bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection
Authors: Te Nigeer , Rodon Jordi , Ballester Maria , Pérez Mónica , Pailler-García Lola , Segalés Joaquim , Vergara-Alert Júlia , Bensaid Albert 
Published: November 2020

ABSTRACTWhile MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.
The novel PII-interacting protein PirA regulates flux into the cyanobacterial ornithine-ammonia cycle
Authors: Bolay Paul , Muro-Pastor M. Isabel , Rozbeh Rokhsareh , Timm Stefan , Hagemann Martin , Florencio Francisco J. , Forchhammer Karl , Klähn Stephan 
Published: November 2020

AbstractAmong prokaryotes, cyanobacteria have an exclusive position due to the fact that they perform oxygenic photosynthesis. Cyanobacteria substantially differ from other bacteria in further aspects, e.g. they evolved a plethora of unique regulatory mechanisms to control primary metabolism. This is exemplified by the regulation of glutamine synthetase (GS) via small proteins termed inactivating factors (IFs). Here we reveal another small, 51 amino acid protein, which is encoded by thessr0692gene, to regulate flux into the ornithine-ammonia cycle (OAC), the key hub of cyanobacterial nitrogen stockpiling and remobilization. This regulation is achieved by the interaction with the central carbon/nitrogen control protein PII, which commonly controls the entry into the OAC by activating the key enzyme of arginine synthesis, N-acetyl-L-glutamate kinase (NAGK). We suggest that Ssr0692 competes with NAGK for PIIbinding and thereby prevents NAGK activation, which in turn lowers arginine synthesis. Accordingly, we termed itPII-interacting regulator ofarginine synthesis (PirA). Similar to the GS IFs, PirA accumulates in response to ammonium upshift due to relief from repression by the global nitrogen-control transcription factor NtcA. Consistently, deletion of PirA affects the cell to balance metabolite pools of the OAC in response to ammonium shocks. Moreover, its interaction with PIIrequires ADP and is prevented by PIImutations affecting the T-loop conformation, the major protein-interaction surface of this signal processing protein. Thus, we propose that PirA is an integrator determining flux into N storage compounds not only depending on the N availability but also the energy state of the cell.ImportanceCyanobacteria contribute a significant portion to the annual oxygen yield and play important roles in biogeochemical cycles, e.g. as major primary producers. Due to their photosynthetic lifestyle cyanobacteria also arouse interest as hosts for the sustainable production of fuel components and high-value chemicals. However, their broad application as microbial cell factories is hampered by limited knowledge about the regulation of metabolic fluxes in these organisms. Our research identified a novel regulatory protein that controls nitrogen flux, in particular arginine synthesis in the cyanobacterial model strainSynechocystissp. PCC 6803. Beside its role as proteinogenic amino acid, arginine is a precursor for the cyanobacterial storage compound cyanophycin, which is of potential interest to biotechnology. The obtained results will therefore not only enhance our understanding of flux control in these organisms, it will also help to provide a scientific fundament for targeted metabolic engineering and hence the design of photosynthesis-driven biotechnological applications.
Bidirectional redox cycling of phenazine-1-carboxylic acid byCitrobacter portucalensisMBL drives increased nitrate reduction
Authors: Tsypin Lev M. , Newman Dianne K. 
Published: November 2020

ABSTRACTPhenazines are secreted metabolites that microbes use in diverse ways, from quorum sensing to antimicrobial warfare to energy conservation. Phenazines are able to contribute to these activities due to their redox activity. The physiological consequences of cellular phenazine reduction have been extensively studied, but the counterpart phenazine oxidation has been largely overlooked. Phenazine-1-carboxylic acid (PCA) is common in the environment and readily reduced by its producers. Here, we describe its anaerobic oxidation byCitrobacter portucalensisstrain MBL, which was isolated from topsoil in Falmouth, MA, and which does not produce phenazines itself. This activity depends on the availability of a suitable terminal electron acceptor, specifically nitrate or fumarate. WhenC. portucalensisMBL is provided reduced PCA and either nitrate or fumarate, it continuously oxidizes the PCA. We compared this terminal electron acceptor-dependent PCA-oxidizing activity ofC. portucalensisMBL to that of several other γ-proteobacteria with varying capacities to respire nitrate and/or fumarate. We found that PCA oxidation by these strains in a fumarate-or nitrate-dependent manner is decoupled from growth and correlated with their possession of the fumarate or periplasmic nitrate reductases, respectively. We infer that bacterial PCA oxidation is widespread and genetically determined. Notably, reduced PCA enhances the rate of nitrate reduction to nitrite byC. portucalensisMBL beyond the stoichiometric prediction, which we attribute toC. portucalensisMBL’s ability to also reduce oxidized PCA, thereby catalyzing a complete PCA redox cycle. This bidirectionality highlights the versatility of PCA as a biological redox agent.IMPORTANCEPhenazines are increasingly appreciated for their roles in structuring microbial communities. These tricyclic aromatic molecules have been found to regulate gene expression, be toxic, promote antibiotic tolerance, and promote survival under oxygen starvation. In all of these contexts, however, phenazines are studied as electron acceptors. Even if their utility arises primarily from being readily reduced, they would need to be oxidized in order to be recycled. While oxygen and ferric iron can oxidize phenazines abiotically, biotic oxidation of phenazines has not been studied previously. We observed bacteria that readily oxidize phenazine-1-carboxylic acid (PCA) in a nitrate-dependent fashion, concomitantly increasing the rate of nitrate reduction to nitrite. Because nitrate is a prevalent terminal electron acceptor in diverse anoxic environments, including soils, and phenazine-producers are widespread, this observation of linked phenazine and nitrogen redox cycling suggests an underappreciated role for redox-active secreted metabolites in the environment.
The experience of distress during the COVID-19 outbreak: a cross-country examination on the fear of COVID-19 and the sense of loneliness
Authors: Coco Gianluca Lo , Gentile Ambra , Bosnar Ksenija , Milovanovic Ivana , Bianco Antonino , Drid Patrik , Pišot Saša 
Published: November 2020

AbstractObjectivesTo examine gender, age and cross-country differences in fear of COVID-19 and sense of loneliness during the lockdown, by comparing people from countries with a high rate of infections and deaths (i.e. Spain and Italy) and from countries with a mild spread of infection (i.e. Croatia, Serbia, Slovakia, Slovenia, Bosnia and Herzegovina).MethodsA total of 3876 participants (63% female) completed an online survey on “Everyday life practices in COVID-19 time” in April 2020, including measures of fear of COVID-19 and loneliness.ResultsMales and females of all age groups in countries suffering from a strong impact of the COVID-19 pandemic reported higher fear of COVID-19 and sense of loneliness. In less endangered countries females and elder stated more symptoms than males and younger; in Spanish and Italian sample the pattern of differences is considerably more complex.ConclusionFuture research should thoroughly examine different age and gender groups. The analysis of emotional well-being in groups at risk of mental health issues can help to lessen the long term social and economic costs due to the COVID-19 outbreak.
Embryo classification beyond pregnancy: Early prediction of first trimester miscarriage using machine learning
Authors: Amitai Tamar , Kan-Tor Yoav , Srebnik Naama , Buxboim Amnon 
Published: November 2020

ABSTRACTObjectiveDevelop a machine learning classifier for predicting the risk of cleavage-stage embryos to undergo first trimester miscarriage based on time-lapse images of preimplantation development.DesignRetrospective study of a 4-year multi-center cohort of women undergoing intra-cytoplasmatic sperm injection (ICSI). The study included embryos with positive indication of clinical implantation based on gestational sac visualization either with first trimester miscarriage or live birth outcome. Miscarriage was determined based on negative fetal heartbeat indication during the first trimester.SettingData were recorded and obtained in hospital setting and research was performed in university setting.Patient(s)Data from 391 women who underwent fresh single or double embryo transfers were included.Intervention(s)None.Main Outcome Measure(s)A minimal subset of six non-redundant morphodynamic features were screened that maintain high prediction capacity. Using this feature subset, XGBoost and Random Forest models were trained following a 100-fold Monte-Carlo cross validation scheme. Feature importance was scored using the SHapley Additive exPlanations (SHAP) methodology. Miscarriage versus live-birth outcome prediction was evaluated using a non-contaminated balanced test set and quantified in terms of the area under the receiver operating characteristic (ROC) curve (AUC), precision-recall curve, positive predictive value (PPV), and confusion matrices.Result(s)Features that account for the distribution of the nucleolus precursor bodies within the small pronucleus and pronuclei dynamics were highly predictive of miscarriage outcome. AUC for miscarriage prediction of validation and test set embryos using both models was 0.68-to-0.69. Clinical utility was tested by setting two classification thresholds accounting for high sensitivity 0.73 with 0.6 specificity and high specificity 0.93 with 0.33 sensitivity.Conclusion(s)We report the development of a decision-support tool for identifying the embryos with high risk of miscarriage. Prioritizing embryos for transfer based on their predicted risk of miscarriage in combination with their predicted implantation potential will improve live-birth rates and shorten time-to-pregnancy.CapsuleThe risk of first trimester miscarriage of cleavage stage embryos is predicted with AUC 68% by screening a minimal subset of six non-redundant morpho-dynamic features and training a machine-learning classifier.
Glucolipotoxicity-induced Mig6 desensitizes EGFR signaling and promotes pancreatic beta cell death
Authors: Chen Yi-Chun , Lutkewitte Andrew J. , Basavarajappa Halesha D. , Fueger Patrick T. 
Published: November 2020

ABSTRACTA loss of functional beta cell mass is a final etiological event in the development of frank type 2 diabetes (T2D). To preserve or expand beta cells and therefore treat/prevent T2D, growth factors have been considered therapeutically but have largely failed to achieve robust clinical success. The molecular mechanisms preventing the activation of mitogenic signaling pathways from maintaining functional beta cell mass during the development of T2D remain unknown. We speculated that endogenous negative effectors of mitogenic signaling cascades impede beta cell survival/expansion. Thus, we tested the hypothesis that a stress-inducible epidermal growth factor receptor (EGFR) inhibitor, Mitogen-inducible gene 6 (Mig6), regulates beta cell fate in a T2D milieu. To this end, we determined that: 1) glucolipotoxicity (GLT) induces Mig6, thereby blunting EGFR signaling cascades, and 2) Mig6 mediates molecular events regulating beta cell survival/death. We discovered that GLT impairs EGFR activation, and Mig6 is elevated in human islets from T2D donors as well as GLT-treated rodent islets and 832/13 INS-1 beta cells. Mig6 is essential for GLT-induced EGFR desensitization, as Mig6 suppression rescued the GLT-impaired EGFR and ERK1/2 activation. Further, Mig6 mediated EGFR but not insulin-like growth factor-1 receptor nor hepatocyte growth factor receptor activity in beta cells. Finally, we identified that elevated Mig6 augmented beta cell apoptosis, as Mig6 suppression reduced apoptosis during GLT. In conclusion, we established that T2D and GLT induce Mig6 in pancreatic beta cells. The elevated Mig6 desensitizes EGFR signaling and induces beta cell death. Our findings suggest that Mig6 could be a novel therapeutic target for T2D, as blocking Mig6 could possibly enhance mitogenic signaling cascades in a diabetic milieu to promote beta cell survival and prevent beta cell death.
Hacking The Diversity Of SARS-CoV-2 And SARS-Like Coronaviruses In Human, Bat And Pangolin Populations
Authors: Dimonaco Nicholas J. , Salavati Mazdak , Shih Barbara 
Published: November 2020

AbstractIn 2019, a novel coronavirus, SARS-CoV-2/nCoV-19, emerged in Wuhan, China, and has been responsible for the current COVID-19 pandemic. The evolutionary origins of the virus remain elusive and understanding its complex mutational signatures could guide vaccine design and development. As part of the international “CoronaHack” in April 2020 (https://www.coronahack.co.uk/), we employed a collection of contemporary methodologies to compare the genomic sequences of coronaviruses isolated from human (SARS-CoV-2;n=163), bat (bat-CoV;n=215) and pangolin (pangolin-CoV;n=7) available in public repositories. Followingde novogene annotation prediction, analyses of gene-gene similarity network, codon usage bias and variant discovery were undertaken. Strong host-associated divergences were noted in ORF3a, ORF6, ORF7a, ORF8 and S, and in codon usage bias profiles. Lastly, we have characterised several high impact variants (inframe insertion/deletion or stop gain) in bat-CoV and pangolin-CoV populations, some of which are found in the same amino acid position and may be highlighting loci of potential functional relevance.
Identifying genetic variants associated with cerebellar volume in 33,265 individuals from the UK-Biobank
Authors: Chambers Tom , Escott-Price Valentina , Legge Sophie , Baker Emily , Singh Krish D. , Walters James TR , Caseras Xavier , Anney Richard JL 
Published: November 2020

AbstractThere is expanding interest in researching the cerebellum given accumulating evidence of its important contributions to cognitive and emotional functions, in addition to more established sensorimotor roles. While large genome-wide association studies (GWAS) have shed light on the common allele architecture of cortical and subcortical brain structures, the cerebellum remains under investigated. We conducted a meta-GWAS of cerebellar volume in 33,265 UK-Biobank European participants. Results show cerebellar volume to be moderately heritable (h2SNP=50.6%). We identified 33 independent genome-wide associated SNPs with total cerebellar volume, with 6 of these SNPs mapped to protein-coding genes and 5 more shown to alter cerebellar gene expression. We highlight 21 unique candidate genes for follow-up analysis. Cerebellar volume showed significant genetic correlation with brainstem, pallidum and thalamus volumes, but no significant correlations with neuropsychiatric phenotypes. Our results provide important new knowledge of the genetic architecture of cerebellar volume and its relationship with other brain phenotypes.
In vitro immunization approach to generate specific murine monoclonal IgG antibodies
Authors: Michelchen Sophia , Micheel Burkhard , Hanack Katja 
Published: November 2020

AbstractGenerating monoclonal antibodies to date is a time intense process requiring immunization of laboratory animals. The transfer of the humoral immune response intoin vitrosettings shortens this process and circumvents the necessity of animal immunization. However, orchestrating the complex interplay of immune cellsin vitrois very challenging. We aimed for a simplified approach focusing on the protagonist of antibody production: the B lymphocyte. We activated purified murine B lymphocytesin vitrowith combinations of antigen and stimuli. Within ten days of culture we induced specific IgM and IgG antibody responses against a viral coat protein. Permanently antibody-producing hybridomas were generated. Furthermore we used this method to induce a specific antibody response againstLegionella pneumophila. We thus established an effective protocol to generate monoclonal antibodiesin vitro. By overcoming the necessity ofin vivoimmunization it may be the first step towards a universal strategy to generate antibodies from various species.
PARKIN REGULATES DRUG TAKING-BEHAVIOR IN RAT MODEL OF METHAMPHETAMINE USE DISORDER
Authors: Sharma Akhil , Harutyunyan Arman , Schneider Bernard L. , Moszczynska Anna 
Published: November 2020

ABSTRACTThere is no FDA-approved medication for Methamphetamine (METH) Use Disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH Use Disorder. PARKIN knockout, PARKIN-overexpressing and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH Use Disorder, and identify PARKIN as a novel potential drug target to treat heavy use of METH.
Chromatin Accessibility Maps Provide Evidence of Multilineage Gene Priming in Hematopoietic Stem Cells
Authors: Martin Eric W. , Krietsch Jana , Reggiardo Roman E. , Sousae Rebekah , Kim Daniel H. , Forsberg E. Camilla 
Published: November 2020

ABSTRACTHematopoietic stem cells (HSCs) have the capacity to differentiate into vastly different types of mature blood cells. The epigenetic mechanisms regulating the multilineage ability, or multipotency of HSCs are not well understood. To test the hypothesis thatcisregulatory elements that control fate decisions for all lineages are primed in HSCs, we used ATAC-seq to compare chromatin accessibility of HSCs with five unipotent cell types. We observed the highest similarity in accessibility profiles between Megakaryocyte Progenitors and HSCs, whereas B cells had the greatest number of regions withde novogain in accessibility during differentiation. Despite these differences, we identifiedcisregulatory elements from all lineages that displayed epigenetic priming in HSCs. These findings provide new insights into the regulation of stem cell multipotency, as well as a resource to identify functional drivers of lineage fate.HIGHLIGHTSHSCs have higher global chromatin accessibility than any unilineage progenyMegakaryocyte Progenitors are the most closely related unipotent cell type to HSCsB cell commitment involvesde novochromatin accessibilityEvidence ofciselement priming of lineage-specific genes in HSCs