bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical course and risk factors for mortality of COVID-19 patients with pre-existing cirrhosis: A multicenter cohort study
Authors: Qi Xiaolong , Liu Yanna , Fallowfield Jonathan A. , Wang Jitao , Wang Jianwen , Li Xinyu , Shi Jindong , Pan Hongqiu , Zou Shengqiang , Zhang Hongguang , Chen Zhenhuai , Li Fujian , Luo Yan , Mei Mei , Liu Huiling , Wang Zhengyan , Li Jinlin , Yang Hua , Xiang Huihua , Li Xiaodan , Liu Tao , Zheng Ming-Hua , Liu Chuan , Huang Yifei , Xu Dan , Li Xiaoguo , Kang Ning , He Qing , Gu Ye , Zhang Guo , Shao Chuxiao , Liu Dengxiang , Zhang Lin , Li Xun , Kawada Norifumi , Jiang Zicheng , Wang Fengmei , Xiong Bin , Takehara Tetsuo , Rockey Don C. ,   for the COVID-Cirrhosis-CHESS Group
Published: April 2020

Background

Patients with pre-existing cirrhosis are considered at increased risk of severe coronavirus disease 2019 (COVID-19) but the clinical course in these patients has not yet been reported. This study aimed to provide a detailed report of the clinical characteristics and outcomes among COVID-19 patients with pre-existing cirrhosis.

Methods

In this retrospective, multicenter cohort study, we consecutively included all adult inpatients with laboratory-confirmed COVID-19 and pre-existing cirrhosis that had been discharged or had died by 24 March 2020 from 16 designated hospitals in China.

Demographic, clinical, laboratory and radiographic findings on admission, treatment, complications during hospitalization and clinical outcomes were collected and compared between survivors and non-survivors.

Findings

Twenty-one patients were included consecutively in this study, of whom 16 were cured and 5 died in hospital. Seventeen patients had compensated cirrhosis and hepatitis B virus infection was the most common etiology. Lymphocyte and platelet counts were lower, and direct bilirubin levels were higher in patients who died than those who survived (p= 0·040, 0·032, and 0·006, respectively). Acute respiratory distress syndrome and secondary infection were both the most frequently observed complications. Only one patient developed acute on chronic liver failure. Of the 5 non-survivors, all patients developed acute respiratory distress syndrome and 2 patients progressed to multiple organ dysfunction syndrome.

Interpretation

Lower lymphocyte and platelet counts, and higher direct bilirubin level might represent poor prognostic indicators in SARS-CoV-2-infected patients with pre-existing cirrhosis.
The incubation period of COVID-19 – A rapid systematic review and meta-analysis of observational research
Authors: McAloon Conor G. , Collins Áine B. , Hunt Kevin , Barber Ann , Byrne Andrew W. , Butler Francis , Casey Miriam , Griffin John , Lane Elizabeth , McEvoy David , Wall Patrick , Green Martin J. , O’Grady Luke , More Simon J.
Published: April 2020

Background

Reliable estimates of the incubation period are important for decision making around the control of infectious diseases. Knowledge of the incubation period distribution can be used directly to inform decision-making or as inputs into mathematical models.

Objectives

The aim of this study was to conduct a rapid systematic review and meta-analysis of estimates of the incubation periods of COVID-19.

Design

Rapid systematic review and meta-analysis of observational research

Data sources

Publications on the electronic databases PubMed, Google Scholar, MedRxiv and BioRxiv were searched. The search was not limited to peer-reviewed published data, but also included pre-print articles.

Study appraisal and synthesis methods

Studies were selected for meta-analysis if they reported either the parameters and confidence intervals of the distributions fit to the data, or sufficient information to facilitate calculation of those values. The majority of studies suitable for inclusion in the final analysis modelled incubation period as a lognormal distribution. We conducted a random effects meta-analysis of the parameters of this distribution.

Results

The incubation period distribution may be modelled with a lognormal distribution with pooled mu and sigma parameters of 1.63 (1.51, 1.75) and 0.50 (0.45, 0.55) respectively. The corresponding mean was 5.8 (5.01, 6.69 days). It should be noted that uncertainty increases towards the tail of the distribution: the pooled parameter estimates resulted in a median incubation period of 5.1 (4.5, 5.8) days, whereas the 95thpercentile was 11.6 (9.5, 14.2) days.

Conclusions and implications

The choice of which parameter values are adopted will depend on how the information is used, the associated risks and the perceived consequences of decisions to be taken. These recommendations will need to be revisited once further relevant information becomes available. Finally, we present an RShiny app that facilitates updating these estimates as new data become available.

ARTICLE SUMMARY

Strengths and limitations of this study

This study provides a pooled estimate of the distribution of incubation periods which may be used in subsequent modelling studies or to inform decision-making

This estimate will need to be revisited as subsequent data become available. We present an RShiny app to allow the meta-analysis to be updated with new estimates
Sensory and motor electrophysiological mapping of the cerebellum in humans
Authors: Ashida Reiko , Walsh Peter , Brooks Jonathan C.W. , Edwards Richard J. , Cerminara Nadia L. , Apps Richard
Published: April 2020

Damage to the cerebellum during posterior fossa surgery can lead to ataxia and in paediatric cases, the risk of cerebellar mutism syndrome. Animal electrophysiological and human imaging studies have shown compartmentalisation of sensorimotor and cognitive functions within the cerebellum. In the present study, electrophysiological monitoring of sensory and motor pathways was carried out to assess the location of limb sensorimotor representation within the human cerebellum, as a potential approach for real time assessment of neurophysiological integrity to reduce the incidence of cerebellar surgical morbidities.

Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. For sensory mapping (n=8), electrical stimulation was applied to the median nerves, the posterior tibial nerves, or proximal and distal limb muscles and evoked field potential responses were sought on the cerebellar surface. For motor mapping (n=5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles.

Evoked potentials on the cerebellar surface were found in two patients (25% of cases). In one patient, the evoked response was located on the surface of the right inferior posterior cerebellum in response to stimulation of the right leg. In the second patient, stimulation of the extensor digitorum muscle in the left forearm evoked a response on the surface of the left inferior posterior lobe. In the motor mapping cases no evoked EMG responses could be found.

Intraoperative electrophysiological mapping, therefore, indicates it is possible to record evoked potentials on the surface of the human cerebellum in response to peripheral stimulation.
Time course of changes in the long latency feedback response parallels the fast process of short term motor adaptation
Authors: Coltman Susan K. , Gribble Paul L.
Published: April 2020

Adapting to novel dynamics involves modifying both feedforward and feedback control. We investigated whether the motor system alters feedback responses during adaptation to a novel force field in a manner similar to adjustments in feedforward control. We simultaneously tracked the time course of both feedforward and feedback systems via independent probes during a force field adaptation task. Participants (n=35) grasped the handle of a robotic manipulandum and performed reaches to a visual target while the hand and arm were occluded. We introduced an abrupt counter-clockwise velocity-dependent force field during a block of reaching trials. We measured movement kinematics and shoulder and elbow muscle activity with surface EMG electrodes. We tracked the feedback stretch response throughout the task. Using force channel trials we measured overall learning, which was later decomposed into a fast and slow process. We found that the long-latency feedback response (LLFR) was upregulated in the early stages of learning and was correlated with the fast component of feedforward adaptation. The change in feedback response was specific to the long-latency epoch (50-100 ms after muscle stretch) and was observed only in the triceps muscle, which was the muscle required to counter the force field during adaptation. The similarity in time course for the LLFR and the estimated time course of the fast process suggests both are supported by common neural circuits. While some propose that the fast process reflects an explicit strategy, we argue instead that it may be a proxy for the feedback controller.

New & Noteworthy

We investigated whether changes in the feedback stretch response were related to the proposed fast and slow processes of motor adaptation. We found that the long latency component of the feedback stretch response was upregulated in the early stages of learning, and the time course was correlated with the fast process. While some propose that the fast process reflects an explicit strategy, we argue instead that it may be a proxy for the feedback controller.
Ultra-sparse connectivity within the lateral hypothalamus
Authors: Burdakov Denis , Karnani Mahesh M.
Published: April 2020

The lateral hypothalamus (LH) contains neuronal populations which generate fundamental behavioural actions such as feeding, sleep, movement, attack and evasion. Their activity is also correlated with various appetitive and consummatory behaviours as well as reward seeking. It is unknown how neural activity within and among these populations is coordinated. One hypothesis postulates that they communicate using inhibitory and excitatory synapses, forming local microcircuits. We inspected this hypothesis using quadruple whole cell recordings and optogenetics to screen thousands of potential connections in brain slices. In contrast to the neocortex, we found near zero connectivity within the LH. In line with its ultra-sparse intrinsic connectivity, we found that the LH does not generate local beta and gamma oscillations. This suggests that LH neurons integrate incoming input within individual neurons rather than through local network interactions, and that input from other brain structures is decisive for selecting active populations in LH.
Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel
Authors: Barnhouse Victoria , Petrikas Nathan , Crosby Cody , Zoldan Janet , Harley Brendan
Published: April 2020

Adult hematopoietic stem cells (HSCs) produce the body’s full complement of blood and immune cells. They reside in specialized microenvironments, or niches, within the bone marrow. The perivascular niche near blood vessels is believed to help maintain primitive HSCs in an undifferentiated state but demonstration of this effect is difficult.In vivostudies make it challenging to determine the direct effect of the endosteal and perivascular niches as they can be in close proximity, and two-dimensionalin vitrocultures often lack an instructive extracellular matrix environment. We describe a tissue engineering approach to develop and characterize a three-dimensional perivascular tissue model to investigate the influence of the perivascular secretome on HSC behavior. We generate 3D endothelial networks in methacrylamide-functionalized gelatin hydrogels using human umbilical vein endothelial cells (HUVECs) and mesenchymal stromal cells (MSCs). We identify a subset of secreted factors important for HSC function, and examine the response of primary murine HSCs in hydrogels to the perivascular secretome. Within 4 days of culture, perivascular conditioned media promoted maintenance of a greater fraction of hematopoietic stem and progenitor cells. This work represents an important first-generation perivascular model to investigate the role of niche secreted factors on the maintenance of primary HSCs.
Lineage-specific diversification in the usage of D-glutamate and D-aspartate in early-branching metazoans
Authors: Moroz Leonid L. , Sohn Dosung , Romanova Daria Y. , Kohn Andrea B.
Published: April 2020

D-amino acids are unique and essential signaling molecules in neural, hormonal, and immune systems. However, the presence of D-amino acids and their recruitment in early animals is mostly unknown due to limited information about prebilaterian metazoans. Here, we performed the comparative survey of L-/D-aspartate and L-/D-glutamate in representatives of four phyla of basal Metazoa: cnidarians (Aglantha); placozoans (Trichoplax), sponges (Sycon) and ctenophores (Pleurobrachia, Mnemiopsis, Bolinopsis, andBeroe), which are descendants of ancestral animal lineages distinct from Bilateria. Specifically, we used high-performance capillary electrophoresis for microchemical assays and quantification of the enantiomers. L-glutamate and L-aspartate were abundant analytes in all species studied. However, we showed that the placozoans, cnidarians, and sponges had high micromolar concentrations of D-aspartate, whereas D-glutamate was not detectable. In contrast, we found that in ctenophores, D-glutamate was the dominant enantiomer with no or trace amounts of D-aspartate. This situation illuminates prominent lineage-specific diversifications in the recruitment of D-amino acids and suggests distinct signaling functions of these molecules early in the animal evolution. We also hypothesize that a deep ancestry of such recruitment events might provide some constraints underlying the evolution of neural and other signaling systems in Metazoa.

Highlights

D-amino acids are essential for intercellular signaling and evolution

Enantiomers have been quantified in early-branching animals

Lineage-specific recruitment of D-glutamate could occur in ctenophores

D-aspartate is one of the primary enantiomers in other metazoans

Deep ancestry of such events could provide constraints in the evolution of signaling

Graphical Abstract

D-amino acids are essential for intercellular signaling. Direct microchemical quantification of enantiomers in representatives of early-branching animals suggests lineage-specific recruitments of D-glutamate and D-aspartate. Deep ancestry of such events might provide some constraints underlying the evolution of neural and other signaling systems in Metazoa.
What does your cell really do? Model-based assessment of mammalian cells metabolic functionalities using omics data
Authors: Richelle Anne , Kellman Benjamin P. , Wenzel Alexander T. , Chiang Austin W.T. , Reagan Tyler , Gutierrez Jahir M. , Joshi Chintan , Li Shangzhong , Liu Joanne K. , Masson Helen , Lee Jooyong , Li Zerong , Heirendt Laurent , Trefois Christophe , Juarez Edwin F. , Bath Tyler , Borland David , Mesirov Jill P. , Robasky Kimberly , Lewis Nathan E.
Published: April 2020

Large-scale omics experiments have become standard in biological studies, leading to a deluge of data. However, researchers still face the challenge of connecting changes in the omics data to changes in cell functions, due to the complex interdependencies between genes, proteins and metabolites. Here we present a novel framework that begins to overcome this problem by allowing users to infer how metabolic functions change, based on omics data. To enable this, we curated and standardized lists of metabolic tasks that mammalian cells can accomplish. We then used genome-scale metabolic networks to define gene modules responsible for each specific metabolic task. We further developed a framework to overlay omics data on these modules to predict pathway usage for each metabolic task. The proposed approach allows one to directly predict how changes in omics experiments change cell or tissue function. We further demonstrated how this new approach can be used to leverage the metabolic functions of biological entities from the single cell to their organization in tissues and organs using multiple transcriptomic datasets (human and mouse). Finally, we created a web-based CellFie module that has been integrated into the list of tools available in GenePattern (www.genepattern.org) to enable adoption of the approach.
A quantitative model for the regulation of innate immune activation
Authors: Qin Yawei , Mace Emily M. , Barton John P.
Published: April 2020

The immune system employs a wide variety of strategies to protect the body from infection. Cells such as natural killer (NK) cells and macrophages can recognize and eliminate targets with aberrant surface ligand expression in a manner that is not antigen-specific. This innate mechanism of activation must be tightly regulated to prevent autoimmunity. Here we introduce a quantitative model of the regulation of nonspecific activation inspired by Bayesian inference. Our model captures known behaviors of innate immune cells, including adaptation to changing environments and the development of hyposensitivity after prolonged exposure to activating signals. Our analysis also reveals a tradeoff between precision and adaptation. Maintaining the ability to adapt to different environments leads to heterogeneous responses, even for hypothetical populations of immune cells and targets that have identical surface receptor and ligand expression. Collectively, our results describe an adaptive algorithm for self/nonself discrimination that functions even in the absence of antigen restriction. The same model could also apply more broadly to the adaptive regulation of activation for other immune cell types.
Allelic differences of clustered terpene synthases contribute to correlated intra-specific variation of floral and herbivory-induced volatiles in a wild tobacco
Authors: Xu Shuqing , Kreitzer Christoph , McGale Erica , Lackus Nathalie D. , Guo Han , Köllner Tobias G. , Schuman Meredith C. , Baldwin Ian T. , Zhou Wenwu
Published: April 2020

Plant volatile emissions can recruit predators of herbivores for indirect defence and attract pollinators to aid in pollination. Although volatiles involved in defence and pollinator attraction are primarily emitted from leaves and flowers, respectively, they will co-evolve if their underlying genetic basis is intrinsically linked, either due to pleiotropy or genetic linkage. However, direct evidence of co-evolving defence and floral traits is scarce.

We characterized intra-specific variation of herbivory-induced plant volatiles (HIPVs), the key components of indirect defence against herbivores, and floral volatiles in the wild tobaccoNicotiana attenuata.

We found that variation of (E)-β-ocimene and (E)-α-bergamotene contributed to the correlated changes in HIPVs and floral volatiles amongN. attenuatanatural accessions. Intra-specific variations of (E)-β-ocimene and (E)-α-bergamotene emissions resulted from allelic variation of two genetically co-localized terpene synthase genes,NaTPS25andNaTPS38respectively.

Analyzing haplotypes ofNaTPS25andNaTPS38revealed that allelic variations ofNaTPS25andNaTPS38resulted in correlated changes of (E)-β-ocimene and (E)-α-bergamotene emission in HIPVs and floral volatiles inN. attenuata.

Together, these results provide evidence that pleiotropy and genetic linkage result in correlated changes in defences and floral signals in natural populations, and the evolution of plant volatiles is likely under diffuse selection.
Phylogenetic analysis of Michigan’s freshwater sponges (Porifera, Spongillidae) using extended COI mtDNA sequences
Authors: Kolomyjec Stephen H. , Willford Roger A. ,   THE FALL 2019 GENETICS CLASS
Published: April 2020

Kolomyjecet al.(2020). Phylogenetic analysis of Michigan’s freshwater sponges (Porifera, Spongillidae) using extended COI mtDNA sequences. –Zoologica Scripta, 00, 000-000. The phylogenetic relationships of eight species of freshwater sponges sampled throughout the State of Michigan in the North American Great Lakes region were examined as part of a Course-based Undergraduate Research Experience (CURE). An extended version of the standard cytochrome oxidase subunit I (COI) metazoan DNA was used for sequencing and Bayesian phylogenetic inference. The extended gene region (COI-ext) produces a 1,200 bp amplicon instead of the standard 640 bp fragment which compensates for the standard amplicon’s low informatics value in Phylum Porifera. The species examined clustered into strongly supported monophyletic species groups within the familySpongillidae. This study represents the first look at the phylogenetic relationships of freshwater sponges in the Great Lakes Region.

Per Kolomyjec, College of Science and the Environment, Lake Superior State University, 650 W Easterday Ave., Sault Sainte Marie, MI 49783, USA. E-mailskolomyjec@lssu.edu
Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans
Authors: Kanen Jonathan W. , Apergis-Schoute Annemieke M. , Yellowlees Robyn , Arntz Frederique E. , van der Flier Febe E. , Price Annabel , Cardinal Rudolf N. , Christmas David M. , Clark Luke , Sahakian Barbara J. , Crockett Molly J. , Robbins Trevor W.
Published: April 2020

Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively. Upon depleting the serotonin precursor tryptophan – in a double-blind randomised placebo-controlled design – healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.
Genomes of Animal Mitochondria have not Evolved According to Common Models of Substitution Probabilities
Authors: Cavender James
Published: April 2020

Common probabilistic models of substitutions of bases (Jukes-Cantor, Kimura 2-parameter, Tamura-Nei, F84, HKY, and the 6-parameter models used in linear invariants methods) must be rejected, at least for mitochondrial genomes of animals. They are rejected by a new test that is simple and lenient.
A C++ library for protein sub-structure search
Authors: Zhou Jianfu , Grigoryan Gevorg
Published: April 2020

MASTER is a previously published algorithm for protein sub-structure search. Given a database of protein structures and a query structural motif, composed of multiple disjoint segments, it finds all sub-structures from the database that align onto the query to within a pre-specified backbone root-mean-square deviation. Here, we present an improved version of the algorithm, MASTER v.2, in the form of an open-source C++ Application Program Interface library, thereby providing programmatic access to structure search functionality. An entirely reorganized approach to database representation now enables large structural databases to be stored in memory, further simplifying development of automated search-based methods. Given the increasingly important role of structure-based data mining, our improved implementation should find ample uses in structural biology applications.

Availability

MASTER is available athttps://grigoryanlab.org/master/master-v2.php.

Contact

gevorg.grigoryan@dartmouth.edu
Machine learning uncovers independently regulated modules in the Bacillus subtilis transcriptome
Authors: Rychel Kevin , Sastry Anand V. , Palsson Bernhard O.
Published: April 2020

The transcriptional regulatory network (TRN) of Bacillus subtilis coordinates cellular functions of fundamental interest, including metabolism, biofilm formation, and sporulation. Here, we use unsupervised machine learning to modularize the transcriptome and quantitatively describe regulatory activity under diverse conditions, creating an unbiased summary of gene expression. We obtain 83 independently modulated gene sets that explain most of the variance in expression, and demonstrate that 76% of them represent the effects of known regulators. The TRN structure and its condition-dependent activity uncover novel or recently discovered roles for at least 5 regulons, such as a relationship between histidine utilization and quorum sensing. The TRN also facilitates quantification of population-level sporulation states, revealing a putative anaerobic metabolism role for SigG. As this TRN covers the majority of the transcriptome and concisely characterizes the global expression state, it could inform research on nearly every aspect of transcriptional regulation in B. subtilis.
Effects of optogenetic stimulation of basal forebrain parvalbumin neurons on Alzheimer’s disease pathology
Authors: Wilson Caroline A , Fouda Sarah , Sakata Shuzo
Published: April 2020

Neuronal activity can modify Alzheimer’s disease pathology. Although overexcitation of neurons can facilitate disease progression, the induction of cortical gamma oscillations can reduce amyloid load and improve cognitive functions in mouse models. These beneficial effects of gamma oscillations can be caused by either optogenetic activation of cortical parvalbumin-positive (PV+) neurons or 40 Hz repetitive sensory stimuli. However, given the fact that cortical gamma oscillations can be induced by multiple mechanisms, it is still unclear whether other approaches to induce gamma oscillations can also be beneficial. Here we show that optogenetic activation of PV+ neurons in the basal forebrain (BF) increases amyloid burden, rather than reducing it. We applied 40 Hz optical stimulation in the BF of 5xFAD mice by expressing channelrhodopsin-2 (ChR2) in PV+ neurons. After one-hour induction of cortical gamma oscillations over three days, we observed the increase in the concentration of amyloid-β42 in the frontal cortical region, but not amyloid-β40. The density of amyloid plaques also increased in the medial prefrontal cortex and the septal nuclei, both of which are targets of BF PV+ neurons. These results suggest that effects of cortical gamma oscillations on Alzheimer’s disease pathology can be bidirectional depending on their induction mechanisms.

Significance Statement

Alzheimer’s disease (AD) is the most common cause of dementia. Although numerous molecular targets have been identified, the development of treatment is still a challenge. Accumulating evidence shows that artificial control of neuronal activity can modify AD pathology. In particular, the induction of cortical gamma (~40 Hz) oscillations can ameliorate AD pathology and improve cognitive functions. Here we show that optogenetic activation of parvalbumin-positive (PV+) neurons in the basal forebrain (BF) has opposite effects. By expressing channelrhodopsin-2 (ChR2) in PV+ neurons of an AD mouse model and optically stimulating BF PV+ neurons, we induced gamma oscillations and found increased amyloid burden. These results imply that AD pathology can be modified bidirectionally depending on induction mechanisms of gamma oscillations.
BD5: an open HDF5-based data format to represent quantitative biological dynamics data
Authors: Kyoda Koji , Ho Kenneth H. L. , Tohsato Yukako , Itoga Hiroya , Onami Shuichi
Published: April 2020

BD5 is a new binary data format based on HDF5 (hierarchical data format version 5). It can be used for representing quantitative biological dynamics data obtained from bioimage informatics techniques and mechanobiological simulations. Biological Dynamics Markup Language (BDML) is an XML(Extensible Markup Language)-based open format that is also used to represent such data; however, it becomes difficult to access quantitative data in BDML files when the file size is large because parsing XML- based files requires large computational resources to first read the whole file sequentially into computer memory. BD5 enables fast random (i.e., direct) access to quantitative data on disk without parsing the entire file. Therefore, it allows practical reuse of data for understanding biological mechanisms underlying the dynamics.
Coronavirus, as a source of pandemic pathogens
Authors: Konishi T.
Published: April 2020

The coronavirus and the influenza virus have similarities and differences. In order to comprehensively compare them, their genome sequencing data were examined by principal component analysis. Variations in coronavirus were smaller than those in a subclass of the influenza virus. In addition, differences among coronaviruses in a variety of hosts were small. These characteristics may have facilitated the infection of different hosts. Although many of the coronaviruses were more conservative, those repeatedly found among humans showed annual changes. If SARS-CoV-2 changes its genome like the Influenza H type, it will repeatedly spread every few years. In addition, the coronavirus family has many other candidates for subsequent pandemics.

One Sentence Summary

The genome data of coronavirus were compared to influenza virus, to investigate its spreading mechanism and future status. Coronavirus would repeatedly spread every few years. In addition, the coronavirus family has many other candidates for subsequent pandemics.
Machine Learning to Predict Mortality and Critical Events in COVID-19 Positive New York City Patients
Authors: Vaid Akhil , Somani Sulaiman , Russak Adam J , De Freitas Jessica K , Chaudhry Fayzan F , Paranjpe Ishan , Johnson Kipp W , Lee Samuel J , Miotto Riccardo , Zhao Shan , Beckmann Noam D , Naik Nidhi , Arfer Kodi , Kia Arash , Timsina Prem , Lala Anuradha , Paranjpe Manish , Glowe Patricia , Golden Eddye , Danieletto Matteo , Singh Manbir , Meyer Dara , O’Reilly Paul F , Huckins Laura H , Kovatch Patricia , Finkelstein Joseph , Freeman Robert M , Argulian Edgar , Kasarskis Andrew , Percha Bethany , Aberg Judith A , Bagiella Emilia , Horowitz Carol R , Murphy Barbara , Nestler Eric J , Schadt Eric E , Cho Judy H , Cordon-Cardo Carlos , Fuster Valentin , Charney Dennis S , Reich David L , Bottinger Erwin P , Levin Matthew A , Narula Jagat , Fayad Zahi A , Just Allan C , Charney Alexander W , Nadkarni Girish N , Glicksberg Benjamin S
Published: April 2020

Coronavirus 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become the deadliest pandemic in modern history, reaching nearly every country worldwide and overwhelming healthcare institutions. As of April 20, there have been more than 2.4 million confirmed cases with over 160,000 deaths. Extreme case surges coupled with challenges in forecasting the clinical course of affected patients have necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods for achieving this are lacking. In this paper, we use electronic health records from over 3,055 New York City confirmed COVID-19 positive patients across five hospitals in the Mount Sinai Health System and present a decision tree-based machine learning model for predicting in-hospital mortality and critical events. This model is first trained on patients from a single hospital and then externally validated on patients from four other hospitals. We achieve strong performance, notably predicting mortality at 1 week with an AUC-ROC of 0.84. Finally, we establish model interpretability by calculating SHAP scores to identify decisive features, including age, inflammatory markers (procalcitonin and LDH), and coagulation parameters (PT, PTT, D-Dimer). To our knowledge, this is one of the first models with external validation to both predict outcomes in COVID-19 patients with strong validation performance and identify key contributors in outcome prediction that may assist clinicians in making effective patient management decisions.

One-Sentence Summary

We identify clinical features that robustly predict mortality and critical events in a large cohort of COVID-19 positive patients in New York City.
Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes
Authors: Barnabei Laura , Lamrini Hicham , Castela Mathieu , Jeremiah Nadia , Stolzenberg Marie-Claude , Chentout Loïc , Jacques Sidonie , Bouafia Amine , Magérus-Chatinet Aude , Moncan Matthieu , Mirshahvalad Sajedeh , Pellé Olivier , Bondet Vincent , Duffy Darragh , Parisot Mélanie , Bras Marc , Uggenti Carolina , Salomon Rémi , Bodemer Christine , Rabant Marion , Cavazzana Marina , Miner J.J. , Belot Alexandre , Hié Miguel , Picard Capucine , Bader-Meunier Brigitte , Kracker Sven , Rieux-Laucat Frédéric
Published: April 2020

Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified twoRELAheterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.

Heterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.
Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer
Authors: Guillot Jérémy , Dominici Chloé , Lucchesi Adrien , Nguyen Thi Trang Huyen , Nigri Jérémy , Guillaumond Fabienne , Bigonnet Martin , Dusetti Nelson , Etzerodt Anders , Lawrence Toby , Pudlo Pierre , Hubert Florence , Scoazec Jean-Yves , van de Pavert Serge A. , Tomasini Richard , Chauvet Sophie , Mann Fanny
Published: April 2020

Recent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.
Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
Authors: Tsutsui Ko , Machida Hiroki , Morita Ritsuko , Nakagawa Asako , Sekiguchi Kiyotoshi , Miner Jeffrey H. , Fujiwara Hironobu
Published: April 2020

Inter-tissue interaction is fundamental to multicellularity. Although the basement membrane (BM) is located at tissue interfaces, its mode of action in inter-tissue interactions remains poorly understood, mainly because the molecular and structural details of the BM at distinct inter-tissue interfaces remain unclear. By combining quantitative transcriptomics and immunohistochemistry, we systematically identify the cellular origin, molecular identity and tissue distribution of extracellular matrix molecules in mouse hair follicles, and reveal that BM composition and architecture are exquisitely specialized for distinct inter-tissue interactions, including epidermal–fibroblast, epidermal–muscle and epidermal–nerve interactions. The epidermal–fibroblast interface, namely, hair germ–dermal papilla interface, makes asymmetrically organized side-specific heterogeneity in BM, defined by the newly characterized interface, hook and mesh BMs. One component of these BMs, laminin α5, is required for the topological and functional integrity of hair germ–dermal papilla interactions. Our study highlights the significance of BM heterogeneity in distinct inter-tissue interactions.
Disparate temperature-dependent virus – host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium
Authors: V’kovski Philip , Gultom Mitra , Kelly Jenna , Steiner Silvio , Russeil Julie , Mangeat Bastien , Cora Elisa , Pezoldt Joern , Holwerda Melle , Kratzel Annika , Laloli Laura , Wider Manon , Portmann Jasmine , Tran Thao , Ebert Nadine , Stalder Hanspeter , Hartmann Rune , Gardeux Vincent , Alpern Daniel , Deplancke Bart , Thiel Volker , Dijkman Ronald
Published: April 2020

Since its emergence in December 2019, SARS-CoV-2 has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human respiratory tract have been shown to affect the replication kinetics of several viruses, as well as host immune response dynamics, we investigated the impact of temperatures during SARS-CoV-2 and SARS-CoV infection in the human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated more efficiently at temperatures encountered in the upper respiratory tract, and displayed higher sensitivity to type I and type III IFNs. Time-resolved transcriptome analysis highlighted a temperature-dependent and virus-specific induction of the IFN-mediated antiviral response. These data reflect clinical features of SARS-CoV-2 and SARS-CoV, as well as their associated transmission efficiencies, and provide crucial insight on pivotal virus - host interaction dynamics.
Adiposome Targeting and Enzymatic Activity of Lipid Droplet-Specific Proteins
Authors: Ma Xuejing , Zhi Zelun , Zhang Shuyan , Zhou Chang , Mechler Adam , Liu Pingsheng
Published: April 2020

New strategies to decode the specific protein targeting mechanism on lipid droplet (LD) are urgently needed. Using adiposome, the LD binding of perilipin 2 (PLIN2), perilipin 3 (PLIN3), and adipose triglyceride lipase (ATGL) were studied. Scatchard analysis found that the binding of PLIN2 to the adiposome surface was saturable, pointing to a specific membrane binding partner. Phosphatidylinositol (PI) was found to inhibit PLIN2 binding while it did not impede PLIN3. Structural analysis combined with mutagenesis revealed that the 73rdglutamic acid of PLIN2 is significant for the effect of PI on the protein binding. The presence of PI significantly stimulated the activity of ATGLin vitro. The phosphorylation site mutants of ATGL were found reducing the lipase activity in the adiposome system. Our study demonstrates the utility of adiposome as a powerful, manipulatable model system for the characterization of LD binding and enzymatic activity of LD proteinsin vitro.
Optogenetic control of the Bone Morphogenetic Protein signalling pathway through engineered blue light-sensitive receptors
Authors: Humphreys Paul A. , Woods Steven , Smith Christopher A. , Cain Stuart A. , Lucas Robert , Kimber Susan J.
Published: April 2020

Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily and have crucial roles during development; including mesodermal patterning and specification of renal, hepatic and skeletal tissues.In vitrodevelopmental models currently rely upon costly and unreliable recombinant BMP proteins that do not enable dynamic or precise perturbation of the BMP signalling pathway. Here, we develop a novel optogenetic BMP signalling system (optoBMP) that enables rapid induction of the canonical BMP signalling pathway through illumination with blue light. We demonstrate the utility of the optoBMP system in multiple human cell lines to initiate signal transduction through phosphorylation and nuclear translocation of SMAD1/5, leading to upregulation of BMP target genes includingInhibitors of DNA binding ID2andID4. Furthermore, we demonstrate how the optoBMP system can be used to fine-tune activation of the BMP signalling pathway through variable light stimulation. Optogenetic control of BMP signalling will enable dynamic and high-throughput intervention across a variety of applications in cellular and developmental systems.
Withania somniferashowed neuroprotective effect and increase longevity inDrosophilaAlzheimer’s disease model
Authors: Halim Mardani Abdul , Rosli Izzah Madihah , Jaafar Siti Shafika Muhamad , Ooi Hoi-Min , Leong Pui-Wei , Shamsuddin Shaharum , Najimudin Nazalan , Azzam Ghows
Published: April 2020

Alzheimer’s disease is a complex neurodegenerative disease and is only unique to human. The disease is defined in human brain by the accumulation of amyloid beta in the parenchyma of the brain. Withania somnifera, commonly known as Ashwagandha is an Indian Ayurvedic medicine that has been used for centuries to treat countless range of human health problem. The active compound of Ashwagandha was shown to be beneficial in treating many neurodegenerative diseases including Alzheimer’s disease (AD). In this study,Drosophilamelanogaster AD model was used to study the effect of Ashwagandha on the toxicity of beta amyloid and also the longevity effect of the compound. We found that 20 mg/mL of Ashwagandha was shown to be effective in rescuing the “rough eye phenotype” of ADDrosophila. Furthermore, Ashwagandha also promotes longevity in AD as well as wild-typeDrosophila. The results above showed that Ashwagandha could potentially be a potent drug to treat AD as well as maintaining the wellbeing of cells.
Neurodegeneration-related beta-amyloid as autocatabolism-attenuator in amicro-in vivosystem
Authors: Balazs Evelin , Galik-Olah Zita , Galik Bence , Bozso Zsolt , Kalman Janos , Datki Zsolt
Published: April 2020

Investigation of human neurodegeneration-related aggregates of beta-amyloid 1-42 (Aβ42) on bdelloid rotifers is a novel interdisciplinary approach in life sciences. We reapplied an organ size-basedin vivomonitoring system, exploring the autocatabolism-related alterations evoked by Aβ42, in a glucose-supplemented starvation model. The experientially easy-to-follow size reduction of the bilateral reproductive organ (germovitellaria) in fasted rotifers was rescued by Aβ42, serving as a nutrient source- and peptide sequence-specific attenuator of the organ shrinkage phase and enhancer of the regenerative one including egg reproduction. Recovery of the germovitellaria was significant in comparison with the greatly shrunken form. In contrast to the well-known neurotoxic Aβ42 (except the bdelloids) with specific regulatory roles, the artificially designed scrambled version (random order of amino acids) was inefficient in autocatabolism attenuation, behaving as negative control. This native Aβ42-related modulation of the ‘functionally reversible organ shrinkage’ can be a potential experiential and supramolecular marker of autocatabolismin vivo.
Association of 4 epigenetic clocks with measures of functional health, cognition, and all-cause mortality in The Irish Longitudinal Study on Ageing (TILDA)
Authors: McCrory Cathal , Fiorito Giovanni , Hernandez Belinda , Polidoro Silvia , O’Halloran Aisling M. , Hever Ann , Cheallaigh Cliona Ni , Lu Ake T. , Horvath Steve , Vineis Paolo , Kenny Rose Anne
Published: April 2020

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes, and with all-cause mortality at up to 10-year follow-up in a sample of 490 participants in the Irish Longitudinal Study on Ageing. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes.
Loss of CNOT9 begets impairment in gastrulation leading to embryonic lethality
Authors: Sarmah Hemanta , Ito Kentaro , Kaneko Mari , Abe Takaya , Yamamoto Tadashi
Published: April 2020

The multi-subunit eukaryotic CCR4-NOT complex imparts gene expression control primarily via messenger RNA (mRNA) decay. Here, we present the role of subunit CNOT9 in target mRNA decay during embryonic development. CNOT9 null mice appear normal by the onset of gastrulation (E7.0), however, exhibit growth and differentiation defects accompanied by extensive cell death by embryonic day 9.5 (E9.5). Sox-2 Cre conditional CNOT9 knockout mice show almost identical phenotype with brief delay in onset and progression, suggesting defects to be epiblast-dominant. Among various identified targets, we show thatLefty2mRNA expression is post-transcriptionally regulated by CNOT9.Lefty2 3’-UTRcontaining mRNA has significantly higher stability in cells expressing mutant form of CNOT9, relative to cells expressing wild-type CNOT9. In addition, CNOT9 primarily localizes within the cytoplasm and bridges interactions between the CCR4-NOT complex and miRNA-RISC complex in gastrulating embryos.
Osteogenic differentiation potential and marker gene expression of different porcine bone marrow mesenchymal stem cell subpopulations selected in different basal media
Authors: Kannan Sangeetha , Ghosh Jyotirmoy , Dhara Sujoy K.
Published: April 2020

Multipotent porcine mesenchymal stem cells (pMSC) are indispensable for research and therapeutic use. Derivation and culture media might affect the selection of MSC subpopulation and thus the differentiation potential of cells. In this study we evaluated the effects of αMEM, aDMEM, M199, αMEM/M199, aDMEM/M199 and αMEM/aDMEM media on porcine bone marrow MSC derivation; pre-differentiation expression of ALP, COL1A1, SPP1 and BGLAP osteogenic marker genes at passage 5 and 10 pMSC; and differentiation potential of passage 5 pMSC. Morphological changes and matrix formation in osteogenic cells were evaluated by microscopical examination and calcium deposit in osteocytes was confirmed by Alizarin Red S staining. Results indicated media independent selection of different bone marrow MSC subpopulations with different surface marker gene expressions. Many pMSC subpopulations in different media had CD14+ expressing cells. We also observed basal media dependent changes in osteogenic markers expression and differentiation potential of pMSC. The αMEM/aDMEM media grown pMSC showed best osteogenic differentiation potential. We thus recommended the testing of αMEM/aDMEM mixed media in other species for pre-differentiation MSC culture that are intended for better osteogenic differentiation.

Pre-differentiation basal media influence osteogenic differentiation potential of mesenchymal stem cells (MSC). Among the tested media, αMEM/aDMEM was the best for pre-differentiation porcine MSC culture intending to use in osteogenesis.