julilili42/papers huggingface dataset:
Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay
2021-05-22

PARP6, a member of a family of enzymes (17 in humans) known as poly-ADP-ribose polymerases (PARPs), is a neuronally enriched PARP. While previous studies from our group show that Parp6 is a regulator of dendrite morphogenesis in rat hippocampal neurons, its function in the nervous system in vivo is poorly understood. Here, we describe the generation of a Parp6 loss-of-function mouse model for examining the function of Parp6 during neurodevelopment in vivo. Using CRISPR-Cas9 mutagenesis, we generated a mouse line that expressed a Parp6 truncated variant (Parp6TR) in place of Parp6WT. Unlike Parp6WT, Parp6TR is devoid of catalytic activity. Homozygous Parp6TR do not exhibit obvious neuromorphological defects during development, but nevertheless die perinatally. This suggests that Parp6 catalytic activity is important for postnatal survival. We also report PARP6 mutations in six patients with several neurodevelopmental disorders, including microencephaly, intellectual disabilities, and epilepsy. The most severe mutation in PARP6 (C563R) results in the loss of catalytic activity. Expression of Parp6C563R in hippocampal neurons decreases dendrite morphogenesis. To gain further insight into PARP6 function in neurons we also performed a BioID proximity labeling experiment in hippocampal neurons and identified several microtubule-binding proteins (e.g., MAP-2) using proteomics. Taken together, our results suggest that PARP6 is an essential microtubule-regulatory gene in mice, and that the loss of PARP6 catalytic activity has detrimental effects on neuronal function in humans.
“This Nothing of a Voice”: Kafka’s Josefine Narrative as a Modern Reflection on Revelation and Language
2021-05-22

Abstract In reference to the paradoxical classification of art in Kafka’s Josefine story, religious aspects of the artist’s performances and their effect on the audience are scrutinized. The leading question is to what extent it evokes an allusion to the primal scene of divine revelation, following Stéphane Mosès’ commentary in his readings of the Bible. Josefine’s singing with a “nothing of a voice”, reduced to “the slightest of nullities”, the zero-point of signification, nevertheless affects an experience of presence and community that touches the listeners’ entire being. From the perspective of the artist, her song recitals are manifestations of supreme art of which she claims a soteriological significance in respect of her audience who belongs in Kafka’s portrayal obviously to the Jewish people. Around such a tension between maximal restraint of an utterance (the voice onset of the aleph of the word anokhi/I) and all-encompassing meaning (the name of God and all Commandments whose acceptance is constitutive for the Jewish people) circle the theological exegeses of the Sinai-scene (esp. Ex. 20,1) in the tradition of Rashi and Maimonides, in modernity e.g. of Gershom Scholem in dispute with Walter Benjamin on Kafka. It will be shown that the depicted paradoxes of Josefine’s art performances unfold the mentioned tension as an original literary reflection on revelation and language under the conditions of modernity.
A proteomics sample metadata representation for multiomics integration, and big data analysis
2021-05-23

Abstract The amount of public proteomics data is increasing at an extraordinary rate. Hundreds of datasets are submitted each month to ProteomeXchange repositories, representing many types of proteomics studies, focusing on different aspects such as quantitative experiments, post-translational modifications, protein-protein interactions, or subcellular localization, among many others. For every proteomics dataset, two levels of data are captured: the dataset description, and the data files (encoded in different file formats). Whereas the dataset description and data file formats are supported by all ProteomeXchange partner repositories, there is no standardized format to properly describe the sample metadata and their relationship with the dataset files in a way that fully allows their understanding or re-analysis. It is left to the user’s choice whether to provide or not an ad hoc document containing this information. Therefore, in many cases, understanding the study design and data requires going back to the associated publication. This can be tedious and may be restricted in the case of non-open access publications. In many cases, this problem limits the generalization and reuse of public proteomics data. Here we present a standard representation for sample metadata tailored to proteomics datasets produced by the HUPO Proteomics Standards Initiative and supported by ProteomeXchange resources. We repurposed the existing data format MAGE-TAB used routinely in the transcriptomics field to represent and annotate proteomics datasets. MAGETAB-Proteomics defines a set of annotation rules that the datasets submitted to ProteomeXchange should follow, ranging from sample properties to data analysis protocols. We also introduce a crowdsourcing project that enabled the manual curation of over 200 public datasets using MAGE-TAB-Proteomics. In addition, we describe an ecosystem of tools and libraries that were developed to validate and submit sample metadata-related information to ProteomeXchange. We expect that these tools will improve the reproducibility of published results and facilitate the reanalysis and integration of public proteomics datasets.
Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations
2021-05-23

Abstract Background KCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (K V 3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid. Conclusion These findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of K V 3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.
Impact of Mantle Cell Lymphoma Contamination of Autologous Stem Cell Grafts on Outcome after High-Dose Chemotherapy
2021-05-23

Novel predictive factors are needed to identify mantle cell lymphoma (MCL) patients at increased risk for relapse after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDCT/Auto-HSCT). Although bone marrow and peripheral blood involvement is commonly observed in MCL and lymphoma cell contamination of autologous stem cell grafts might facilitate relapse after Auto-HSCT, prevalence and prognostic significance of residual MCL cells in autologous grafts are unknown. We therefore performed a multiparameter flow cytometry (MFC)-based measurable residual disease (MRD) assessment in autologous stem cell grafts and analyzed its association with clinical outcome in an unselected retrospective cohort of 36 MCL patients. MRD was detectable in four (11%) autologous grafts, with MRD levels ranging from 0.002% to 0.2%. Positive graft-MRD was associated with a significantly shorter progression-free and overall survival when compared to graft-MRD negative patients (median 9 vs. 56 months and 25 vs. 132 months, respectively) and predicted early relapse after Auto-HSCT (median time to relapse 9 vs. 44 months). As a predictor of outcome after HDCT/Auto-HSCT, MFC-based assessment of graft-MRD might improve risk stratification and support clinical decision making for risk-oriented treatment strategies in MCL.
Genome-Scale Metabolic Model of Infection with SARS-CoV-2 Mutants Confirms Guanylate Kinase as Robust Potential Antiviral Target
2021-05-24

The current SARS-CoV-2 pandemic is still threatening humankind. Despite first successes in vaccine development and approval, no antiviral treatment is available for COVID-19 patients. The success is further tarnished by the emergence and spreading of mutation variants of SARS-CoV-2, for which some vaccines have lower efficacy. This highlights the urgent need for antiviral therapies even more. This article describes how the genome-scale metabolic model (GEM) of the host-virus interaction of human alveolar macrophages and SARS-CoV-2 was refined by incorporating the latest information about the virus’s structural proteins and the mutant variants B.1.1.7, B.1.351, B.1.28, B.1.427/B.1.429, and B.1.617. We confirmed the initially identified guanylate kinase as a potential antiviral target with this refined model and identified further potential targets from the purine and pyrimidine metabolism. The model was further extended by incorporating the virus’ lipid requirements. This opened new perspectives for potential antiviral targets in the altered lipid metabolism. Especially the phosphatidylcholine biosynthesis seems to play a pivotal role in viral replication. The guanylate kinase is even a robust target in all investigated mutation variants currently spreading worldwide. These new insights can guide laboratory experiments for the validation of identified potential antiviral targets. Only the combination of vaccines and antiviral therapies will effectively defeat this ongoing pandemic.
Late Pleistocene paleoecology and phylogeography of woolly rhinoceroses
2021-05-24

The woolly rhinoceros (Coelodonta antiquitatis) was a cold-adapted herbivore, widely distributed from western Europe to north-east Siberia during the Late Pleistocene. Previous studies have associated the extinction of the species ∼14,000 calendar years before present to climatic and vegetational changes, suggesting the later survival of populations in north-east Siberia may have related to the later persistence of open vegetation in the region. Here, we analyzed carbon (δ13C) and nitrogen (δ15N) stable isotopes and mitochondrial DNA sequences to elucidate the evolutionary ecology of the species. Our dataset comprised 286 woolly rhinoceros isotopic records, including 192 unpublished records, from across the species range, dating from >58,600 to 12,135 14C years before present (equivalent to 14,040 calendar years ago). Crucially, we present the first 71 isotopic records available to date of the 15,000 years preceding woolly rhinoceros extinction. The data revealed ecological flexibility and geographic variation in woolly rhinoceros stable isotope compositions across time. In north-east Siberia, we detected stability in δ15N through time, which could reflect long-term environmental stability, and may have enabled the later survival of the species in the region. To further investigate the paleoecology of woolly rhinoceroses, we compared their isotopic compositions with other contemporary herbivores. Our findings suggested isotopic similarities between woolly rhinoceros and both musk ox (Ovibos moschatus) and saiga (Saiga tatarica), albeit at varying points in time, and possible niche partitioning between woolly rhinoceros and both horse (Equus spp.) and woolly mammoth (Mammuthus primigenius). To provide phylogeographic context to the isotopic data, we compiled and analyzed the 61 published mitochondrial control region sequences. The genetic data showed a lack of geographic structuring; we found three haplogroups with overlapping distributions, all of which showed a signal of expansion during the Last Glacial Maximum. Furthermore, our genetic findings support the notion that environmental stability in Siberia influenced the paleoecology of woolly rhinoceroses in the region. Our study highlights the utility of combining stable isotopic records with ancient DNA to advance our knowledge of the evolutionary ecology of past populations and extinct species.
Rational Suspension
2021-05-24

Abstract The article argues that there are different ways of justifying suspension of judgement. We suspend judgement not only privatively, that is, because we lack evidence, but also positively, that is, because there is evidence that provides reasons for suspending judgement: suspension is more than the rational fallback position in cases of insufficient evidence. The article applies the distinction to recent discussions about the role of suspension for inquiry, Turri's puzzle about withholding, and formal representations of suspension.
Tuning Organocerium Electrochemical Potentials by Extending Tris(cyclopentadienyl) Scaffolds with Terminal Halogenido, Siloxy, and Alkoxy Ligands
2021-05-24

Treatment of cerous CpR3Ce(thf) (CpR = C5H4R; R = H, Me) with the halogenating reagents C2Cl6, TeBr4, and I2 afforded the ceric halides CpR3CeX (X = Cl, Br, I) in high yield. Subsequent salt metathesis with sodium alkoxides and siloxides led to a series of alkoxy and siloxy derivatives. Compounds CpR3CeOR′ with R′ = Me, Et, CH2tBu, iPr, tBu, SiMe3, SiEt3, Si(iPr)3 SiPh3 (and Si(OtBu)3) have been isolated and characterized by 1H, 13C, and 29Si NMR and DRIFT spectroscopy, magnetic measurements, X-ray structure analyses, cyclic voltammetry, and elemental analyses. The ceric complexes CpR3CeX and CpR3CeOR′ are isostructural, featuring terminal ligands X and OR′. The magnetic measurements revealed temperature-independent paramagnetism (TIP), with positive magnetic susceptibilities in the range χ0 (1.53–3.9) × 10–4 emu/mol. Cyclic voltammetry indicated two types of redox processes: (a) chemical and electrochemical reversibility for halide and siloxide complexes and (b) EC- or ECE-type mechanisms for the alkoxides (chemical reversibility at high scan rates). In all cases formal potentials could be determined ranging from −0.583 V vs Fc/Fc+ for Cp3CeI to −1.259 V vs Fc/Fc+ for CpMe3Ce(OEt). The electrochemical data revealed an increase in stabilization with respect to reduction of the cerium(IV) center in the series I < Br < Cl < siloxy < alkoxy ligand and a better stabilization with CpMe in comparison to Cp ligands by approximately 0.05–0.1 V. As a result, an improved stabilization of Ce(IV) was observed for more strongly electron donating ligands.
Framed and non‐framed robotics in neurosurgery: A 10‐year single‐center experience
2021-05-24

Abstract Background Safety, efficacy and efficiency of neurosurgical robots are defined by their design (i.e., framed and non‐framed) and procedural workflow (PW) (from image to surgery). The present study describes the quality indicators of three different robots in brain and spine surgery. Methods This single‐centre study enrolled 252 patients over a 10‐year period. Safety (complication rate) and efficacy (diagnostic yield, pedicle screw placement) were determined. Predictors of workflow efficiency (e.g., skin‐to‐skin) were evaluated and compared to conventional techniques (neuronavigation, stereotaxy). Results All robots showed excellent reliability (97.5%–100%) with low complication rates (4.5%–5.3%) and high efficacy (94.7%–97.7%). Robotics demonstrated a better time‐efficiency than neuronavigation. However, there was no shortening of surgery time compared to conventional stereotaxy. Time‐efficiency differed significantly between framed and non‐framed workflows. Conclusion While all neurosurgical robots were reliable, safe and efficacious, there were significant differences in time‐efficiency. PWs should be improved to increase the acceptance of robotics in neurosurgery.
The Impact of Fixation on the Detection of Oligodendrocyte Precursor Cell Morphology and Vascular Associations
2021-05-24

Oligodendrocyte precursor cells (OPCs) display numerous protrusions that extend into the surrounding parenchyma in the brain. Depending on the preparation of the tissue analyzed, these protrusions are more or less visible. We applied six different fixation methods and compared the effect of prolonged and stronger fixation on fluorescence intensity of platelet-derived growth factor receptor alpha, a surface marker of OPCs. Importantly, the fluorescence signal is mostly lost on protrusions as compared to the cell body, which has to be considered for specific analyses. Additionally, we show numerous contacts established between OPCs and the brain vasculature, which will contribute to the understanding of the interactions between these two elements.
Meaning and Measures: Interpreting and Evaluating Complexity Metrics
2021-05-24

Research on language complexity has been abundant and manifold in the past two decades. Within typology, it has to a very large extent been motivated by the question of whether all languages are equally complex, and if not, which language-external factors affect the distribution of complexity across languages. To address this and other questions, a plethora of different metrics and approaches has been put forward to measure the complexity of languages and language varieties. Against this backdrop we address three major gaps in the literature by discussing statistical, theoretical, and methodological problems related to the interpretation of complexity measures. First, we explore core statistical concepts to assess the meaningfulness of measured differences and distributions in complexity based on two case studies. In other words, we assess whether observed measurements are neither random nor negligible. Second, we discuss the common mismatch between measures and their intended meaning, namely, the fact that absolute complexity measures are often used to address hypotheses on relative complexity. Third, in the absence of a gold standard for complexity metrics, we suggest that existing measures be evaluated by drawing on cognitive methods and relating them to real-world cognitive phenomena. We conclude by highlighting the theoretical and methodological implications for future complexity research.
Abyssomicins—A 20-Year Retrospective View
2021-05-24

Abyssomicins represent a new family of polycyclic macrolactones. The first described compounds of the abyssomicin family were abyssomicin B, C, atrop-C, and D, produced by the marine actinomycete strain Verrucosispora maris AB-18-032, which was isolated from a sediment collected in the Sea of Japan. Among the described abyssomicins, only abyssomicin C and atrop-abyssomicin C show a high antibiotic activity against Gram-positive bacteria, including multi-resistant and vancomycin-resistant strains. The inhibitory activity is caused by a selective inhibition of the enzyme 4-amino-4-deoxychorismate synthase, which catalyzes the transformation of chorismate to para-aminobenzoic acid, an intermediate in the folic acid pathway.
Influence of Resilience and Optimism on Distress and Intention to Self-Isolate: Contrasting Lower and Higher COVID-19 Illness Risk Samples From an Extended Health Belief Model
2021-05-24

The study investigated the influence of resilience and dispositional optimism on, first, emotional distress and, second, the intention to self-isolate, experienced by people with a lower and higher illness risk, during the lockdown imposed in Spain during the first COVID-19 wave. These effects were investigated against the background of the Health Belief Model (HBM). A convenience sample of N = 325 participants completed an online survey including an ad-hoc questionnaire measuring the HBM core factors: Perceived health threat (susceptibility and severity of getting infected), and perceived quarantine benefits and costs. Self-efficacy and perceived social pressure were also measured. Based on reviews regarding pandemic outbreaks, quarantine benefits were conceptualized as the perceived effectiveness and solidary contribution of self-isolating in line with the quarantine protocols. Quarantine “psychosocial” costs were conceptualized as a composite of perceived boredom, loneliness, and economic concerns. Findings revealed an asymmetrical pattern of results so that (i) people at higher risk were more distressed by the perceived severity of getting infected whereas people at lower risk were more distressed by the psychosocial costs. Moreover, (ii) resilience and optimism were more “protective” against distress within the lower and higher risk groups, respectively. In addition, (iii) quarantine benefits and self-efficacy promoted the intention to self-isolate within both groups. However, (iv) optimism hindered such intention. This finding is discussed in the light of links between dispositional optimism and optimistic bias; the underestimation of experiencing negative events, which can relax the perceived health risk. Based on these findings, communication campaigns should prioritize information about the effectiveness of the implemented preventive behaviors rather than the costs of not implementing them, and be cautionary in encouraging excessive optimism.
Amlodipine accelerates bone healing in a stable closed femoral fracture model in mice
2021-05-24

Calcium channel blockers (CCBs), which are widely used in the treatment of hypertension, have been shown to influence bone metabolism. However, there is little information on whether CCBs also influence the process of fracture healing. Therefore, the effect of the CCB amlodipine on bone healing was studied in a stable closed fracture model in mice using intramedullary screw fixation. Bone healing was investigated by radiology, biomechanics, histomorphometry and Western blot analysis 2 and 5 weeks after fracture healing. Animals were treated daily (post operatively) per per os using a gavage with amlodipine low dose (1 mg/ kg body weight, n = 20), amlodipine high dose (3 mg/kg body weight, n = 20) or vehicle (NaCl) (control, n = 20) serving as a negative control. At 2 and 5 weeks, histomorphometric analysis revealed a significantly larger amount of bone tissue within the callus of amlodipine low-dose- and high-dose-treated animals when compared to controls. This was associated with a smaller amount of cartilaginous and fibrous tissue, indicating an acceleration of fracture healing. Biomechanics showed a slightly, but not significantly, higher bending stiffness in amlodipine low-dose- and high-dose-treated animals. Western blot analysis revealed a significantly increased expression of bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF). Moreover, the analysis showed a 5-fold higher expression of osteoprotegerin (OPG) and a 10-fold elevated expression of the receptor activator of NF-κB ligand (RANKL), indicating an increased bone turnover. These findings demonstrated that amlodipine accelerated fracture healing by stimulating bone formation, callus remodelling and osteoclast activity.
Importance of active and passive smoking as one of the risk factors for female sexual dysfunction in Chinese women
2021-05-24

The risk of FSD was closely related to depletion of ovarian function. Active smokers had the highest risk, but passive smoking also had a significant relationship to FSD. Although female smokers are rare in China, 'husband smoking' is frequent. Thus, our results should have significant healthcare consequences.