bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is Netrin-1 Associated with the Development of Fibrosis in Systemic Sclerosis?
Authors: Maraş Yüksel , Kor Ahmet , Oğuz Esra Fırat , Sarı Alper , Gök Kevser , Akdoğan Ali 
Published: February 2022

AbstractBackgroundNetrin-1 is a laminin class protein that guides the axonal during the first embryonic development, has pushing and pulling properties, and has axonal chemoattractant activity. Netrin-1 has been shown to increase the effect of fibrosis in mouse lung and human SSc lung cell cultures. In this study, we aimed to investigate the relationship between Netrin-1 and Systemic sclerosis (SSc) and to emphasize the role of Netrin-1 in the pathophysiology of SSc by increasing the known VEGF and M2 macrophage expression, which supports the fibrotic process.MethodsThe study included 56 SSc patients with a mean age of 48·.08±13.59 years and 58 healthy volunteers with a mean age of 48.01±11.59 years. SSc organ involvements were scanned retrospectively from patient files, and patients were grouped according to SSc complications. Calculation of Netrin-1 levels was performed using a quantitative sandwich enzyme immunoassay method with an ELISA kit (Elabscience, Texas, USA; catalog number: E-EL-H2328; lot number: GZWTKZ5SWK). The modified Rodnan skin score (mRSS) was used for skin thickness scoring in SSc patients.ResultsThe median value of Netrin-1 was found to be significantly higher in SSc (268.8 [82.75-1006.64]) than in controls (108.63 [21.02-351.49]) (p<0.0001). In ROC analysis, a cut-off value of 354.24 for Netrin in SSc was found to provide a sensitive confidence interval with 32.8% sensitivity and 98.3% specificity (AUC[95% CI]: 0.746-0.895, p<0.0001). There was no significant correlation between Netrin-1 level, organ involvement in SSc, and mRSS (p>0.05).ConclusionWe found a significant relationship between Netrin-1 levels and SSc disease in this study. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients.
Biologically informed deep learning to infer gene program activity in single cells
Authors: Lotfollahi Mohammad , Rybakov Sergei , Hrovatin Karin , Hediyeh-zadeh Soroor , Talavera-López Carlos , Misharin Alexander V , Theis Fabian J. 
Published: February 2022

AbstractThe increasing availability of large-scale single-cell datasets has enabled the detailed description of cell states across multiple biological conditions and perturbations. In parallel, recent advances in unsupervised machine learning, particularly in transfer learning, have enabled fast and scalable mapping of these new single-cell datasets onto reference atlases. The resulting large-scale machine learning models however often have millions of parameters, rendering interpretation of the newly mapped datasets challenging. Here, we propose expiMap, a deep learning model that enables interpretable reference mapping using biologically understandable entities, such as curated sets of genes and gene programs. The key concept is the substitution of the uninterpretable nodes in an autoencoder’s bottleneck by labeled nodes mapping to interpretable lists of genes, such as gene ontologies, biological pathways, or curated gene sets, for which activities are learned as constraints during reconstruction. This is enabled by the incorporation of predefined gene programs into the reference model, and at the same time allowing the model to learnde novonew programs and refine existing programs during reference mapping. We show that the model retains similar integration performance as existing methods while providing a biologically interpretable framework for understanding cellular behavior. We demonstrate the capabilities of expiMap by applying it to 15 datasets encompassing five different tissues and species. The interpretable nature of the mapping revealed unreported associations between interferon signaling via the RIG-I/MDA5 and GPCRs pathways, with differential behavior in CD8+T cells and CD14+monocytes in severe COVID-19, as well as the role of annexins in the cellular communications between lymphoid and myeloid compartments for explaining patient response to the applied drugs. Finally, expiMap enabled the direct comparison of a diverse set of pancreatic beta cells from multiple studies where we observed a strong, previously unreported correlation between the unfolded protein response and asparagine N-linked glycosylation. Altogether, expiMap enables the interpretable mapping of single cell transcriptome data sets across cohorts, disease states and other perturbations.
Mechanistic origin of different binding affinities of SARS-CoV and SARS-CoV-2 spike RBDs to human ACE2
Authors: Zhang Zhi-Bi , Xia Yuan-Ling , Shen Jian-Xin , Du Wen-Wen , Fu Yun-Xin , Liu Shu-Qun 
Published: February 2022

AbstractThe receptor-binding domain (RBD) of the SARS-CoV-2 spike protein mediates viral entry into host cells through binding to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). It has been shown that SARS-CoV-2 RBD (RBDCoV2) has a higher binding affinity to human ACE2 than its highly homologous SARS-CoV RBD (RBDCoV), for which the mechanistic reasons still remain to be elucidated. Here, we used the multiple-replica molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, and interface residue contact network (IRCN) analysis approach to explore the mechanistic origin of different ACE2 binding affinities of these two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, the RBDCoV-ACE2 complex features the enhanced overall structural fluctuations and inter-protein positional movements and increased conformational entropy and diversity. The inter-protein electrostatic attractive interactions are a dominant force in determining the high ACE2 affinities of both RBDs, while the significantly strengthened electrostatic forces of attraction of ACE2 to RBDCoV2 determine the higher ACE2 binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue binding free energy components and IRCNs reveal that, although any RBD residue substitution involved in the charge change can significantly impact the inter-protein electrostatic interaction strength, it is the substitutions at the RBD interface that lead to the overall stronger electrostatic attractive force of RBDCoV2-ACE2, which in turn not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2 binding affinity of RBDCoV2 compared to that of RBDCoV. Since the RBD residue substitutions involving gain/loss of the positively/negatively charged residues, in particular those near/at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2, can greatly enhance the ACE2 binding affinity, the SARS-CoV-2 variants carrying such mutations should be paid special attention to.
Development of Prognostic Models for Survival and Care Status in Sporadic Creutzfeldt-Jakob disease
Authors: Nihat Akın , Ranson Janice M. , Harris Dominique , McNiven Kirsty , Rudge Peter , Collinge John , Llewellyn David J. , Mead Simon 
Published: February 2022

AbstractSporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. 537 patients were visited by mobile teams of doctors and nurses from the NHS National Prion Clinic within 5 days of notification of a suspected diagnosis of sCJD, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. 280 (52.1%) patients were female and the median age was 67.2 (IQR 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; MRC (Medical Research Council) Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical sCJD phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for MM compared to MV polymorphism; 95% CI 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sCJD patients using clinical, imaging and genetic data routinely available in a tertiary national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care.
Research Letter: Genetically determined blood pressure traits are associated with increased risk of aortic dissection: a Mendelian randomization study
Authors: Zhou Jiawei , Lin Jianfeng , Zheng Yuehong 
Published: February 2022

AbstractObjectiveTo identify blood pressure traits influencing aortic dissection susceptibility using Mendelian randomization (MR).MethodsSummary statistics of AD genome-wide association studies (GWAS) was obtained from FinnGen R5 release, which included 470 individuals with AD and 206541 controls. Firstly, inverse variance weighted (IVW) was used to calculate the overall OR for blood pressure traits. Further, directional pleiotropy and heterogeneity were tested as well as MR pleiotropy residual sum and outlier (MR-PRESSO) method.ResultsPositive associations were observed between DBP (OR=1.13, 95%CI 1.09-1.18, P-adjusted < 0.001), hypertension (OR=9.71, 95%CI 2.45-38.25, P-adjusted = 0.006) and AD. Further, there was potential causal relationship between MAP and AD (OR=1.15, 95%CI 1.02-1.30, P-unadjusted = 0.020). No significant association between SBP or PP and AD in the European populations were observed. No directional pleiotropy was observed. Heterogeneity was only detected in the genetic instruments for SBP (Cochran’s Q statistics = 491.7, P = 0.010). The MR-PRESSO suggested one outlier SNP for SBP and one for PP which did not affect the result above.ConclusionIn this study, we identified a forward causation between hypertension, SBP and AD. In addition, there were nominal significant causations between MAP and AD. No significant causal relationships were detected between other investigated blood pressure traits (SBP, PP) and AD.
Protection of COVID-19 vaccination and previous infection against Omicron BA.1, BA.2 and Delta SARS-CoV-2 infections
Authors: Andeweg Stijn P. , de Gier Brechje , Eggink Dirk , van den Ende Caroline , van Maarseveen Noortje , Ali Lubna , Vlaemynck Boris , Schepers Raf ,   RIVM COVID-19 surveillance and epidemiology team, Hahné Susan J.M. , Reusken Chantal B.E.M. , de Melker Hester E. , van den Hof Susan , Knol Mirjam J. 
Published: February 2022

AbstractGiven the emergence of the SARS-CoV-2 Omicron BA.1 and BA.2 variants and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection by variant.We employed a test-negative design and used multinomial logistic regression on data from community PCR testing in the Netherlands. S-gene target failure (SGTF) was used as proxy to discern Delta, Omicron BA.1 and Omicron BA.2 infections. Two cohorts were defined to assess protection from vaccination and previous infection by variant: Delta-Omicron BA.1 cohort including data from 22 November 2021 to 7 January 2022 (n = 354,653) and Omicron BA.1-BA.2 cohort including data from 26 January to 31 March 2022 (n = 317,110).In the Delta-Omicron BA.1 cohort, including 39,889 Delta and 13,915 Omicron BA.1 infections, previous infection, primary vaccination or both protected well against Delta infection (76%, 71%, 92%, respectively, at 7+ months after infection or vaccination). Protection against Omicron BA.1 was much lower compared to Delta infections, but BA.1 estimates were imprecise. In the Omicron BA.1-BA.2 cohort, including 67,887 BA.1 and 41,670 BA.2 infections, protection was similar against Omicron BA.1 compared to BA.2 infection for previous infection (34 and 38% at 7+ months post-infection), primary (39 and 32% at 7+ months post-vaccination) and booster vaccination (68 and 63% at 1 month post-vaccination). Higher protection was observed against all variants in individuals with both vaccination and previous infection compared with either one. Protection against all variants by either vaccination or infection decreased over time since last vaccination or infection.Primary vaccination with current COVID-19 vaccines and previous SARS-CoV-2 infections offer low protection against Omicron BA.1 and BA.2 infection. Booster vaccination considerably increases protection against Omicron infection, but decreases rapidly after vaccination.
Early genomic, epidemiological, and clinical description of the SARS-CoV-2 Omicron variant in Mexico City
Authors: Cedro-Tanda Alberto , Gómez-Romero Laura , Anda-Jauregui Guillermo de , Garnica-López Dora , Alfaro-Mora Yair , Sánchez-Xochipa Sonia , García-García F. Eulices , Mendoza-Vargas Alfredo , Frías-Jiménez J. Emmanuel , Moreno-Quiroga Bernardo , Campos-Romero Abraham , Luis Moreno-Camacho José , Alcantar-Fernández Jonathan , Ortíz-Ramírez Jesús , Benitez-Gonzalez Mariana , Trejo-Gonzalez Roxana , Aguirre-Chavarria Daniel , Núñez-Martínez Marcela E. , Uribe-Figueroa Laura , Angulo Ofelia , Ruiz Rosaura , Hidalgo-Miranda Alfredo , Herrera Luis A 
Published: February 2022

AbstractBackgroundOmicron is the most mutated SARS-CoV-2 variant that has emerged, resulting in viral phenotype alterations, which can affect transmissibility, disease severity, and immune evasiveness. Genomic surveillance of a highly transmissible variant is important in cities with millions of inhabitants and an economic center such as Mexico City. In this work, we describe the early effects of the Omicron variant in Mexico City, exploring its genomic profile and clinical description.MethodologyWe sequenced SARS-CoV-2-positive samples in November and December 2021 and we using the public database GISAID. Haplotype and phylogenetic analyses were performed to genomically characterize Omicron. We used the Mexican federal database toexplore the association with clinical information such as symptoms and vaccination status.FindingsThe first case of Omicron was detected on November 16, 2022, and until December 31, 2021, we observed an increase from 88% in sequenced samples. Nineteen nonsynonymous mutations were found in the Omicron RBD, and we further explored the R346K substitution, which was prevalent in 42% of the samples and associated with immune escape by monoclonal antibodies. In the phylogenetic analysis, we found that there were several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. The haplotype analysis allowed us to observe that there was no association between haplotype and vaccination status. Of the patients with clinical data, 66% were vaccinated, none of the reported comorbidities were associated with Omicron, the presence of odynophagia and absence of dysgeusia were significant predictor symptoms for Omicron, and the Ct value on RT–qPCR was lower in Omicron.ConclusionsGenomic surveillance in highly populated and fast-moving urban regions such as Mexico City is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, to detect patterns that can inform public health decisions. It is also necessary to continue sequencing to detect the spread of any mutation that may affect the therapeutic efficacy or guide it.
Cumulative seroprevalence among healthcare workers after the first wave of the COVID-19 pandemic in El Salvador, Central America
Authors: Nakagama Yu , Rodriguez-Funes Maria-Virginia , Dominguez Rhina , Candray-Medina Katherine-Sofia , Uemura Naoto , Tshibangu-Kabamba Evariste , Nitahara Yuko , Kaku Natsuko , Kaneko Akira , Kido Yasutoshi 
Published: February 2022

AbstractBackgroundThe impact of novel coronavirus disease 2019 (COVID-19) on healthcare workers (HCWs) has been under-evaluated in Central America. We performed a seroepidemiological survey at a tertiary healthcare facility in El Salvador, where a large number of confirmed and far more suspected cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected HCWs had been documented during the first wave of the pandemic.MethodsDuring January–February 2021, a total 973 HCWs were tested for SARS-CoV-2 antibodies. Participants completed a questionnaire asking of their demographic data. Occupational risk was assessed by statistically comparing the seropositivity rates among different occupational categories.ResultsOverall seroprevalence in HCWs reached 52.6% (512 of 973). Of the seropositive individuals, 61.7% (316 of 512) had experienced a documented COVID-19 diagnosis, while the remaining 38.3% (196 of 512) were unrecognized seroconversions. Differences in seropositivity rates existed between occupational categories; nurses demonstrated the highest at 63.8% (222 of 348, risk ratio 1.44, p < 0.0001), followed by auxiliary HCWs assigned to patient-related work (55.9%, 52 of 93), and medical doctors (46.7%, 50 of 107). Several non-patient-related professions showed above-average seroprevalence, suggesting substantial SARS-CoV-2 contacts outside the workplace: 60.0% (6 of 10) and 68.0% (17 of 25) for nutritionists and pharmacists, respectively.ConclusionsSARS-CoV-2 seroprevalence exceeded 50% among HCWs in El Salvador, with disparity among occupational categories with different workplace exposure risks. Importance of not only nosocomial infection prevention but also screening for transmissions having occurred outside the workplace were highlighted to efficiently control nosocomial spreads during a pandemic wave.Key pointsHealthcare workers in El Salvador were tested for SARS-CoV-2 antibodies. Seroprevalence reached 52.6%, with disparity among occupation; nurses ranked highest at 63.8% seropositivity. Alongside nosocomial transmissions, high seroprevalence associated with non-patient-related work suggested substantial SARS-CoV-2 contacts outside the workplace.
Development of a Ribosome Profiling Protocol to Study Translation in the yeast Kluyveromyces marxianus
Authors: Fenton Darren A , Kiniry Stephen J , Yordanova Martina M , Baranov Pavel V , Morrissey John P 
Published: February 2022

AbstractKluyveromyces marxianus is an interesting and important yeast because of particular traits like thermotolerance and rapid growth, and applications in food and industrial biotechnology. Knowing how K. marxianus responds and adapts to changing environments is important to achieve a full understanding of the its biology and to develop bioprocesses. For this, a full suite of omics tools to measure and compare global patterns of gene expression and protein synthesis is needed. Whereas transcriptome analysis by RNA-Seq quantifies mRNA abundance, ribosome profiling allows codon-resolution of translation on a genome-wide scale by deep sequencing of ribosome locations on mRNAs and is emerging as a valuable tool to study translation control of gene expression. We report here the development of a ribosome profiling method for K. marxianus and we make the procedure available as a step by step protocol. To aid in the analysis and sharing of ribosome profiling data, we also added the K. marxianus genome as well as transcriptome and ribosome profiling data to the publicly accessible GWIPS-viz and Trips-Viz browsers. Users are able to upload custom ribosome profiling and RNA-Seq data to both browsers, therefore allowing easy analysis and sharing of data. As many studies only focus on the use of RNA-Seq to study K. marxianus in different environments, the availability of ribosome profiling is a powerful addition to the K. marxianus toolbox.Graphical abstractDevelopment of a Ribosome Profiling protocol to study gene expression in the thermotolerant yeast Kluyveromyces marxianus.
Entrainment to sleep spindles reflects dissociable patterns of connectivity between cortex and basal ganglia
Authors: Mizrahi-Kliger Aviv D. , Kaplan Alexander , Israel Zvi , Bergman Hagai 
Published: February 2022

AbstractCommunication between the basal ganglia (BG) and cortex is crucial for behavior as it allows learning through external reinforcement. Non-REM sleep benefits learning in the corticostriatal system through the sleep spindle-associated reactivation of previously active neuronal ensembles and the subsequent modification of synaptic weights. However, how sleep spindles coordinate cross-region spiking, and whether spindle-driven reactivation occurs in other BG structures, remains unknown. We recorded field potentials (FP) and spiking activity in cortex and BG during sleep in two non-human primates immediately following a task that involved the learning of new cue-reward contingencies. FP sleep spindles were widespread in the BG, and they were similar to cortical spindles in morphology, spectral content and response to learning prior to sleep. Further, BG FP spindles were concordant with EEG spindles and associated with increased cortico-BG correlation. However, spindles across the BG differed markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibited consistent phase locking to striatal FP spindles and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, in the subthalamic nucleus (STN), which like the striatum receives substantial thalamocortical input, and in BG nuclei downstream to the striatum and STN, neuronal firing was not entrained to either local or EEG sleep spindles. These results dissociate striatal projection neurons from the rest of the BG, and suggest corticostriatal synapses as the main hub for offline communication between cortex and BG.
Assessing human genome-wide variation in the Massim region of Papua New Guinea and implications for the Kula trading tradition
Authors: Liu Dang , Peter Benjamin M. , Schiefenhövel Wulf , Kayser Manfred , Stoneking Mark 
Published: February 2022

AbstractThe Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.