bluuebunny/crossref_metadata_2025 huggingface dataset:
The potential impact of Omicron and future variants of concern on SARS-CoV-2 transmission dynamics and public health burden: a modelling study
Authors: Le Rutte Epke A , Shattock Andrew J , Chitnis Nakul , Kelly Sherrie L , Penny Melissa A
Published: December 2021

SARS-CoV-2 variant Omicron (B.1.1.529) was classified as a variant of concern (VOC) on November 26, 2021. (1, 2) The infectivity, severity, and immune evasion properties of Omicron relative to the Delta variant would determine 1) the probability of dominant future transmission, and 2) the impact on disease burden. (3, 4) Here we apply individual-based transmission model OpenCOVID to identify thresholds for Omicron’s or any VOC’s potential future dominance, impact on health, and risk to health systems; and identify for which combinations of viral properties, current interventions would be sufficient to control transmission. We show that, with first-generation SARS-CoV-2 vaccines (5) and limited physical distancing in place, the threshold for Omicron’s future dominance was primarily be driven by its degree of infectivity. However, we identified that a VOC’s potential dominance will not necessarily lead to increased public health burden. Expanded vaccination, that includes a third-dose for adults and child vaccination strategies, was projected to have the biggest public health benefit for a highly infective, highly severe VOC with low immune evasion capacity. However, a highly immune evading variant that becomes dominant would likely require alternative measures for control, such as strengthened physical distancing measures, novel treatments, and second-generation vaccines. These findings provide quantitative guidance to decision-makers at a critical time while Omicron’s properties are being assessed and preparedness for new VOC’s is eminent. (6) We emphasize the importance of both genomic and population epidemiological surveillance.
Black chromatin is indispensable for accurate simulations of Drosophila melanogaster chromatin structure
Authors: Tuszynska Irina , Bednarz Pawel , Wilczynski Bartek
Published: December 2021

The interphase chromatin structure is extremely complex, precise and dynamic. Experimental methods can only show the frequency of interaction of the various parts of the chromatin. Therefore, it is extremely important to develop theoretical methods to predict the chromatin structure. In this publication, we describe the necessary factors for the effective modeling of the chromatin structure in Drosophila melanogaster. We also compared Monte Carlo with Molecular Dynamic methods. We showed that incorporating black, non-reactive chromatin is necessary for successfully prediction of chromatin structure, while the loop extrusion model or using Hi-C data as input are not essential for the basic structure reconstruction.

Abstract Figure
Dynamics of CTCF and cohesin mediated chromatin looping revealed by live-cell imaging
Authors: Gabriele Michele , Brandão Hugo B. , Grosse-Holz Simon , Jha Asmita , Dailey Gina M. , Cattoglio Claudia , Hsieh Tsung-Han S. , Mirny Leonid , Zechner Christoph , Hansen Anders S.
Published: December 2021

Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and cohesin, but whether these loops are stable or dynamic is unknown. Here, we directly visualize chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantify looping dynamics by Bayesian inference. Our results are consistent with cohesin-mediated loop extrusion in cells, and with CTCF both stopping and stabilizing cohesin. Surprisingly, the Fbn2 loop is both rare and dynamic, with a looped fraction of ~3-6.5% and a median loop lifetime of ~10-30 minutes. Instead of a stable loop, our results establish a highly dynamic view of TADs and loops where the Fbn2 TAD exists predominantly in a partially extruded conformation. This dynamic and quantitative view of TADs may facilitate a mechanistic understanding of their functions.
Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift
Authors: Cameroni Elisabetta , Saliba Christian , Bowen John E. , Rosen Laura E. , Culap Katja , Pinto Dora , VanBlargan Laura A. , De Marco Anna , Zepeda Samantha K. , Iulio Julia di , Zatta Fabrizia , Kaiser Hannah , Noack Julia , Farhat Nisar , Czudnochowski Nadine , Havenar-Daughton Colin , Sprouse Kaitlin R. , Dillen Josh R. , Powell Abigail E. , Chen Alex , Maher Cyrus , Yin Li , Sun David , Soriaga Leah , Bassi Jessica , Silacci-Fregni Chiara , Gustafsson Claes , Franko Nicholas M. , Logue Jenni , Iqbal Najeeha Talat , Mazzitelli Ignacio , Geffner Jorge , Grifantini Renata , Chu Helen , Gori Andrea , Riva Agostino , Giannini Olivier , Ceschi Alessandro , Ferrari Paolo , Cippà Pietro , Franzetti-Pellanda Alessandra , Garzoni Christian , Halfmann Peter J. , Kawaoka Yoshihiro , Hebner Christy , Purcell Lisa A. , Piccoli Luca , Pizzuto Matteo Samuele , Walls Alexandra C. , Diamond Michael S. , Telenti Amalio , Virgin Herbert W. , Lanzavecchia Antonio , Veesler David , Snell Gyorgy , Corti Davide
Published: December 2021

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb1, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab2, S2X2593 and S2H974, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.
genomicSimulation: fast R functions for stochastic simulation of breeding programs
Authors: Villiers Kira , Dinglasan Eric , Hayes Ben J. , Voss-Fels Kai P.
Published: December 2021

Simulation tools are key to designing and optimising breeding programs that are multi-year, high-effort endeavours. Tools that operate on real genotypes and integrate easily with other analysis software are needed to guide users to crossing decisions that best balance genetic gains and diversity to maintain gains in the future. This paper presents genomicSimulation, a fast and flexible tool for the stochastic simulation of crossing and selection on real genotypes. It is fully written in C for high execution speeds, has minimal dependencies, and is available as an R package for integration with R’s broad range of analysis and visualisation tools. Comparisons of a simulated recreation of a breeding program to the real data shows that the tool’s simulated offspring correctly show key population features, such as linkage disequilibrium patterns and genomic relationships. Both versions of genomicSimulation are freely available on GitHub: The R package version at https://github.com/vllrs/genomicSimulation/ and the C library version at https://github.com/vllrs/genomicSimulationC/
Randomized controlled trial transfusing convalescent plasma as post-exposure prophylaxis against SARS-CoV-2 infection
Authors: Shoham Shmuel , Bloch Evan M , Casadevall Arturo , Hanley Daniel , Lau Bryan , Gebo Kelly , Cachay Edward , Kassaye Seble G. , Paxton James H. , Gerber Jonathan , Levine Adam C , Currier Judith , Patel Bela , Allen Elizabeth S. , Anjan Shweta , Appel Lawrence , Baksh Sheriza , Blair Paul W. , Bowen Anthony , Broderick Patrick , Caputo Christopher A , Cluzet Valerie , Cordisco Marie Elena , Cruser Daniel , Ehrhardt Stephan , Forthal Donald , Fukuta Yuriko , Gawad Amy L. , Gniadek Thomas , Hammel Jean , Huaman Moises A. , Jabs Douglas A. , Jedlicka Anne , Karlen Nicky , Klein Sabra , Laeyendecker Oliver , Lane Karen , McBee Nichol , Meisenberg Barry , Merlo Christian , Mosnaim Giselle , Park Han-Sol , Pekosz Andrew , Petrini Joann , Rausch William , Shade David M. , Shapiro Janna R. , Singleton J. Robinson , Sutcliffe Catherine , Thomas David L. , Yarava Anusha , Zand Martin , Zenilman Jonathan M. , Tobian Aaron A.R. , Sullivan David
Published: December 2021

BACKGROUND

The efficacy of SARS-CoV-2 convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. We hypothesized that CCP might prevent infection when administered before symptoms or laboratory evidence of infection.

METHODS

This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed COVID-19 in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was development of SARS-CoV-2 infection.

RESULTS

180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for SARS-CoV-2 RT-PCR positivity at screening. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. There were 28 adverse events in CCP and 58 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs. 25.2 days; p=0.49) and COVID-19 (26.3 vs. 25.9 days; p=0.35) were similar for both groups.

CONCLUSION

In this trial, which enrolled persons with recent exposure to a person with confirmed COVID-19, high titer CCP as post-exposure prophylaxis appeared safe, but did not prevent SARS-CoV-2 infection.

Trial Registration

Clinicaltrial.gov number NCT04323800.
Evaluating the impact and cost-effectiveness of scaling-up HCV treatment among people who inject drugs in Ukraine
Authors: Stone Jack , Walker Josephine G , Bivegete Sandra , Trickey Adam , Chasela Charles , Semchuk Nadiya , Sazonova Yana , Varetska Olga , Saliuk Tetiana , Altice Frederick L , Tsenilova Zhanna , Islam Zahedul , Marunko Dina , Wang Bangyuan , Voets Ancella , Chawla Revati , Vickerman Peter
Published: December 2021

Introduction

People who inject drugs (PWID) in Ukraine have a high prevalence of hepatitis C virus (HCV). Since 2015, PWID have been receiving HCV treatment, but their impact and cost-effectiveness has not been estimated.

Methods

We developed a dynamic model of HIV and HCV transmission among PWID in Ukraine, incorporating ongoing HCV treatment (5,933 treatments) over 2015–2021; 46.1% among current PWID. We estimated the impact of these treatments and different treatment scenarios over 2021-2030: continuing recent treatment rates (2,394 PWID/year) with 42.5/100% among current PWID, or treating 5,000/10,000 current PWID/year. We also estimated the treatment rate required to decrease HCV incidence by 80% if preventative interventions are scaled-up or not. Required costs were collated from previous studies in Ukraine. We estimated the incremental cost-effectiveness ratio (ICER) of the HCV treatments undertaken in 2020 (1,059) by projecting the incremental costs and disability adjusted life years (DALYs) averted over 2020-2070 (3% discount rate) compared to a counterfactual scenario without treatment from 2020 onwards.

Results

On average, 0.4% of infections among PWID were treated annually over 2015-2021, without which HCV incidence would have been 0.6% (95%CrI: 0.3-1.0%) higher in 2021. Continuing existing treatment rates could reduce HCV incidence by 10.2% (7.8-12.5%) or 16.4% (12.1-22.0%) by 2030 if 42.5% or 100% of treatments are given to current PWID, respectively. HCV incidence could reduce by 29.3% (20.7-44.7%) or 93.9% (54.3-99.9%) by 2030 if 5,000 or 10,000 PWID are treated annually. To reduce incidence by 80% by 2030, 19,275 (15,134-23,522) annual treatments are needed among current PWID, or 17,955 (14,052-21,954) if preventative interventions are scaled-up. The mean ICER was US$828.8/DALY averted; cost-effective at a willingness-to-pay threshold of US$3,096/DALY averted (1xGDP).

Implications

Existing HCV treatment is cost-effective but has had little preventative impact due to few current PWID being treated. Further treatment expansion for current PWID could significantly reduce HCV incidence.
Proinflammatory Cytokine Levels in Sepsis and in Health and TNFα Association with Sepsis Mortality and patient characteristics: a Systematic Review and Meta-analysis
Authors: Gharamti Amal A. , Samara Omar , Monzon Anthony , Montalbano Gabrielle , Scherger Sias , DeSanto Kristen , Chastain Daniel B. , Sillau Stefan , Montoya Jose G. , Franco-Paredes Carlos , Henao-Martínez Andrés F. , Shapiro Leland
Published: December 2021

Background

Sepsis is a global health problem associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to a “cytokine storm.” However, anti-cytokine therapies have failed to lower sepsis mortality. We aim to characterize levels of key cytokines in sepsis patients and healthy controls and relate TNFα levels to patient characteristics and outcomes.

Methods

We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1985 to May 2020 for studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy persons. Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800).

Findings

We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8-85.8 pg/ml) and 5.5 pg/ml (95% CI 3.8-8.0 pg/ml) in healthy controls. Pooled estimate means for IL-1β and IFNγ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNFα concentrations associated with increased 28-day sepsis mortality (p=0.001). In subgroup analyses, TNFα levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score.

Interpretation

TNFα concentration in sepsis is increased approximately 10-fold compared to healthy persons, and TNFα associated with sepsis mortality but not with sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data.

Funding

None.
Oxoglutarate dehydrogenase coordinates myofibril growth by maintaining amino acid homeostasis
Authors: Morales Nicanor González , Marescal Océane , Szikora Szilárd , Erdelyi Miklos , Bíró Péter , Mesquita Tuana , Mihály József , Schöck Frieder
Published: December 2021

Myofibrils are long intracellular cables specific to muscles, composed mainly of actin and myosin filaments. The actin and myosin filaments are organized into repeated units called sarcomeres, which form the myofibril cables. Muscle contraction is achieved by the simultaneous shortening of sarcomeres and for a highly coordinated contraction to occur all sarcomeres should have the same size. Muscles have evolved a variety of ways to ensure sarcomere homogeneity, one example being the controlled oligomerization of Zasp proteins that sets the diameter of the myofibril. To understand how Zasp proteins effect myofibril growth, we looked for Zasp-binding proteins at the Z-disc. We found that the E1 subunit of the oxoglutarate dehydrogenase complex is recruited to the Z-disc by Zasp52 and is required to sustain myofibril growth. By making specific mutants, we show that its enzymatic activity is important for myofibril growth, and that the other two subunits of the complex are also required for myofibril formation. Using super resolution microscopy, we revealed the overall organization of the complex at the Z-disc. Then, using metabolomic analysis, we uncovered an amino acid balance defect affecting protein synthesis, that we also confirmed by genetic tools. In summary, we show that Zasp controls the local amino acid pool responsible for myofibril growth by recruiting the OGDH complex to the Z-disc.
Regenerated crustacean limbs are precise replicas
Authors: Almazán Alba , Çevrim Çağrı , Musser Jacob M. , Averof Michalis , Paris Mathilde
Published: December 2021

Animals can regenerate complex organs, yet this frequently results in imprecise replicas of the original structure. In the crustacean Parhyale, embryonic and regenerating legs differ in gene expression dynamics but produce apparently similar mature structures. We examine the fidelity of Parhyale leg regeneration using complementary approaches to investigate microanatomy, sensory function, cellular composition and cell molecular profiles. We find that regeneration precisely replicates the complex microanatomy and spatial distribution of external sensory organs, and restores their sensory function. Single-nuclei sequencing shows that regenerated and uninjured legs are indistinguishable in terms of cell type composition and transcriptional profiles. This remarkable fidelity highlights the ability of organisms to achieve identical outcomes via distinct processes.
Automated image analysis method to detect and quantify fat cell infiltration in hematoxylin and eosin stained human pancreas histology images
Authors: Naik Roshan Ratnakar , Rajan Annie , Kalita Nehal
Published: December 2021

Fatty infiltration in pancreas leading to steatosis is a major risk factor in pancreas transplantation. Hematoxylin and eosin (H and E) is one of the common histological staining techniques that provides information on the tissue cytoarchitecture. Adipose (fat) cells accumulation in pancreas has been shown to impact beta cell survival, its endocrine function and pancreatic steatosis and can cause non-alcoholic fatty pancreas disease (NAFPD). The current automated tools (E.g. Adiposoft) available for fat analysis are suited for white adipose tissue which is homogeneous and easier to segment unlike heterogeneous tissues such as pancreas where fat cells continue to play critical physiopathological functions. The currently, available pancreas segmentation tool focuses on endocrine islet segmentation based on cell nuclei detection for diagnosis of pancretic cancer. In the current study, we present a fat quantifying tool, Fatquant, which identifies fat cells in heterogeneous H and E tissue sections with reference to diameter of fat cell. Using histological images of pancreas from a publicly available database, we observed an intersection over union of 0.797 to 0.966 for manual versus fatquant based machine analysis.

Author Summary

We have developed an automated tool, Fatquant, for identification of fat cells based on its diameter in complex hematoxylin and eosin tissue sections such as pancreas which can aid the pathologist for diagnosis of fatty pancreas and related metabolic conditions. Fatquant is unique as current fat automated tools (adiposoft, adipocount) works well for homogeneous white adipose tissue but not for other tissue samples. The currently available pancreas analysis tool are mostly suited for segmentation of endocrine β-cell based on cell nuclei detection, extracting colour features and cannot estimate fat cell infiltration in pancreas.

Graphical Abstract

Currently available fat quantification tools like adiposoft can analyze homogenous adipose tissue (left) with intersection over union (IoU) of 0.935 and 0.954 with adiposoft and fatquant, respectively. While in heterogenous tissue (e.g. pancreas on right) which contains adipose (fat cells), acinar cells, adiposoft fails to detect fat cells with IoU=0 while fatquant had IoU=0.797.
CHARM: COVID-19 Health Action Response for Marines – association of antigen-specific interferon-gamma and IL2 responses with asymptomatic and symptomatic infections after a positive qPCR SARS-CoV-2 test
Authors: Sedegah Martha , Porter Chad , Hollingdale Michael R. , Ganeshan Harini , Huang Jun , Goforth Carl W. , Belmonte Maria , Belmonte Arnel , Weir Dawn L. , Lizewski Rhonda A. , Lizewski Stephen E. , Sealfon Stuart C. , Jani Vihasi , Cheng Ying , Inoue Sandra , Velasco Rachael , Villasante Eileen , Sun Peifang , Letizia Andrew
Published: December 2021

SARS-CoV-2 T cell responses are associated with COVID-19 recovery, and Class I- and Class II-restricted epitopes have been identified in the spike (S), nucleocapsid (N) and membrane (M) proteins and others. This prospective COVID-19 Health Action Response for Marines (CHARM) study enabled assessment of T cell responses in symptomatic and asymptomatic SARS-CoV-2 infected participants.

At enrollment all participants were negative by qPCR; follow-up occurred biweekly and then bimonthly for the next 6 weeks. Study participants who tested positive by qPCR SARS-CoV-2 test were asked to enroll in an immune response sub-study. FluoroSpot interferon-gamma (IFN-γ) and IL2 responses following qPCR-confirmed infection at enrollment (day 0), day 7 and 14 and more than 28 days later were measured using pools of 17mer peptides covering S, N, and M proteins, or CD4+CD8 peptide pools containing predicted epitopes from multiple SARS-CoV-2 antigens.

Among 124 asymptomatic and 105 symptomatic participants, SARS-CoV-2 infection generated IFN-γ responses to the S, N and M proteins that persisted longer in asymptomatic cases. IFN-γ responses were significantly (p=0.001) more frequent to the N pool (51.4%) than the M pool (18.9%) among asymptomatic subjects; however, the difference was not statistically significant (p=0.06) for symptomatic subjects (N pool: 44.4%; M pool: 25.9%). In asymptomatic participants IFN-γ responders to the CD4+CD8 pool responded more frequently to the S pool (55.6%) and N pool (57.1%), than the M pool (7.1%), but symptomatic participants, IFN-γ responses were more frequent to the S pool (75.0%) than N pool (33.3%) and M pool (33.3%). The frequencies of IFN-γ responses to the S and N+M pools peaked 7 days after the positive qPCR test among asymptomatic (S pool: 22.2%; N+M pool: 28.7%) and symptomatic (S pool: 15.3%; N+M pool 21.9%) participants and dropped by >28 days. Magnitudes of post-infection IFN-γ and IL2 responses to the N+M pool were significantly correlated with IFN-γ and IL2 responses to the N and M pools.

These data further support the central role of Th1-biased cell mediated immunity IFN-γ and IL2 responses, particularly to the N protein, in controlling COVID-19 symptoms, and justify T cell-based COVID-19 vaccines that include the N and S proteins.
Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression
Authors: Kerr Ryan , Jabbari Sara , Blair Jessica M. A. , Johnston Iain G.
Published: December 2021

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalisable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Further, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.
Modeling of microRNA-derived disease network repurposes methotrexate for the prevention and therapy of abdominal aortic aneurysm in mice
Authors: Shen Yicong , Gao Yuanxu , Shi Jiangcheng , Huang Zhou , Dai Rongbo , Fu Yi , Zhou Yuan , Kong Wei , Cui Qinghua
Published: December 2021

Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease characterized by permanent dilatation of the abdominal aorta. The main purpose of the current study is to search for noninvasive medical therapies for abdominal aortic aneurysm (AAA), for which there is currently no effective drug therapy. Network medicine represents a cutting-edge technology, as analysis and modeling of disease networks can provide critical clues regarding the etiology of specific diseases and which therapeutics may be effective. Here, we proposed a novel algorithm to quantify disease relations based on a large accumulated microRNA-disease association dataset and then built a disease network that covered 15 disease classes and included 304 diseases. Analysis revealed a number of patterns for these diseases; for example, diseases tended to be clustered and coherent in the network. Surprisingly, we found that AAA showed the strongest similarity with rheumatoid arthritis and systemic lupus erythematosus, both of which are autoimmune diseases, suggesting that AAA could be one type of autoimmune disease in etiology. Based on this observation, we further hypothesized that drugs for autoimmune disease could be repurposed for the prevention and therapy of AAA. Finally, animal experiments confirmed that methotrexate, a drug for autoimmune disease, was able to prevent the formation and inhibit the development of AAA.
N-glycosylation modulates enzymatic activity ofTrypanosoma congolensetrans-sialidase
Authors: Rosenau Jana , Grothaus Isabell Louise , Yang Yikun , Kumar Nilima Dinesh , Ciacchi Lucio Colombi , Kelm Sørge , Waespy Mario
Published: December 2021

Trypanosomes cause the devastating disease trypanosomiasis, in which the action of trans-sialidase (TS) enzymes harbored on their surface is a key virulence factor. TS areN-glycosylated, but the biological functions of their glycans has remained elusive. In this study, we investigated the influence ofN-glycans on the enzymatic activity and structural stability of TconTS1, a recombinant TS from the African parasiteTrypanosoma congolense. The enzyme was expressed in CHO Lec1 cells, which produce high-mannose typeN-glycans similar to the TSN-glycosylation patternin vivo. MALDI-TOF MS data revealed that up to eight putativeN-glycosylation sites were glycosylated.N-glycan removal via EndoHftreatment of TconTS1 led to a decrease in substrate affinity relative to the untreated enzyme, but apparently has no impact on the conversion rate. No changes in secondary structure elements of hypoglycosylated TconTS1 were observed in circular dichroism experiments. Molecular dynamics simulations provided evidence for interactions between monosaccharide units of the highly flexibleN-glycans and some conserved amino acids located at the catalytic site. These interactions led to conformational changes, possibly enhancing substrate accessibility and enzyme-substrate complex stability. The here-observed modulation of catalytic activity viaN-glycans represents a so far unknown structure-function relationship potentially inherent in several members of the TS enzyme family.
Models for Evaluation of Biological Age Based on Multi-omics
Authors: Huang Ce , Zhu Yingqian , Huo Fengjiao , Feng Shengyu , Gong Xue , Jiang Hua , Liu Zhongmin , Liu Hailiang
Published: December 2021

Aging is a complex process of systemic degeneration at multiple cellular and tissue levels that has a complex mechanism. Individuals age at different rates, and there is a high degree of aging heterogeneity. Therefore, it is inaccurate to judge an individual’s degree of aging by their chronological age. We performed transcriptome-focused multi-omics analyses (including transcriptomics, DNA methylation, proteomics, cytokine and telomere analysis, and single-cell transcriptome sequencing) on 139 healthy individuals aged 23 to 88 years. We systematically analyzed linear and non-linear changes in gene expression throughout aging. Genes with similar expression trajectories were enriched in similar biological pathways, including the PI3K-AKT signaling pathway and the inflammatory response. Through DNA methylation detection, we found that the expression of the top genes correlated with age was affected by methylation in the gene promoter region. These genes had no significant correlation with the expression of downstream proteins, but they were enriched in PI3K-AKT-associated proteins. Single-cell transcriptome sequencing showed that the expression of these genes did not significantly change in different cell subtypes, which proves that the gene expression changes were caused by internal age-related cellular changes rather than cell composition changes. We designed a transcriptome age clock and a methylation age clock using a set of 787 genes. Our models can accurately predict age with a mean absolute error (MAE) of 5.203 and 3.28, respectively, which is better than previously established aging models. The accuracy of our model was further verified by the detection of telomeres, which can identify accelerated aging of individuals.
The mating type transcription factor MAT1-1-1 from the fungal human pathogen Aspergillus fumigatus: synthesis, purification, and crystallization of the DNA binding domain
Authors: Ramšak Barbara , Kück Ulrich , Hofmann Eckhard
Published: December 2021

Mating type (MAT) loci are the most important and significant regulators of sexual reproduction and development in ascomycetous fungi. Usually, they encode two transcription factors (TFs), named MAT1-1-1 or MAT1-2-1. Mating-type strains carry only one of the two TF genes, which control expression of pheromone and pheromone receptor genes, involved in the cell-cell recognition process. The present work presents the crystallization for the alpha1 (α1) domain of MAT1-1-1 from the human pathogenic fungus Aspergillus fumigatus (AfMAT1-1-1). Crystals were obtained for the complex between a polypeptide containing the α1 domain and DNA carrying the AfMAT1-1-1 recognition sequence. A streak seeding technique was applied to improve native crystal quality, resulting in diffraction data to 3.2 Å resolution. Further, highly redundant data sets were collected from the crystals of selenomethionine-substituted AfMAT1-1-1 with a maximum resolution of 3.2 Å. This is the first report of structural studies on the α1 domain MAT regulator involved in the mating of ascomycetes.

Synopsis

An optimized purification and crystallization protocol together with initial X-ray datasets are described for this mating type transcription factor from human pathogenic fungus Aspergillus fumigatus.
Pentoxifylline-induced Protein Expression Change in RAW 264.7 Cells as Determined by Immunoprecipitation-based High Performance Liquid Chromatography
Authors: Seo Mi Hyun , Kim Dae Won , Kim Yeon Sook , Lee Suk Keun
Published: December 2021

Although pentoxifylline (PTX) was identified as a competitive non-selective phosphodiesterase inhibitor, its pharmacological effect has not been clearly elucidated. The present study explored the effect of low dose 10 μg/mL PTX (therapeutic dose) compared to high dose 300 μg/mL PTX (experimental dose) in RAW 264.7 cells through immunoprecipitation-based high performance liquid chromatography (IP-HPLC), immunohistochemistry, and western blot. 10 μg/mL PTX increased the expression of proliferation (Ki-67, PCNA, cyclin D2, cdc25A), epigenetic modification (KDM4D, PCAF), protein translation (DOHH, DHPS, eIF5A1), RAS signaling (KRAS, pAKT1/2/3, PI3K), NFkB signaling (NFkB, GADD45, p38), protection (HSP70, SOD1, GSTO1/2), neuromuscular differentiation (NSEγ, myosin-1a, desmin), osteoblastic differentiation (BMP2, RUNX2, osterix), acute inflammation (TNFα, IL-1, CXCR4), innate immunity (β-defensin 1, lactoferrin, TLR-3, -4), cell-mediated immunity (CD4, CD8, CD80), while decreased the expression of ER stress (eIF2α, eIF2AK3, ATF6α), fibrosis (FGF2, CTGF, collagen 3A1), and chronic inflammation (CD68, MMP-2, -3, COX2) versus the untreated controls. The activation of proliferation by 10 μg/mL PTX was also supported by the increase of cMyc-MAX heterodimer and β-catenin-TCF1 complex in double IP-HPLC. 10 μg/mL PTX enhanced FAS-mediated apoptosis but diminished p53-mediated apoptosis, and downregulated many angiogenesis proteins (angiogenin, VEGF-A, and FLT4), but upregulated HIF1α, VEGFR2, and CMG2 reactively. Whereas, 300 μg/mL PTX consistently decreased proliferation, epigenetic modification, RAS and NFkB signaling, neuromuscular and osteoblastic differentiation, but increased apoptosis, ER stress, and fibrosis compared to 10 μg/mL PTX. These data suggest PTX has different biological effect on RWA 264.7 cells depending on the concentration of 10 μg/mL and 300 μg/mL PTX. The low dose 10 μg/mL PTX enhanced RAS/NFkB signaling, proliferation, differentiation, and inflammation, particularly, it stimulated neuromuscular and osteoblastic differentiation, innate immunity, and cell-mediated immunity, but attenuated ER stress, fibrosis, angiogenesis, and chronic inflammation, while the high dose 300 μg/mL PTX was found to alleviate the 10 μg/mL PTX-induced biological effects, resulted in the suppression of RAS/NFkB signaling, proliferation, neuromuscular and osteoblastic differentiation, and inflammation.
Temporally precise movement-based predictions in the mouse auditory cortex
Authors: Audette Nicholas J. , Zhou WenXi , Schneider David M.
Published: December 2021

Many of the sensations experienced by an organism are caused by their own actions, and accurately anticipating both the sensory features and timing of self-generated stimuli is crucial to a variety of behaviors. In the auditory cortex, neural responses to self-generated sounds exhibit frequency-specific suppression, suggesting that movement-based predictions may be implemented early in sensory processing. Yet it remains unknown whether this modulation results from a behaviorally specific and temporally precise prediction, nor is it known whether corresponding expectation signals are present locally in the auditory cortex. To address these questions, we trained mice to expect the precisely timed acoustic outcome of a forelimb movement using a closed-loop sound-generating lever. Dense neuronal recordings in the auditory cortex revealed suppression of responses to self-generated sounds that was specific to the expected acoustic features, specific to a precise time within the movement, and specific to the movement that was coupled to sound during training. Predictive suppression was concentrated in L2/3 and L5, where deviations from expectation also recruited a population of prediction-error neurons that was otherwise unresponsive. Recording in the absence of sound revealed abundant movement signals in deep layers that were biased toward neurons tuned to the expected sound, as well as temporal expectation signals that were present throughout the cortex and peaked at the time of expected auditory feedback. Together, these findings reveal that predictive processing in the mouse auditory cortex is consistent with a learned internal model linking a specific action to its temporally precise acoustic outcome, while identifying distinct populations of neurons that anticipate expected stimuli and differentially process expected versus unexpected outcomes.
Isolation and Characterization of SARS-CoV-2 strains circulating in Eastern India
Authors: Singh Bharati , Avula Kiran , Chatterjee Sanchari , Datey Ankita , Ghosh Arup , De Saikat , Keshry Supriya Suman , Ghosh Soumyajit , Suryawanshi Amol , Dash Rupesh , Senapati Shantibhusan , Beuria Tushar K. , Prasad Punit , Raghav Sunil , Swain Rajeeb , Parida Ajay , Syed Gulam Hussain , Chattopadhyay Soma
Published: December 2021

Emergence of SARS-CoV-2 as a serious pandemic has altered the global socioeconomic dynamics. The wide prevalence, high death counts and rapid emergence of new variants urge for establishment of research infrastructure to facilitate rapid development of efficient therapeutic modalities and preventive measures. In agreement with this, five SARS-CoV2 strains (ILS01, ILS02, ILS03, ILS15 and ILS24) of four different clades (19A, 19B, 20A and 20B) were isolated from patient swab samples collected during the 1st COVID-19 wave in Odisha, India. The viral isolates were adapted to in-vitro cultures and further characterized to identify strain specific variations in viral growth characteristics. All the five isolates showed substantial amount of virus induced CPE however ILS03 belonging to 20A clade displayed highest level of CPE. Time kinetics experiment revealed spike protein expression was evident after 16th hours post infection in all five isolates. ILS03 induced around 90% of cytotoxicity. Further, the susceptibility of various cell lines (human hepatoma cell line (Huh-7), CaCo2 cell line, HEK-293T cells, Vero, Vero-E6, BHK-21, THP-1 cell line and RAW 264.7 cells) were assessed. Surprisingly, it was found that the human monocyte cells THP-1 and murine macrophage cell line RAW 264.7 were permissive to all the SARS-CoV-2 isolates. The neutralization susceptibility of viral isolates to vaccine-induced antibodies was determined using sera from individuals vaccinated in the Government run vaccine drive in India. The micro-neutralization assay suggested that both Covaxin and Covishield vaccines were equally effective (100% neutralization) against all of the isolates. The whole genome sequencing of culture adapted viral isolates and viral genome from patient oropharyngeal swab sample suggested that repetitive passaging of SARS-CoV2 virus in Vero-E6 cells did not lead to emergence of many mutations during the adaptation in cell culture. Phylogenetic analyses revealed that the five isolates clustered to respective clades. The major goal was to isolate and adapt SARS-CoV-2 viruses in in-vitro cell culture with minimal modification to facilitate research activities involved in understanding the molecular virology, host-virus interactions, application of these strains for drug discovery and animal challenge models development which eventually will contribute towards the development of effective and reliable therapeutics.
mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant
Authors: Garcia-Beltran Wilfredo F. , St. Denis Kerri J. , Hoelzemer Angelique , Lam Evan C. , Nitido Adam D. , Sheehan Maegan L. , Berrios Cristhian , Ofoman Onosereme , Chang Christina C. , Hauser Blake M. , Feldman Jared , Gregory David J. , Poznansky Mark C. , Schmidt Aaron G. , Iafrate A. John , Naranbhai Vivek , Balazs Alejandro B.
Published: December 2021

Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody responses. In addition, we find Omicron pseudovirus is more infectious than any other variant tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.
mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant
Authors: Gruell Henning , Vanshylla Kanika , Tober-Lau Pinkus , Hillus David , Schommers Philipp , Lehmann Clara , Kurth Florian , Sander Leif E. , Klein Florian
Published: December 2021

The Omicron variant of SARS-CoV-2 is causing a rapid increase in infections in various countries. This new variant of concern carries an unusually high number of mutations in key epitopes of neutralizing antibodies on the spike glycoprotein, suggesting potential immune evasion. Here we assessed serum neutralizing capacity in longitudinal cohorts of vaccinated and convalescent individuals, as well as monoclonal antibody activity against Omicron using pseudovirus neutralization assays. We report a near-complete lack of neutralizing activity against Omicron in polyclonal sera after two doses of the BNT162b2 vaccine, in convalescent individuals, as well as resistance to different monoclonal antibodies in clinical use. However, mRNA booster immunizations in vaccinated and convalescent individuals resulted in a significant increase of serum neutralizing activity against Omicron. Our study demonstrates that booster immunizations will be critical to substantially improve the humoral immune response against the Omicron variant.
Organizational citizenship behaviors perceived by collectivistic 50-and-older customers and medical-care service performance: an application of stimulus-organism-response theory
Authors: Kim Wooyang , Hantula Donald A. , Di Benedetto Anthony
Published: December 2021

Purpose

The study aims to examine the underexplored agenda in organizational citizenship behaviors (OCBs) through the collectivistic 50-and-older customers' lens when encountering medical-care services by applying stimulus-organism-response (S-O-R) theory.

Design/methodology/approach

The authors propose an integrative causal model derived from employees OCBs perceived by the collectivistic 50-and-older outpatients in Korean medical-care organizations and test the causal relationships using structural equation modeling (SEM).

Findings

The three dimensions of OCBs are external stimuli to the synergistic relationship of both cognitive and affective organisms for enhancing the organization's external outcomes. The customers' organismic processes mediate the relationships between OCBs and the resultant outcomes. Customer satisfaction plays a pivotal role in determining customers' future behavior when converting the business relationship to friendship.

Practical implications

The proposed integrated model provides an overall mechanism of the collectivistic customer decision process in the medical-care service setting. The integrated model helps to understand better how customers proceed mental and emotional states with the encountered services and how frontline employees offer extra-roles beyond in-roles to their customers in touching points to maintain superior organizational performance.

Originality/value

The authors respond to the underexplored agenda in the OCB research discipline. The study is one of the few studies to examine the effect of OCBs from collectivistic customers' perspectives and apply a consumer behavior theory to explain a service organizational performance in an integrative causal model.
Maximum entropy snapshot sampling for reduced basis modelling
Authors: Bannenberg Marcus W.F.M. , Kasolis Fotios , Günther Michael , Clemens Markus
Published: December 2021

Purpose

The maximum entropy snapshot sampling (MESS) method aims to reduce the computational cost required for obtaining the reduced basis for the purpose of model reduction. Hence, it can significantly reduce the original system dimension whilst maintaining an adequate level of accuracy. The purpose of this paper is to show how these beneficial results are obtained.

Design/methodology/approach

The so-called MESS method is used for reducing two nonlinear circuit models. The MESS directly reduces the number of snapshots by recursively identifying and selecting the snapshots that strictly increase an estimate of the correlation entropy of the considered systems. Reduced bases are then obtained with the orthogonal-triangular decomposition.

Findings

Two case studies have been used for validating the reduction performance of the MESS. These numerical experiments verify the performance of the advocated approach, in terms of computational costs and accuracy, relative to gappy proper orthogonal decomposition.

Originality/value

The novel MESS has been successfully used for reducing two nonlinear circuits: in particular, a diode chain model and a thermal-electric coupled system. In both cases, the MESS removed unnecessary data, and hence, it reduced the snapshot matrix, before calling the QR basis generation routine. As a result, the QR-decomposition has been called on a reduced snapshot matrix, and the offline stage has been significantly scaled down, in terms of central processing unit time.
The Lean principle respect for people as respect for craftsmanship
Authors: Ljungblom Mia , Lennerfors Thomas Taro
Published: December 2021

Purpose

The purpose of this paper is to reach a deeper understanding of the Lean principle of respect for people (RFP to facilitate Lean implementation in Western organizations outside Toyota.

Design/methodology/approach

This study uses an interpretative, hermeneutic approach to understand the RFP concept through a literature study of existing research about Lean implementation, and an inquiry into the underlying meaning of the RFP principle, by studying sources from Toyota and discussions about the RFP principle in Japan.

Findings

RFP is seen as a central principle in Lean implementations, but the failure of RFP is believed to cause Lean implementations to fail. The literature about Lean discusses the RFP principle both as a general positive atmosphere and as focused on developing the work capacity of employees. By studying the sources from Toyota, it could be understood that RFP is based on ought-respect. The authors also find that RFP is related to takumi, a perfected form of craftsmanship. The authors translate the concept to English by tying it to the recent literature about craft to develop RFP as RFC – respect for craftsmanship.

Research limitations/implications

As this is a conceptual paper, it is difficult to translate the findings into a tool for companies and organizations to use. However, that is the point of the paper: that the most important ideas are not translatable into tools.

Practical implications

It is necessary in Lean implementations to connect people’s work to craftsmanship. Through a discussion of craftsmanship before Lean implementations, it might be possible to nurture an understanding of the underlying values of Lean.

Originality/value

The authors have not found any papers that propose takumi as the base of the RFP principle, nor as a foundational concept at Toyota. It is necessary to understand the concept of takumi, as perfection in craft, to understand the RFP principle.