bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of autoimmune encephalitis
Authors: Bien Christian G.
Published: January 2021

Purpose of review

Autoimmune encephalitides are established diagnoses in contemporary neurology. Their management poses a regular challenge for almost all neurologists. One may ask if the concept of 1st line and 2nd line treatment is still up to date, which new data on the antibody-defined encephalitis types exist, and how to organize long-term management.

Recent findings

The 1st line/2nd line concept of initial immunological intervention is accepted worldwide. A randomized controlled trial confirmed that one 1st line compound (intravenous immunoglobulins) is superior to a placebo in patients with antibodies against leucine-rich glioma inactivated protein 1. Rituximab, a 2nd line compound, is increasingly and apparently successfully used in treating different types of autoimmune encephalitis. It may find its place even earlier in the treatment cascade. Long-term management needs to be improved and is under development.

There have been no groundbreaking new developments in the field. The published experience confirms existing suggestions. Aspects of long-term management including rehabilitation measures and counseling about driving eligibility require further research.
Immunochromatographic SARS-CoV-2 IgG antibody assay: a cross-sectional study conducted at Wakayama Medical University in Japan
Authors: Iwabuchi Sadahiro , Katsuda Masahiro , Koizumi Yusuke , Hatai Mayuko , Kojima Mitsue , Tokudome Nahomi , Tamura Shinobu , Nishio Machiko , Kondo Toshikazu , Hironisi Masaya , Kakutani Chiemi , Yamaue Hiroki , Hashimoto Shinichi
Published: January 2021

Asymptomatic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection must be quickly identified and isolated to prevent the spread of the virus. The number of asymptomatic healthy people is completely unknown because they remain untested. Detection of specific SARS-CoV-2 antibodies has been widely accepted as a diagnostic test, and an immunochromatographic test, which is simpler and relatively cheaper than other methods, is becoming the gold standard for identifying healthy people who had been infected with SARS-CoV-2 in the past. In this study, 1,528 volunteers who worked at a particular hospital were subjected to an immunochromatographic IgG test for SARS-CoV-2 to determine the ratio of asymptomatic people. Only 12 volunteers (0.79%) were IgG+, with no significant background differences in the sex, age, profession, experiences of working at the emergency department or caring for coronavirus disease 2019 patients. If this IgG+ ratio was to be extrapolated to Wakayama city’s population, 2,780 out of 3,54,063 people may be asymptomatic for SARS-CoV-2. The results imply that anyone may get infected with SARS-CoV-2 but remain asymptomatic.
Factors Influencing AVF Dysfunction in Patients with Maintenance Hemodialysis: A retrospective study
Authors: Li Yu , Cui Wenhao , Wang Jukun , Zhang Chao , Luo Tao
Published: January 2021

Objective

To explore factors influencing primary dysfunction of autologous arteriovenous fistula (AVF) in patients with maintenance hemodialysis (MHD).

Methods

This is a retrospectively study. One hundred and twenty-one patients who underwent anastomosis for AVF in our hospital Between 1st January 2016 and 31st December 2018 were selected. Seventy-seven patients satisfied the inclusion criteria and were included in the final analyses. Patients were divided into two groups based on the function of vascular access. The comparisons of complete blood count and other blood biochemical parameters were made between two groups. Factors influencing AVF dysfunction were analyzed by multivariate Cox proportional hazard regression model for patients with End stage renal disease (ESRD).

Results

There were significant differences in total cholesterol (TC), low density lipoprotein (LDL) and serum phosphorus levels between patency and dysfunction group (P<0.05) of AVFs. Further multivariate COX proportional risk regression showed that hypercholesterolemia and hyperphosphatemia were independent risk factors for AVF dysfunction.

Conclusions

Hypercholesterolemia and hyperphosphatemia are independent risk factors for primary AVF dysfunction in patients with MHD.
Methylation of Q105 on histone H2A is part of a dynamic regulatory mechanism integrating metabolism with ribosome biogenesis through recruitment of Nhp2
Authors: Mawer Julia S.P. , Grabenhorst Niklas , Mylonas Constantine , Tessarz Peter
Published: January 2021

Ribosome biogenesis is an essential cellular process that requires integration of extracellular cues, such as metabolic state, with intracellular signaling, transcriptional regulation and chromatin accessibility at the ribosomal DNA. Here, we demonstrate that the recently identified histone modification, methylation of H2AQ105, is an integral part of a dynamic chromatin network at the rDNA locus. Its deposition depends on a functional mTor signaling pathway as well as acetylation of histone H3 at position K56, thus integrating signals from cell cycle, metabolic and proliferative states. Furthermore, we identify a first epigenetic reader of this modification, the ribonucleoprotein Nhp2, which specifically recognizes the methylation on H2AQ105. Based on functional and proteomic data we suggest that Nhp2 functions as an adapter to bridge the rDNA chromatin with components of the small subunit processome and might help to efficiently coordinate transcription of rRNA with its post-transcriptional processing.
An investigation towards understanding the role of CDH1 gene in different types of Breast Cancers
Authors: Sengupta Antara , Banerjee Raja
Published: January 2021

At recent age breast cancer attracts the attention of both the medical and the scientific community for its deadly occurrence throughout the globe as it is considered to be happened due to genetic aberration. Out of several genes expressed, it is found that cadherin 1, type 1 (CDH1) is responsible in several ways to control the metabolic order in human. Hence we focus on CDH1 gene whether any deviation in it especially alteration/modification in its sequence is responsible for the occurrence of this deadly disease. Towards this end study of the available genomic sequences of CDH1 gene of several patients, suffering from various types of breast cancer (obtained from the Sanger Database), are studied. The results emphasizes that alternation/modification in the sequence of the CDH1 gene affect its regular function which may have a potential role in damaging the different types of breast tissues, causing malfunction and leading to breast cancers in patients.
Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis
Authors: Meizlish Matthew L. , Goshua George , Liu Yiwen , Fine Rebecca , Amin Kejal , Chang Eric , DeFilippo Nicholas , Keating Craig , Liu Yuxin , Mankbadi Michael , McManus Dayna , Wang Stephen , Price Christina , Bona Robert D. , Chaar Cassius Iyad Ochoa , Chun Hyung J. , Pine Alexander B. , Rinder Henry M. , Siner Jonathan , Neuberg Donna S. , Owusu Kent A. , Lee Alfred Ian
Published: January 2021

Background

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain.

Research Question

How does in-hospital mortality compare with intermediate-versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19?

Study Design and Methods

Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation (“anticoagulation cohort”, N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy (“aspirin cohort”, N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death.

Results

Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate-compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]).

Interpretation

In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Summary conflict of interest statements

No conflict of interest exists for any author on this manuscript.
Robust RNA editing via recruitment of endogenous ADARs using circular guide RNAs
Authors: Katrekar Dhruva , Yen James , Xiang Yichen , Saha Anushka , Meluzzi Dario , Savva Yiannis , Mali Prashant
Published: January 2021

Akin to short-hairpin RNAs and antisense oligonucleotides which efficaciously recruit endogenous cellular machinery such as Argonaute and RNase H to enable targeted RNA knockdown, simple long antisense guide RNAs (1) can recruit endogenous adenosine deaminases acting on RNA (ADARs) to enable programmable A-to-I RNA editing, without requiring co-delivery of any exogenous proteins. This approach is highly specific, however the efficiency is typically lower than observed with enzyme overexpression. Conjecturing this was due in part to the short half-life and residence times of guide RNAs, here we engineer highly stablecircularADAR recruiting guideRNAs(cadRNAs), which can be delivered not only by genetically encoding on DNA vectors, but also via transfection of RNA molecules transcribedin vitro. Using these cadRNAs, we observed robust RNA editing across multiple sites and cell lines, in both untranslated and coding regions of RNAs, vastly improved efficiency and durability of RNA editing, and high transcriptome-wide specificity. High transcript-level specificity was achieved by further engineering to reduce bystander editing. Additionally,in vivodelivery of cadRNAs via adeno-associated viruses (AAVs) enabled robust 38% RNA editing of the mPCSK9 transcript in C57BL/6J mice livers, and 12% UAG-to-UGG RNA correction of the amber nonsense mutation in the IDUA-W392X mouse model of mucopolysaccharidosis type I-Hurler (MPS I-H) syndrome. Taken together, cadRNAs enable efficacious programmable RNA editing with application across diverse protein modulation and gene therapeutic settings.
Ultrastructural features of presynaptic active zones and dense core vesicles of olfactory projection neuron boutons inDrosophila melanogaster
Authors: Yang Kai , Liu Tong , Liu He , Di Zengru , Zhang Ke
Published: January 2021

InDrosophila melanogaster, olfactory projection neurons (PNs) convey odor information from the peripheral olfactory center to higher brain regions. The anatomical and physiological properties of PNs have been well characterized at the cellular and circuit level. The ultrastructural features of PNs remain unknown however, particularly with respect to presynaptic active zones (PAZs) and dense core vesicles (DCVs). In the current study, membrane-labeled electron microscopy was used to volume-reconstruct 89 PN axonal boutons and identify the internal PAZs and DCVs. Based on ultrastructural parameters, these PN boutons could be classified into three morphological distinct subtypes. Interestingly, the distributions of PAZs and DCVs were distinct within these three subtypes. DCVs were enriched in membrane labeled GH146-positive boutons, suggesting that GH146-positive PNs release both neurotransmitters and neuromodulators. The study identified the detailed distributions of PAZs and DCVs in PN boutons and indicates that neuromodulators mediated by DCVs may play an important role in PNs for olfactory processing.
Multidimensional Boolean Patterns in Multi-omics Data
Authors: Golovko George , Reyes Victor , Pinchuk Iryna , Fofanov Yuriy
Published: January 2021

Motivation

Virtually all biological systems are governed by a set of complex relations between their components. Identification of relations within biological systems involves a rigorous search for patterns among variables/parameters. Two-dimensional (involving two variables) patterns are identified using correlation, covariation, and mutual information approaches. However, these approaches are not suited to identify more complicated multidimensional relations, which simultaneously include 3, 4, and more variables.

Results

We present a novel pattern-specific method to quantify the strength and estimate the statistical significance of multidimensional Boolean patterns in multiomics data. In contrast with dimensionality reduction and AI solutions, patterns identified by the proposed approach may provide a better background for meaningful mechanistic interpretation of the biological processes. Our preliminary analysis suggests that multidimensional patterns may dominate the landscape of multi-omics data, which is not surprising because complex interactions between components of biological systems are unlikely to be reduced to simple pairwise interactions.
Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis
Authors: Ting Christopher , Aspal Mohit , Vaishampayan Neil , Huang Steven K. , Riemondy Kent A. , Wang Fa , Farver Carol , Zemans Rachel L.
Published: January 2021

ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.
DsbA-L protects against diabetic renal injury through the adipo-renal axis
Authors: Zeng Lingfeng , Yang Ming , Hu Chun , Zhao Li , Chen Xianghui , Wei Yaping , Lin Huapeng
Published: January 2021

Disulfide-bond A oxidoreductase-like protein (DsbA-L) is an adiponectin-interacting protein that is highly expressed in adipose tissue. The adipo-renal axis involves adipocyte release of signaling molecules that are recruited to kidney and regulate kidney function. We have found that the DsbA-L modulated the progression of diabetic nephropathy, but the precise mechanism of this modulation is unknown. Here, the transgenic mice overexpressing DsbA-L protein in fat (fDsbA-L) were used to verify that the renoprotective role of DsbA-L whether by adipo-renal axis. Mice were divided into four groups: a normal (Control) group, STZ induced diabetic mice, fDsbA-L mice and diabetic fDsbA-L mice (n=6). Diabetes was induced in mice by STZ 100mg/kg and continued HFD feeding for 12 weeks. Compared with the control group, the weight, blood glucose,and urine protein levels and the pathological changes in the kidney tissue of diabetic mice were increased significantly, accompanied by increased NLRP3,caspase-1, IL-1β, IL-18, FN, and Collagen1 mRNA and protein expression, which were reduced in diabetic fDsbA-L mice. Interestingly, the level of adiponectin in serum and kidney expression in diabetic mice was reduced significantly compared to that in the control group. However this change was reversed in diabetic fDsbA-L mice. These data suggest that the overexpression of DsbA-L in the adipocytes of mice can protect against diabetic renal injury through anti-inflammatory mediators,and may be mediated by the adipo-renal axis.
GN1, Glucosamine Analog, attenuate the neuronal hyperactivity of c-fosgene in Adjuvant-Induced Arthritis in Rats
Authors: Jawed Huma , Shah Syed Uzair Ali , Awan Shahid I. , Anjum Shazia , Simjee Shabana U.
Published: January 2021

The anti-inflammatory and anti-arthritic activity of GN1 (6-hydroxymethyl-3-(1-methylene-allylamino)-tetrahydro-pyran-2,4,5-triol), an analog of glucoseamine was investigated in the adjuvant induced arthritis (AIA) in rats. It was observed that the highly increased hind paw swelling was significantly reduced (p <0.001) with no noticeable retardation of body weight in the GN1 treated arthritic rats as compared to arthritic control rats. The histopathological analysis of isolated rat joints by scaling system classification of different stages appear in arthritic inflammatory lesion development, disclosed the suppressive effect in the inflammation processing in the GN1 treated animals. Different predictive markers such as TNF-α, nitric oxide IL-1β, peroxide and glutathione were also determined in the serum samples of the treated and non-treated arthritic rats in order to measure the intensity of inflammation. Our results show that GN-1 treatment in arthritic groups demonstrated marked reduction inc-fosexpression. Results also revealed that GN1 significantly reduces the peroxide production (p < 0.002) and both the pro-inflammatory cytokines TNF-α (p < 0.015) and IL-1β (p < 0.001) in the arthritic rats receiving this treatment. Although, nitric oxide formation was found to be less than the arthritic control, but this reduction was not significant. The level of glutathione was significantly increased in GN1 treated arthritic rats (p < 0.037). These observations suggest that GN1 may help in reducing the inflammation and have anti-arthritic properties.
Modelling tuberculosis drug resistance amplification rates in high-burden settings
Authors: Karmakar Malancha , Ragonnet Romain , Ascher David B. , Trauer James M. , Denholm Justin T.
Published: January 2021

Background

Antimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used molecular understanding to develop a compartmental epidemiological model ofMycobacterium tuberculosis(Mtb) transmission.

Methods

A four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministicMtbtransmission model was developed to explore the progression from DS-to MDR-TB. The model incorporated strain-specific fitness costs and was calibrated using data from national tuberculosis prevalence surveys and drug resistance surveys from Philippines and Viet Nam. Using an adaptive Metropolis algorithm, we estimated drug resistance amplification and transmission rates.

Results

The posterior estimates for the proportion of isoniazid mono-resistant amplification among treatment failure was 0.75 (0.64 – 0.85) for Philippines and 0.55 (0.39 – 0.63) for Viet Nam. The proportion of rifampicin mono-resistant amplification among treatment failure was 0.05 (0.04 – 0.06) for Philippines and 0.011 (0.010 – 0.012) for Viet Nam. In Philippines, the estimated proportion of primary resistance resulting from transmission was 56% (42 – 68) for INH-R, 48% (34 – 62) for RIF-R and 42% (34 – 50) for MDR-TB. For Viet Nam, the estimated proportion of drug resistance due to transmission was 79% (70 – 86) for INH-R, 68% (58 – 75) for RIF-R and 50% (45 – 53) for MDR-TB.

Discussion

RIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which also allow for early detection of INH-R.
Bayesian Variable Selection Utilizing Posterior Probability Credible Intervals
Authors: Du Mengtian , Andersen Stacy L. , Perls Thomas T. , Sebastiani Paola
Published: January 2021

In recent years, there has been growing interest in the problem of model selection in the Bayesian framework. Current approaches include methods based on computing model probabilities such as Stochastic Search Variable Selection (SSVS) and Bayesian LASSO and methods based on model choice criteria, such as the Deviance Information Criterion (DIC). Methods in the first group compute the posterior probabilities of models or model parameters often using a Markov Chain Monte Carlo (MCMC) technique, and select a subset of the variables based on a prespecified threshold on the posterior probability. However, these methods rely heavily on the prior choices of parameters and the results can be highly sensitive when priors are changed. DIC is a Bayesian generalization of the Akaike’s Information Criterion (AIC) that penalizes for large number of parameters, it has the advantage that can be used for selection of mixed effect models but tends to prefer overparameterized models. We propose a novel variable selection algorithm that utilizes the parameters credible intervals to select the variables to be kept in the model. We show in a simulation study and a real-world example that this algorithm on average performs better than DIC and produces more parsimonious models.
Aedes aegyptiAag-2 culture cells enter endoreplication process upon pathogen challenge
Authors: Domínguez-Benítez Christian , Serrato-Salas Javier , Condé Renaud , Lanz-Mendoza Humberto
Published: January 2021

Metamorphic insects apparently rely on a finite number of cells after emergence to counterbalance either commensal and pathogen presence. For hematophagous insects, blood-feeding is a crucial step for offspring development, therefore enteric cells repairing molecular mechanisms consists in fine regulated pathways to counterattack biotic and abiotic insults. Nevertheless, recent research suggests that midgut cells are capable to adapt their immune responses to pathogen challenges. Recently,AnophelesandAedesmosquitoes have been observed to increase their DNA cell content upon encounter with parasites, bacteria and virus respectively. Genomic endoreplication is one of the most important processes in larval development for fast transcriptional activity and protein secretion.

So, in this paper we explore the ability ofAedes aegyptiAag-2 culture cells to develop a likely endoreplication process to face pathogen presence. Aag-2 cells at 6 and 12 hours post-biotic insult enter a proliferation arrest and increases DNA content, these two phenomena recovers control levels at 24 h post-treatment. It requires more research data about the type of genomic regions that has been replicated in the process, and the concentration that antimicrobial molecules are released into culture media.
Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling
Authors: Ariosa-Morejon Yoanna , Santos Alberto , Fischer Roman , Davis Simon , Charles Philip , Thakker Rajesh , Wann Angus , Vincent Tonia L.
Published: January 2021

Collagen-rich tissues have poor reparative capacity that is further impaired with age, predisposing to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, skin and plasma of mice across the life course. We report highly dynamic matrisome turnover in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed epigenetic modulation across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFb in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several of these pathways have been associated with age-related disease. Fewer changes were observed for skin and plasma. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.
Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
Authors: Dou Shuaijie , Li Guoxian , Li Ge , Hou Chunmei , Zheng Yang , Tang Lili , Gao Yang , Mo Rongliang , Li Yuxiang , Wang Renxi , Shen Beifen , Zhang Jun , Han Gencheng
Published: January 2021

Nuclear Factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering the stress granules (SGs) formation. However, the regulation of the NF90-SGs pathway remain largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SGs mediated antiviral immunity. Vesicular Stomatitis Virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages which in turn recruited the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiated a proteasome-dependent degradation of the NF90 via K48-linked ubiquitination at Lys297. Targeted inactivation of the Tim-3 enhances the NF90 downstream SGs formation by selectively increasing the phosphorylation of PKR and eIF2a, the expression of SGs markers G3BP1 and TIA-1, and protected mice from lethal VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.
De novoprotein fold families expand the designable ligand binding site space
Authors: Pan Xingjie , Kortemme Tanja
Published: January 2021

A major challenge in designing proteinsde novoto bind user-defined ligands with high specificity and affinity is finding backbones structures that can accommodate a desired binding site geometry with high precision. Recent advances in methods to generate protein fold familiesde novohave expanded the space of accessible protein structures, but it is not clear to what extendde novoproteins with diverse geometries also expand the space of designable ligand binding functions. We constructed a library of 25,806 high-quality ligand binding sites and developed a fast protocol to place (“match”) these binding sites into both naturally occurring andde novoprotein families with two fold topologies: Rossman and NTF2. 5,896 and 7,475 binding sites could be matched to the Rossmann and NTF2 fold families, respectively.De novodesigned Rossman and NTF2 protein families can support 1,791 and 678 binding sites that cannot be matched to naturally existing structures with the same topologies, respectively. While the number of protein residues in ligand binding sites is the major determinant of matching success, ligand size and primary sequence separation of binding site residues also play important roles. The number of matched binding sites are power law functions of the number of members in a fold family. Our results suggest thatde novosampling of geometric variations on diverse fold topologies can significantly expand the space of designable ligand binding sites for a wealth of possible new protein functions.

Author summary

De novodesign of proteins that can bind to novel and highly diverse user-defined small molecule ligands could have broad biomedical and synthetic biology applications. Because ligand binding site geometries need to be accommodated by protein backbone scaffolds at high accuracy, the diversity of scaffolds is a major limitation for designing new ligand binding functions. Advances in computational protein structure design methods have significantly increased the number of accessible stable scaffold structures. Understanding how many new ligand binding sites can be accommodated by thede novoscaffolds is important for designing novel ligand binding proteins. To answer this question, we constructed a large library of ligand binding sites from the Protein Data Bank (PDB). We tested the number of ligand binding sites that can be accommodated byde novoscaffolds and naturally existing scaffolds with same fold topologies. The results showed thatde novoscaffolds significantly expanded the ligand binding space of their respective fold topologies. We also identified factors that affect difficulties of binding site accommodation, as well as the relationship between the number of scaffolds and the accessible ligand binding site space. We believe our findings will benefit future method development and applications of ligand binding protein design.
Multi-strain fermented milk promotes gut microbiota recovery after Helicobacter pylori therapy: a randomised, controlled trial
Authors: Guillemard Eric , Poirel Marion , Schäfer Florent , Quinquis Laurent , Rossoni Caroline , Keicher Christian , Wagner Frank , Szajewska Hania , Barbut Frédéric , Derrien Muriel , Malfertheiner Peter
Published: January 2021

BACKGROUND

Helicobacter pylori (Hp) eradication therapy can alter gut microbiota, provoking gastro-intestinal (GI) symptoms that can be improved by probiotics. The effect on Hp patients of a Test fermented milk containing yogurt and three Lacticaseibacillus (L. paracasei CNCM I-1518, CNCM I-3689, L. rhamnosus CNCM I-3690) strains was assessed on antibiotic associated diarrhea (AAD) (primary aim), GI-symptoms, gut microbiota composition and metabolites. In this aim, a randomized, double-blind, controlled trial was performed in 136 adults under Hp-treatment (14-day amoxicillin, clarithromycin, pantoprazole), who consumed the Test or a Control product for 28 days. Feces were analysed for gut microbiota composition, short chain fatty acids (SCFA), calprotectin, and viability of ingested strains.

RESULTS

No effect of Test product was observed on AAD occurrence or duration, rating scores or number of days of GI symptoms. Hp-treatment induced a significant alteration in bacterial and fungal composition, a decrease of bacterial count and alpha-diversity, an increase of Candida and of calprotectin, and a decrease of SCFA concentration. Following Hp treatment, in the Test as compared to Control group, intra-subject beta-diversity distance from baseline was lower (padj=0.02), Escherichia-Shigella (padj=0.0082) and Klebsiella (padj= 0.013) were significantly less abundant, and concentrations of major SCFA (p=0.035) and valerate (p = 0.045) were higher. Viable Lp and Lr strains from the Test product were mainly detected during product consumption in feces.

CONCLUSIONS

The study showed that 14-day Hp triple therapy alters gut bacterial and fungal community, their metabolites and gut inflammatory markers. Consumption of a multi-strain fermented milk can induce faster recovery of the microbiota composition and SCFA production and limit the bloom of pathobionts. (ClinicalTrials.gov, NCT02900196; First Posted : September 14, 2016; https://www.clinicaltrials.gov/ct2/show/NCT02900196).
Mapping SARS-CoV-2 Antibody Epitopes in COVID-19 Patients with a Multi-Coronavirus Protein Microarray
Authors: Camerini David , Randall Arlo Z. , Trappl-Kimmons Krista , Oberai Amit , Hung Christopher , Edgar Joshua , Shandling Adam , Huynh Vu , Teng Andy A. , Hermanson Gary , Pablo Jozelyn V. , Stumpf Megan M. , Lester Sandra N. , Harcourt Jennifer , Tamin Azaibi , Rasheed Mohammed , Thornburg Natalie J. , Satheshkumar Panayampalli S. , Liang Xiaowu , Kennedy Richard B. , Yee Angela , Townsend Michael , Campo Joseph J.
Published: January 2021

The emergence and rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of varying lengths and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multi-coronavirus arrays to identify specific antibody reactivity. High level IgG, IgM and IgA reactivity to structural proteins S, M and N, as well as accessory proteins, of SARS-CoV-2 were observed that was specific to COVID-19 patients. Overlapping 100, 50 and 30 amino acid fragments of SARS-CoV-2 proteins identified antigenic regions. Numerous proteins of SARS-CoV, MERS-CoV and the endemic human coronaviruses, HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients.
Development of at-home sample collection logistics for large scale SARS-CoV-2 seroprevalence studies
Authors: Aatresh Aishani V. , Cummings Kate , Gerstein Hilary , Knight Christopher S. , Limberopolous Andreas , Stasi Megan A. , Bedugnis Alice , Somberg Kenneth A. , França Camila T. , Mina Michael J.
Published: January 2021

In the midst of a pandemic, serologic studies are a valuable tool to understand the course of the outbreak and guide public health and general pandemic management. However, given significant safety constraints including social distancing and stay-at-home orders, sample collection becomes more difficult given traditional phlebotomy protocols. For such studies, a representative sample of the underlying population is paramount to elicit meaningful insights that capture the spread of the infection, particularly when different sub-populations face varying disease burden. We aimed to address these challenges by conducting a fully remote study to investigate the seroprevalence of SARS-CoV-2 in the state of Massachusetts. Leveraging electronic study engagement and at-home self-collection of finger-prick samples, we enrolled 2,066 participants representative of the ethnic and racial composition of Massachusetts. SARS-CoV-2 total IgG seropositivity was 3.15%, and follow-up measurements at days 7, 15, 45, and 90 indicate a generally durable antibody response. A higher risk of infection was observed for healthcare workers and their cohabitants and those with comorbidities, as well as lower-income, less educated, Hispanic, and those in the age groups of 18-29 and 50-59-years-old. High engagement and positive feedback from the participants and quality of self-collected specimens point to the usefulness of this design for future population-level serological studies that more effectively and safely reach a broad representative cohort, thus yielding more comprehensive insights into the burden of infection and disease in populations.

Key points

Question

We aimed to implement a fully remote seroprevalence study for SARS-CoV-2, leveraging electronic methods and at-home self-collection of specimens to engage a representative study population.

Findings

The population enrolled reflected the ethnic and racial composition of Massachusetts, revealing a SARS-CoV-2 seroprevalence of 3.15% and higher risk of previous infection associated with healthcare workers/their cohabitants, those with comorbidities, lower-income, less educated, Hispanic, and those in age groups 18-29 and 50-59 years old.

Meaning

High engagement and positive feedback from participants as well as quality of self-collected specimens point to the usefulness of this design for future population-level serological studies.
Predicting Emerging Themes in Rapidly Expanding COVID-19 Literature with Dynamic Word Embedding Networks and Machine Learning
Authors: Pal Ridam , Chopra Harshita , Awasthi Raghav , Bandhey Harsh , Nagori Aditya , Gulati Amogh , Kumaraguru Ponnurangam , Sethi Tavpritesh
Published: January 2021

Evidence from peer-reviewed literature is the cornerstone for designing responses to global threats such as COVID-19. The collection of knowledge and interpretation in publications needs to be distilled into evidence by leveraging natural language in ways beyond standard meta-analysis. Several studies have focused on mining evidence from text using natural language processing, and have focused on a handful of diseases. Here we show that new knowledge can be captured, tracked and predicted using the evolution of unsupervised word embeddings and machine learning. Our approach to decipher the flow of latent knowledge in time-varying networks of word-vectors captured thromboembolic complications as an emerging theme in more than 77,000 peer-reviewed publications and more than 11,000 WHO vetted preprints on COVID-19. Furthermore, machine learning based prediction of emerging links in the networks reveals autoimmune diseases, multisystem inflammatory syndrome and neurological complications as a dominant research theme in COVID-19 publications starting March 2021.
Single-cell transcriptome lineage tracing of human pancreatic development identifies distinct developmental trajectories of alpha and beta cells
Authors: Lin Li , Zhang Yufeng , Qian Weizhou , Liu Yao , Zhang Yingkun , Lin Fanghe , Liu Cenxi , Lu Guangxing , Song YanLing , Song Jia , Yang Chaoyong , Li Jin
Published: January 2021

In comparison to mouse, the developmental process of human islets has not been properly elucidated. The advancement of single cell RNA-seq technology enables us to study the properties of alpha and beta cells at single cell resolution. By using mitochondrial genome variants as endogenous lineage-tracing markers, we found that human alpha and beta cells have different lineage features. This finding suggests specific endocrine progenitors for alpha and beta cells, which is different from mouse islet cells. This strategy was also applied to a study of chemically-induced islet cell reprogramming and was used to help identify artemether-induced alpha-to-beta trans-differentiation in human islets. The computational results of this study will inspire future studies to establish, maintain, and expand beta cell-specific progenitorsin vitroandin vivo.
O-specific antigen-dependent surface hydrophobicity mediates aggregate assembly type inPseudomonas aeruginosa
Authors: Azimi Sheyda , Thomas Jacob , Cleland Sara E. , Curtis Jennifer E. , Goldberg Joanna B. , Diggle Stephen P.
Published: January 2021

Bacteria live in spatially organized aggregates during chronic infections, where they adapt to the host environment, evade immune responses and resist therapeutic interventions. Although it is known that environmental factors such as polymers influence bacterial aggregation, it is not clear how bacterial adaptation during chronic infection impacts the formation and spatial organization of aggregates in the presence of polymers. Here we show that in anin vitromodel of cystic fibrosis (CF) containing the polymers eDNA and mucin, O-specific antigen is a major factor in determining the formation of two distinct aggregate assembly types ofPseudomonas aeruginosadue to alterations in cell surface hydrophobicity. Our findings suggest that during chronic infection, interplay between cell surface properties and polymers in the environment may influence the formation and structure of bacterial aggregates, which would shed new light on the fitness costs and benefits of O-antigen production in environments such as CF lungs.

Importance

During chronic infection, several factors contribute to the biogeography of microbial communities. Heterogeneous populations ofPseudomonas aeruginosaform aggregates in cystic fibrosis airways, however, the impact of this population heterogeneity on spatial organization and aggregate assembly is not well understood. In this study we found that changes in O-specific antigen determine the spatial organization ofP. aeruginosacells by altering the relative cell surface hydrophobicity. This finding suggests a role for O-antigen in regulatingP. aeruginosaaggregate size and shape in cystic fibrosis airways.
Early Stopping in Experimentation with Real-time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test
Authors: Carr Sarah J. A. , Chen Weicong , Fondran Jeremy , Friel Harry , Sanchez-Gonzalez Javier , Zhang Jing , Tatsuoka Curtis
Published: January 2021

Introduction

Functional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically-driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed.

Methods

Voxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR).

Results

Use of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 minutes on a 12 minute scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters.

Conclusion

A systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects.
The influence of ethical leadership on the organizational commitment in fire organizations
Authors: Bahadori Mohammadkarim , Ghasemi Matina , Hasanpoor Edris , Hosseini Seyed Mojtaba , Alimohammadzadeh Khalil
Published: January 2021

Purpose

It is necessary for organizations to have committed employees to perform properly and be able to survive in a competitive world. One of the key components of organizational commitment is implementation of ethical leadership. The purpose of this study is to examine the relationship between ethical leadership and organizational commitment in fire organizations of Tehran.

Design/methodology/approach

A descriptive-correlational study was carried out in 2019. The sample consisted of 200 randomly selected participants, active in executive and headquarters divisions of fire department in Tehran. To collect data, a questionnaire with three different parts: demographics, organizational commitment questionnaire and the ethical leadership scale, was used. Data analysis were performed by AMOS24 and SPSS software, and data are presented as descriptive statistics of frequency, percentages, mean ± standard deviation (SD) and Pearson’s correlation coefficient.

Findings

Mean and SD for organizational commitment and ethical leadership were 3.44 ± 0.7 and 3.66 ± 0.62, respectively. Affective commitment had the highest average score among organizational commitment dimensions (3.63 ± 0.75). Among ethical leadership dimensions, ethical management showed the highest average (3.79 ± 0.70). Each component of organizational commitment, i.e. affective commitment, continuance commitment and normative commitment, also showed a significant relationship with ethical leadership (p< 0.05). Model fit results revealed that independent variables could anticipate 87% of changes of dependent variables in organizational commitment.

Originality/value

The results show a significantly positive relationship between ethical leadership and organizational commitment among the firefighters. Therefore, by using ethical leadership method, i.e. being a role model, improving the relations between management and employees, establishing trust and mutual respect, managers of fire departments can increase firefighters’ organizational commitment, affective commitment, continuance commitment and normative commitment and prevent them from quitting.
Promoting mutual adaptation in haptic negotiation using adaptive virtual fixture
Authors: Zhou Hua , Wei Dong , Chen Yinglong , Wu Fa
Published: January 2021

Purpose

To promote the intuitiveness of collaborative tasks, the negotiation ability of humans with each other has inspired a large amount of studies aimed at reproducing the capacity in physical human-robot interaction (pHRI). This paper aims to promote mutual adaptation in negotiation when both parties possess incomplete information.

Design/methodology/approach

This paper introduces virtual fixtures into the traditional negotiation mechanism, locally regulating tracking trajectory and impedance parameters in the negotiating phase until the final plan integrates bilateral intentions well. In the strategy, robots convey its task information to humans and offer groups of guide plans for them to choose, on the premise of maximizing the robot’s own profits.

Findings

Compared with traditional negotiation strategies, humans adapt to robots easily and show lower cognitive load in the method, while the satisfied plan shows better performance for the whole human-robot system.

Originality/value

In this study, this paper proposes a novel negotiation strategy to facilitate the mutual adaptation of humans and robots in complicated shared tasks, especially when both parties possess incomplete information of tasks.