bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic antibodies, targeting the SARS-CoV-2 spike N-terminal domain, protect lethally infected K18-hACE2 mice
Authors: Noy-Porat Tal , Mechaly Adva , Levy Yinon , Makdasi Efi , Alcalay Ron , Gur David , Aftalion Moshe , Falach Reut , Ben-Arye Shani Leviatan , Lazar Shirley , Zauberman Ayelet , Epstein Eyal , Chitlaru Theodor , Weiss Shay , Achdout Hagit , Edgeworth Jonathan D. , Kikkeri Raghavendra , Yu Hai , Chen Xi , Yitzhaki Shmuel , Shapira Shmuel C. , Padler-Karavani Vered , Mazor Ohad , Rosenfeld Ronit 
Published: February 2021

AbstractSince the onset of the current COVID-19 pandemic, high priority is given to the development of neutralizing antibodies, as a key approach for the design of therapeutic strategies to countermeasure and eradicate the disease. Previously, we reported the development of human therapeutic monoclonal antibodies (mAbs) exhibiting very high protective ability. These mAbs recognize epitopes on the spike receptor binding domain (RBD) of SARS-CoV-2 that is considered to represent the main rout of receptor engagement by the SARS-CoV-2 virus. The recent emergence of viral variants emphasizes the notion that efficient antibody treatments need to rely on mAbs against several distinct key epitopes in order to circumvent the occurrence of therapy escape-mutants. Here we report the isolation and characterization of 12 neutralizing mAbs, identified by screening a phage-display library constructed from lymphatic cells collected from severe COVID-19 patients. The antibodies target three distinct epitopes on the spike N-terminal domain (NTD) of SARS-CoV-2, one of them defining a major site of vulnerability of the virus. Extensive characterization of these mAbs suggests a neutralization mechanism which relies both on amino-acid and N-glycan recognition on the virus, and involvement of receptors other than the hACE2 on the target cell. Two of the selected mAbs, which demonstrated superior neutralization potency in vitro, were further evaluated in vivo, demonstrating their ability to fully protect K18-hACE2 transgenic mice even when administered at low doses and late after infection. The study demonstrates the high potential of the mAbs for therapy of SARS-CoV-2 infection and underlines the possible role of the NTD in mediating infection of host cells via alternative cellular portals other than the canonical ACE2 receptor.
Predicting Epigenomic Functions of Genetic Variants in the Context of Neurodevelopment via Deep Transfer Learning
Authors: Lai Boqiao , Qian Sheng , Zhang Hanwen , Zhang Siwei , Kozlova Alena , Duan Jubao , He Xin , Xu Jinbo 
Published: February 2021

AbstractDecoding the regulatory effects of non-coding variants is a key challenge in understanding the mechanisms of gene regulation as well as the genetics of common diseases. Recently, deep learning models have been introduced to predict genome-wide epigenomic profiles and effects of DNA variants, in various cellular contexts, but they were often trained in cell lines or bulk tissues that may not be related to phenotypes of interest. This is particularly a challenge for neuropsychiatric disorders, since the most relevant cell and tissue types are often missing in the training data of such models.To address this issue, we introduce a deep transfer learning framework termed MetaChrom that takes advantage of both a reference dataset - an extensive compendium of publicly available epigenomic data, and epigenomic profiles of cell types related to specific phenotypes of interest. We trained and evaluated our model on a comprehensive set of epigenomic profiles from fetal and adult brain, and cellular models representing early neurodevelopment. MetaChrom predicts these epigenomic features with much higher accuracy than previous methods, and than models without the use of reference epigenomic data for transfer learning. Using experimentally determined regulatory variants from iPS cell-derived neurons, we show that MetaChrom predicts functional variants more accurately than existing non-coding variant scoring tools. By combining genome-wide association study (GWAS) data with MetaChrom predictions, we prioritized 31 SNPs for Schizophrenia (SCZ). These candidate SNPs suggest potential risk genes of SCZ and the biological contexts where they act.In summary, MetaChrom is a general transfer learning framework that can be applied to the study of regulatory functions of DNA sequences and variants in any disease-related cell or tissue types. The software tool is available at https://github.com/bl-2633/MetaChrom and a prediction web server is accessible at https://metachrom.ttic.edu/.
Lateral Undulation Aids Biological and Robotic Earthworm Anchoring and Locomotion
Authors: Ozkan-Aydin Yasemin , Liu Bangyuan , Ferrero Alexandra Carruthers , Seidel Max , Hammond Frank L. , Goldman Daniel I. 
Published: February 2021

AbstractEarthworms (Lumbricus terrestris) are characterized by soft, highly flexible and extensible bodies, and are capable of locomoting in most terrestrial environments. Previous studies of earthworm movement have focused on the use of retrograde peristaltic gaits in which controlled contraction of longitudinal and circular muscles results in waves of shortening/thickening and thinning/lengthening of the hydrostatic skeleton. These waves can propel the animal across ground as well as into soil. However, worms can also benefit from axial body bends during locomotion. Such lateral undulation dynamics can aid locomotor function via hooking/anchoring (to provide propulsion), modify travel orientation (to avoid obstacles and generate turns) and even generate snake-like undulatory locomotion in environments where peristaltic locomotion results in poor performance. To the best of our knowledge, the important aspects of locomotion associated with the lateral undulation of an earthworm body are yet to be systematically investigated. In this study, we observed that within confined environments, the worm uses lateral undulation to anchor its body to the walls of their burrows and tip (nose) bending to search the environment. This relatively simple locomotion strategy drastically improved the performance of our soft bodied robophysical model of the earthworm both in a confined (in an acrylic tube) and above-ground heterogeneous environment (rigid pegs), where the peristaltic gait often fails. In summary, lateral undulation facilitates the mobility of earthworm locomotion in diverse environments and can play an important role in the creation of low cost soft robotic devices capable of traversing a variety of environments.
Semi-quantitative detection for L-asparaginase producing fungi and the impact of carbon and nitrogen sources on enzyme activity
Authors: Hamed Mahdi , Osman Ahmed A , Ateş Mustafa 
Published: February 2021

AbstractObjectiveTo semi-quantitively screen filamentous fungi isolated from different habitats for L-asparaginase production by three indicators; phenol red, cresol red and bromothymol blue and to examine the impact of different carbon and nitrogen sources on the enzyme production using different fungal isolates.Materials and methodsFifty-five fungal isolates were tested for L-asparaginase production by plate assay using Modified Czapek-Dox (MCD) medium. The enzyme activity was estimated using the Nessler method which measures the concentration of ammonia formed owing to the enzyme action on the substrate. The impact of nitrogen and carbon sources on the enzyme production was done by using the best three L-asparaginase producers from the semi-quantitative screening.Results and conclusionsA total of 53/55 (96.36%) fungal isolates were L-asparaginase producing strains, of them, Cladosporium tenuissimum, Penicillium camembertii and Aspergillus carneus showed high enzyme production. Production of L-asparaginase was higher with the glucose and urea as carbon and nitrogen sources, respectively. The highest enzyme level (5,558 U/ml) was produced by C. tenuissimum in a glucose-containing medium. This study shows that P. camemberti, A. carneus, and C. tenuissimum are good L-asparaginase producers and thus could be used for L-asparaginase production
Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males
Authors: Gathercole Laura L , Nikolaou Nikolaos , Arvaniti Anastasia , Harris Shelley E , Poolman Toryn M , Hazlehurst Jonathan M , Kratschmar Denise V , Todorčević Marijana , Moolla Ahmad , Dempster Niall , Pink Ryan C , Saikali Michael F , Bentley Liz , Penning Trevor M , Ohlsson Claes , Cummins Carolyn L , Poutanen Matti , Odermatt Alex , Cox Roger D , Tomlinson Jeremy W 
Published: February 2021

AbstractBackgroundSteroid 5β-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown.MethodsAkr1d1-/-mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/-mice were challenged with a 60% high fat diet.ResultsAkr1d1-/-mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/-mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/-mice were not protected against diet induced obesity and insulin resistance.ConclusionThis study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.
Defining a Connectome-Based Predictive Model of Attentional Control in Aging
Authors: Fountain-Zaragoza Stephanie , Manglani Heena R. , Rosenberg Monica D. , Andridge Rebecca , Prakash Ruchika Shaurya 
Published: February 2021

AbstractWith advancing age, declines in the executive control of attention are accompanied by shifts in the functional topology of brain networks. However, there is increasing recognition of the considerable individual variability in the extent and types of attentional deficits that older adults exhibit, with results from neuroimaging investigations paralleling behavioral heterogeneity. Emerging computational methods leverage whole-brain functional connectivity to predict individual-level behaviors. These approaches are well-suited to the cognitive aging context, as they may elucidate configurations of functional connections that best explain group- and individual-level differences across older adults. Two independent samples of neurologically and psychiatrically healthy older adults were used to separately derive a predictive model of attentional control and test the model’s external validity. Here we show that despite challenges posed by heterogeneity in these aging samples, select functional connections carried meaningful variance, allowing for successful prediction of attention in a novel sample of older individuals.
In vivo amyloid-like fibrils produced under stress
Authors: Fontana Natália A. , Rosse Ariane D. , Watts Anthony , Coelho Paulo S. R. , Costa-Filho Antonio J. 
Published: February 2021

AbstractThe participation of amyloids in neurodegenerative diseases and functional processes has triggered the quest for methods allowing their direct detection in vivo. Despite the plethora of data, those methods are still lacking. The autofluorescence from the extended β-sheets of amyloids is here used to follow fibrillation of S. cerevisiae Golgi Reassembly and Stacking Protein (Grh1). Grh1 has been implicated in starvation-triggered unconventional protein secretion (UPS), and here its participation also in heat shock response (HSR) is suggested. Fluorescence Lifetime Imaging (FLIM) is used to detect fibril autofluorescence in cells (E. coli and yeast) under stress (starvation and higher temperature). The formation of Grh1 large complexes under stress is further supported by size exclusion chromatography and ultracentrifugation. The data show for the first time in vivo detection of amyloids without the use of extrinsic probes as well as bring new perspectives on the participation of Grh1 in UPS and HSR.
Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes
Authors: Quan Hui , Tian Hao , Liu Sirui , Xue Yue , Zhang Yu , Xie Wei , Gao Yi Qin 
Published: February 2021

AbstractThe author has withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2019/521401. Therefore, the author does not wish this work to be cited as a reference for the project. Please cite and refer to the preprint BIORXIV/2019/521401 if necessary. If you have any questions, please contact the corresponding author (gaoyq@pku.edu.cn).
Nascent polypeptide within the exit tunnel ensures continuous translation elongation by stabilizing the translating ribosome
Authors: Chadani Yuhei , Sugata Nobuyuki , Niwa Tatsuya , Ito Yosuke , Iwasaki Shintaro , Taguchi Hideki 
Published: February 2021

SummaryContinuous translation elongation, irrespective of amino acid sequences, is a prerequisite for living organisms to produce their proteomes. However, the risk of elongation abortion is concealed within nascent polypeptide products. Negatively charged sequences with occasional intermittent prolines, termed intrinsic ribosome destabilization (IRD) sequences, destabilizes the translating ribosomal complex. Thus, some nascent chain sequences lead to premature translation cessation. Here, we show that the risk of IRD is maximal at the N-terminal regions of proteins encoded by dozens of Escherichia coli genes. In contrast, most potential IRD sequences in the middle of open reading frames remain cryptic. We found two elements in nascent chains that counteract IRD: the nascent polypeptide itself that spans the exit tunnel and its bulky amino acid residues that occupy the tunnel entrance region. Thus, nascent polypeptide products have a built-in ability to ensure elongation continuity by serving as a bridge and thus by protecting the large and small ribosomal subunits from dissociation.
dcHiC: differential compartment analysis of Hi-C datasets
Authors: Chakraborty Abhijit , Wang Jeffrey , Ay Ferhat 
Published: February 2021

AbstractThe compartmental organization of chromatin and its changes play important roles in distinct biological processes carried out by mammalian genomes. However, differential compartment analyses have been mostly limited to pairwise comparisons and with a main focus on only the compartment flips (e.g., A-to-B). Here, we introduce dcHiC, which utilizes quantile normalized compartment scores and a multivariate distance measure to identify significant changes in compartmentalization among multiple contact maps. Evaluating dcHiC on three collections of Hi-C contact maps from mouse neural differentiation (n=3), mouse hematopoiesis (n=10) and human LCL cell lines (n=20), we show its effectiveness and sensitivity in detecting biologically relevant differences, including those validated by orthogonal experiments. Across these experiments, dcHiC reported regions with dynamically regulated genes associated with cell identity, along with correlated changes in chromatin states, replication timing and lamin B1 association. With its efficient implementation, dcHiC not only enables high-resolution compartment analysis but also includes a suite of additional features, including standalone browser visualization, differential interaction identification, and time-series clustering. As such, it is an essential addition to the Hi-C analysis toolbox for the ever-growing number of contact maps being generated. dcHiC is freely available at https://github.com/ay-lab/dcHiC, and examples from this paper can be seen at https://ay-lab.github.io/dcHiC.
Genetic autonomy and low singlet oxygen yield support kleptoplast functionality in photosynthetic sea slugs
Authors: Havurinne Vesa , Handrich Maria , Antinluoma Mikko , Khorobrykh Sergey , Gould Sven B. , Tyystjärvi Esa 
Published: February 2021

AbstractElysia chlorotica is a kleptoplastic sea slug that preys on Vaucheria litorea, stealing its plastids which then continue to photosynthesize for months inside the animal cells. We investigated the native properties of V. litorea plastids to understand how they withstand the rigors of photosynthesis in isolation. Transcription of specific genes in laboratory-isolated V. litorea plastids was monitored up to seven days. The involvement of plastid-encoded FtsH, a key plastid maintenance protease, in recovery from photoinhibition in V. litorea was estimated in cycloheximide-treated cells. In vitro comparison of V. litorea and spinach thylakoids was applied to investigate ROS formation in V. litorea. Isolating V. litorea plastids triggered upregulation of ftsH and translation elongation factor EF-Tu (tufA). Upregulation of FtsH was also evident in cycloheximide-treated cells during recovery from photoinhibition. Charge recombination in PSII of V. litorea was found to be fine-tuned to produce only small quantities of singlet oxygen (1O2). Our results support the view that the genetic characteristics of the plastids themselves are crucial in creating a photosynthetic sea slug. The plastid’s autonomous repair machinery is likely enhanced by low 1O2 production and by upregulation of FtsH in the plastids.HighlightIsolated Vaucheria litorea plastids exhibit upregulation of tufA and ftsH, key plastid maintenance genes, and produce only little singlet oxygen. These factors likely contribute to plastid longevity in kleptoplastic slugs.
Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol
Authors: Schlagowski Anna M. , Knöringer Katharina , Morlot Sandrine , Sáchez Vicente Ana , Boos Felix , Khalid Nabeel , Ahmed Sheraz , Schramm Jana , Murschall Lena Maria , Haberkant Per , Stein Frank , Riemer Jan , Westermann Benedikt , Braun Ralf J. , Winklhofer Konstanze F. , Charvin Gilles , Herrmann Johannes M. 
Published: February 2021

AbstractThe formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis. (174/175 words)
Impact of central complex lesions on visual orientation in ants: Turning behaviour, but not the overall movement direction, is disrupted
Authors: Dell-Cronin Scarlett , Buehlmann Cornelia , Pathirannahelage Angela Diyalagoda , Goulard Roman , Webb Barbara , Niven Jeremy , Graham Paul 
Published: February 2021

ABSTRACTWood ants are excellent navigators using a combination of innate and learnt navigational strategies to travel between their nest and feeding sites. Visual navigation in ants has been studied extensively, however, we only know little about the underlying neural mechanisms. The central complex (CX) is located at the midline of the insect brain. It receives sensory input that allows an insect to keep track of the direction of sensory cues relative to its own orientation and to control movement. We show here direct evidence for the involvement of the central complex in the innate visual orientation response of freely moving wood ants. Lesions in the CX disrupted the control of turning in a lateralised manner, but had no effect on the overall heading direction, walking speed or path straightness.
Super-resolved local recruitment of CLDN5 to filtration slits implicates a direct relationship with podocyte foot process effacement
Authors: Tesch Florian , Siegerist Florian , Hay Eleonora , Artelt Nadine , Daniel Christoph , Amann Kerstin , Zimmermann Uwe , Kavvadas Panagiotis , Grisk Olaf , Chadjichristos Christos , Endlich Karlhans , Chatziantoniou Christos , Endlich Nicole 
Published: February 2021

AbstractUnder healthy conditions, foot processes of neighboring podocytes are interdigitating and connected by an electron-dense slit diaphragm. Beside slit diaphragm proteins, typical adherens junction proteins are also found to be expressed at this cell-cell junction. It is therefore considered as a highly specialized type of adherens junction.During podocyte injury, podocyte foot processes lose their characteristic 3D structure and the filtration slits typical meandering structure gets linearized. It is still under debate how this change of structure leads to the phenomenon of proteinuria. Using super-resolution 3D structured illumination microscopy, we observed a spatially restricted up-regulation of the tight junction protein claudin 5 (CLDN5) in areas where podocyte processes of patients suffering from minimal change disease (MCD), focal and segmental glomerulosclerosis (FSGS) as well as in murine nephrotoxic serum (NTS) nephritis and uninephrectomy DOCA-salt hypertension models, were locally injured. CLDN5/nephrin ratios in human glomerulopathies and NTS-treated mice were significantly higher compared to controls. In patients, the CLDN5/nephrin ratio is significantly correlated with the filtration slit density as a foot process effacement marker, confirming a direct association of local CLDN5 up-regulation in injured foot processes. Moreover, CLDN5 up-regulation was observed in some areas of high filtration slit density, suggesting that CLND5 up-regulation preceded the changes of foot processes. Therefore, CLDN5 could serve as a biomarker predicting early foot process effacement.
Chromatin Bridges, not Micronuclei, Activate cGAS after Drug-induced Mitotic Errors in Human Cells
Authors: Flynn Patrick J. , Koch Peter D. , Mitchison Timothy J. 
Published: February 2021

SummaryMitotic errors can activate cGAS and induce type-I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of anti-mitotic drugs to perturb mitosis in fibroblasts and measured abnormal nuclear morphologies, cGAS localization and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2′3-cGAMP to fibroblasts. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and anti-tumor actions of taxanes and MPS1 inhibitors, may depend on this effect.