reprogramming into induced pluripotent stem cells (iPSCs). © 2020 The Authors.