bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher Frequency and Mortality Rate of Antimicrobial-resistant Bloodstream Infections in Tertiary-care Hospitals Compared with Secondary-care Hospitals in Thailand
Authors: Lim Cherry , Hantrakun Viriya , Klaytong Preeyarach , Rangsiwutisak Chalida , Tangwangvivat Ratanaporn , phiancharoen Chadaporn , Doung-ngern Pawinee , Kripattanapong Somkid , Hinjoy Soawapak , Yingyong Thitipong , Rojanawiwat Archawin , Unahalekhaka Aekkawat , Kamjumphol Watcharaporn , Khobanan Kulsumpun , Leethongdee Phimrata , Lorchirachoonkul Narisorn , Khusuwan Suwimon , Siriboon Suwatthiya , Chamnan Parinya , Vijitleela Amornrat , Fongthong Traithep , Noiprapai Krittiya , Boonyarit Phairam , Srisuphan Voranadda , Sartorius Benn , Stelling John , Turner Paul , Day Nicholas PJ , Limmathurotsakul Direk
Published: February 2023

There are few studies comparing proportion, frequency, mortality and mortality rate of antimicrobial-resistant (AMR) bacterial infections between tertiary-care hospitals (TCHs) and secondary-care hospitals (SCHs) in low and middle-income countries (LMICs) to inform infection control strategies. We evaluated bloodstream infections (BSIs) from 2012 to 2015 in 15 TCHs and 34 SCHs in Thailand. There were differences in the proportions (%) of BSI caused by AMR strains for some pathogens between TCHs and SCHs. Of 19,665 patients with AMR BSI, 6,746 (34.3%) died. Among patients with AMR BSI, there were no or minimal differences in mortality proportion for all AMR pathogens between TCHs and SCHs. However, the frequency and mortality rates of AMR BSI were considerably higher in TCHs for most pathogens. For example, the mortality rate of hospital-origin carbapenem-resistantAcinetobacter baumanniiBSI in TCHs was nearly three times higher than that in SCHs (10.2 vs. 3.6 per 100,000 patient-days at risk, mortality rate ratio 2.77; 95% confidence interval 1.71 to 4.48, p<0.0001). Targets of and resources for antimicrobial stewardship and infection control programs in LMICs may need to be tailored based on hospital type and size, as burden of AMR infections could differ by hospital setting.
Association between calcium and vitamin D in geriatric patients hospitalized for Covid-19: Results from the GERIA-COVID study
Authors: Bourgeais Alexis , Gautier Jennifer , Sacco Guillaume , Annweiler Cédric , Asfar Marine
Published: February 2023

The deficiency of 25OH vitamin D (25[OH]D) is common in the older population. It physiologically triggers secondary hyperparathyroidism resulting in normal circulating calcium levels. Adjusted calcium (CaA) is estimated by the PAYNE method and several studies report a misclassification of calcium status by corrected calcium compared to ionized calcium (CaI) in older patients. Hypocalcemia is common in older COVID-19 patients. Blunted secondary hyperparathyroidism explain this high prevalence of hypocalcemia in COVID-19. However, no studies have focused on patients older than 75 years despite the high mortality rate in this population. In the present study, the association between the different types of calcium (CaI, CaA, and total calcium [CaT]) and 25(OH)D deficiency (below 50 nmol/L) was investigated. The study of the correlation between each type of calcium was performed secondarily. Observational monocentric study focused on the GERIA-COVID database during the second wave of COVID-19 in France from October 2020 to March 2021. COVID-19 was diagnosed with RT-PCR and/or chest CT-scan. A population of 181 older COVID-19 patients (86.4 years ± 5.7) was analyzed. Sixty-three patients (34.8%) were deficient in 25(OH)D. The prevalence of total and ionized hypocalcemia was 44.1% and 39.2%, respectively. A negative association was reported in linear regression between 25(OH)D deficiency and CaA (β =-0.052 [- 0.093; -0.010], p = 0.015) as well as with CaT (β = -0.05 [-0.09; -0.01], p =0.034) in the multivariate model. No association was found between vitamin D deficiency and CaI. In the multivariate models, there was no association between each type of calcium and PTH. CaI was correlated with CaT (r = 0.39, p < 0.001) and with CaA (r = 0.15, p = 0.043). Secondary hyperparathyroidism was not activated in the context of COVID-19 in this study. After reviewing the literature, this appears to be the first study in older patients to expose such results.
Poor evidence for an effect of tecovirimat in shortening recovery time in hospitalized mpox cases from real-world data
Authors: Mazzotta V , Cozzi-Lepri A , Lanini S , Mondi A , Carletti F , Tavelli A , Gagliardini R , Vita S , Pinnetti C , Aguglia C , Faccendini P , Colavita F , Faraglia F , Beccacece A , Paulicelli J , Girardi E , Nicastri E , Vaia F , Maggi F , Antinori A
Published: February 2023

Objectives

To assess the effectiveness of tecovirimat (TPOXX) for treating mpox in terms of difference in healing time and extent of viral clearance.

Design

Emulation of a target trial based on observational data.

Setting

Italy

Participants

Forty-one men hospitalized for mpox as of September 29th, 2022.

Main outcome measures

Main outcome was the time to clinical recovery. Secondary outcome was the variation in viral load in the upper respiratory tract (URT) after treatment.

Results

The median time from symptoms onset to hospital admission and to initiation of TPOXX was 4 days (IQR 2-6) and 10 days (IQR 8-11), respectively. Fifteen patients completed a course of therapy. No deaths were observed; the overall median healing time was 21 days (IQR 17-26). We found no evidence for a significant improvement in recovery time in treated vs. untreated patients, with an estimated mean of 14.7 days for both groups. A subset of 13 patients had URT samples at T1 (median of 5 days (IQR 3-7) from symptoms onset) and T2 (median 7 days (IQR 7-9) from T1). Overall, mean viral load was 4.65 (0.30) vs. 4.91 (0.35) (log2 scale of cycle threshold) at T1 and T2, respectively. In the unadjusted analysis, variation over T1-T2 was lower in the treated 0.13 log2 (SD=0.53) vs. untreated 0.37 (0.50), although not statistically significant (unpaired t-test p=0.41). After controlling for confounding, there was no evidence for a difference in the potential changes over T1-T2 by treatment arm, and our estimate of the average treatment effect (ATE) was consistent with no difference by treatment group, although with large 95% CI around these estimates.

Conclusions

Our analysis seems to exclude a clinically important effect of TPOXX in hospitalized mpox patients when compared to no treatment. These data are one of the valuable currently available sources of evidence to guide treatment decisions in patients hospitalized with TPOXX. Pending more robust data from randomized comparisons, the use of TPOXX should be restricted to the clinical trials setting.

Trial registration

“MpoxCohort” observational study protocol: approval number 40z, Register of Non-Covid Trials 2022.
A Compound Model of Multiple Treatment Selection with Applications to Marginal Structural Modeling
Authors: Stein David , D’Arinzo Lauren , Gaspar Fraser , Oliver Max , Fitzgerald Kristin , Lu Di , Piantadosi Steven , Amin Alpesh , Webb Brandon
Published: February 2023

Methods of causal inference are used to estimate treatment effectiveness for non-randomized study designs. The propensity score (i.e., the probability that a subject receives the study treatment conditioned on a set of variables related to treatment and/or outcome) is often used with matching or sample weighting techniques to, ideally, eliminate bias in the estimates of treatment effect due to treatment decisions. If multiple treatments are available, the propensity score is a function of the adjustment set and the set of possible treatments. This paper develops a compound model that separates the treatment decision into a binary decision: treat or don’t treat; and a potential treatment decision: choose the treatment that would be given if the subject is treated. It is applicable if the treatment set is finite, treatments are given at one time point, and the outcome is observed at a fixed time point. This representation can reduce bias when not all treatments are available to all patients. Multiple treatment stabilized marginal structural weights were calculated with this approach, and the method was applied to an observational study to evaluate the effectiveness of different neutralizing monoclonal antibodies to treat infection with various severe acute respiratory syndrome coronavirus 2 variants.
Coevolution with a seed bank
Authors: Schwartz Daniel A. , Shoemaker William R. , Măgălie Andreea , Weitz Joshua S. , Lennon Jay T.
Published: February 2023

Dormancy is as an adaptation to living in fluctuating environments. It can also influence species interactions, for example, by providing organisms with a refuge from predators and parasites. Here we test the hypothesis that dormancy generates a seed bank of protected individuals that can modify antagonistic coevolutionary dynamics. We experimentally evolved a spore-forming bacterial host along with a phage parasite that can infect active but not dormant cells. Seed banks buffered population dynamics against phage infection and retained phenotypic diversity that was otherwise lost to directional selection. By storing genetic diversity, seed banks also altered the distribution of host alleles, which contributed to dampened coevolutionary dynamics. Our findings demonstrate that dormancy generates a seed bank that can modify the eco-evolutionary outcomes of host-parasite systems.
Translational control byTrypanosoma bruceiDRBD18 contributes to the maintenance of the procyclic state
Authors: Ciganda Martin , Sotelo-Silveira José , Smith Joseph T. , Shen Shichen , Qu Jun , Smircich Pablo , Read Laurie K.
Published: February 2023

Trypanosoma bruceioccupies distinct niches throughout its life cycle, within both the mammalian and tsetse fly hosts. The immunological and biochemical complexity and variability of each of these environments require a reshaping of the protein landscape of the parasite both to evade surveillance and face changing metabolic demands. Whereas most well-studied organisms rely on transcriptional control as the main regulator of gene expression, post-transcriptional control mechanisms are particularly important inT. brucei, and these are often mediated by RNA-binding proteins. DRBD18 is aT. bruceiRNA-binding protein that interacts with ribosomal proteins and translation factors. Here, we tested a role for DRBD18 in translational control. We show that DRBD18 depletion by RNA interference leads to altered polysomal profiles with a specific depletion of heavy polysomes. Ribosome profiling analysis reveals that 101 transcripts change in translational efficiency (TE) upon DRBD18 depletion: 41 exhibit decreased TE and 60 exhibit increased TE. A further 66 transcripts are buffered,i.e. changes in transcript abundance are compensated by changes in TE such that the total translational output is expected not to change. Proteomic analysis validates these data. In DRBD18-depleted cells, a cohort of transcripts that codes for procyclic form-specific proteins is translationally repressed while, conversely, transcripts that code for bloodstream form- and metacyclic form-specific proteins are translationally enhanced. These data suggest that DRBD18 contributes to the maintenance of the procyclic state through both positive and negative translational control of specific mRNAs.
Palmitic acid reduces viability and increases production of reactive oxygen species and respiration in rat tendon-derived cells
Authors: Konar Subhajit , Hedges Christopher P , Callon Karen E , Bolam Scott , Leung Sophia , Cornish Jillian , Naot Dorit , Musson David S
Published: February 2023

Clinically, there is a positive correlation between BMI and the risk of tendinopathy. However, the underlying mechanisms are not understood. Dyslipidaemia and increased circulating free fatty acids (FFA) are associated with increased BMI. We hypothesised that increased FFA concentrations negatively affect rat tendon-derived cells (rTDCs) through mitochondrial-mediated mechanisms.

rTDCs were isolated and treated with oleic acid (OA), stearic acid (SA), and palmitic acid (PA). Cell viability was assessed using AlamarBlue™ assay, and gene expression using real-time PCR. Cell respiration and reactive oxygen species (ROS) production were measured using high-resolution respirometry and MitoSox staining. PA transport into the mitochondria was blocked by pre-treatment with 50µM etomoxir.

Treatment with SA and PA at 10 µg/ml decreased rTDC viability by 40% and 60%, respectively. PA decreased the gene expression of the tendon markersScxandTnmd, and increased the expression ofMmp3, Mmp13, andPtgs2(encoding Cox-2). FFA treatment increased the expression ofCpt1andPdk4, indicating an increase in mitochondrial FFA oxidation. PA, at 10 µg/ml, increased cellular respiration and ROS production. Pre-treatment with etomoxir partially inhibited the effects of PA on cell viability,Mmp3gene expression, ROS production, and cell respiration, but did not affect PA-induced inhibition ofScxorTnmdexpression.

We found that increased saturated FFA concentrations in the microenvironment reduce cell viability and alter ROS production, respiration, and gene expression. Blocking PA transport into mitochondria partially reversed the negative effects of PA. Overall, an increase in saturated FFA concentrations may contribute to poor tendon health.
Deep learning distinguishes focal epilepsy groups using connectomes: Feasibility and clinical implications
Authors: Maher Christina , Tang Zihao , D’Souza Arkiev , Cabezas Mariano , Cai Weidong , Barnett Michael , Kavehei Omid , Wang Chenyu , Nikpour Armin
Published: February 2023

The application of deep learning models to evaluate connectome data is gaining interest in epilepsy research. Deep learning may be a useful initial tool to partition connectome data into network subsets for further analysis. Few prior works have used deep learning to examine structural connectomes from patients with focal epilepsy. We evaluated whether a deep learning model applied to whole-brain connectomes could classify 28 participants with focal epilepsy from 20 controls and identify nodal importance for each group. Participants with epilepsy were further grouped based on whether they had focal seizures that evolved into bilateral tonic-clonic seizures (17 with, 11 without). The trained neural network classified patients from controls with an accuracy of 72.92%, while the seizure subtype groups achieved a classification accuracy of 67.86%. In the patient subgroups, the nodes and edges deemed important for accurate classification were also clinically relevant, indicating the model’s interpretability. The current work expands the evidence for the potential of deep learning to extract relevant markers from clinical datasets. Our findings offer a rationale for further research interrogating structural connectomes to obtain features that can be biomarkers and aid the diagnosis of seizure subtypes.
Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities Study
Authors: Zhao Naisi , Teles Flavia , Lu Jiayun , Koestler Devin C. , Beck James , Boerwinkle Eric , Bressler Jan , Kelsey Karl T. , Platz Elizabeth A. , Michaud Dominique S.
Published: February 2023

Aim

Our goal was to investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood.

Materials and Methods

For this analysis, we included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at visit 4 and had available data on DNA methylation. DNA methylation levels were compared by periodontal disease severity and edentulism to identify differentially methylated regions (DMRs) and evaluate the CpGs belonging to those DMRs using multinominal logistic regression.

Results

We identified a region in geneZFP57(6p22.1) that was significantly hypomethylated in severe periodontal disease compared to no/mild periodontal disease in European American participants. A separate region in an unknown gene (located in Chr10: 743,992-744,958) demonstrated significant positive association with edentulism compared to no/mild periodontal disease in African American participants. Four CpGs in a region located withinHOXA4were significantly hypermethylated in severe periodontal disease compared to no/mild periodontal disease in African American participants.

Conclusions

Our study highlights epigenetic variations inZPF57andHOXA4that were significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

CLINICAL RELEVANCE

Scientific Rationale for Study

Without altering the DNA sequence, epigenetic effects (e.g., DNA methylation changes) can alter gene activity and influence host response to periodontal infections. Our well-powered study investigates individual susceptibility to periodontitis by conducting a thorough assessment of periodontitis-related DNA methylation levels in blood.

Principal Findings

We identified two gene regions,ZPF57andHOXA4, that are differentially methylated in individuals with compared to those without periodontitis.

Practical implications

Studying differential leukocyte DNA methylation patterns may point to candidate regions and underlying gene regulatory mechanisms that play a key role in the progression and/or susceptibility to periodontitis.
An algorithm that combines machine learning ensemble modeling and network analysis to predict self-tolerant tumor-associated antigens for anti-cancer immunotherapy
Authors: Lischer Christopher , Eberhardt Martin , Weich Adrian , Vera Julio
Published: February 2023

Tumor-associated antigens (TAAs) and their derived peptides constitute the chance to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. Here, we present a computational pipeline that selects and ranks candidate antigens in a multi-pronged approach and applied it to the case of uveal melanoma. In addition to antigen expression in the tumor target and in healthy tissues, we incorporated a network analysis-derived antigen indispensability index motivated by computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model on peptide physicochemical characteristics.
Development of White Matter Fiber Covariance Networks Supports Executive Function in Youth
Authors: Bagautdinova Joëlle , Bourque Josiane , Sydnor Valerie J , Cieslak Matt , Alexander-Bloch Aaron F , Bertolero Max A , Cook Phil A , Gur Raquel C , Gur Ruben E , Larsen Bart , Moore Tyler M , Radhakrishnan Hamsi , Roalf David R , Shinohara Russel T , Tapera Tinashe M , Zhao Chenying , Sotiras Aristeidis , Davatzikos Christos , Satterthwaite Theodore D
Published: February 2023

The white matter architecture of the human brain undergoes substantial development throughout childhood and adolescence, allowing for more efficient signaling between brain regions that support executive function. Increasingly, the field understands grey matter development as a spatially and temporally coordinated mechanism that follows hierarchically organized gradients of change. While white matter development also appears asynchronous, previous studies have largely relied on anatomical atlases to characterize white matter tracts, precluding a direct assessment of how white matter structure is spatially and temporally coordinated. Here, we leveraged advances in diffusion modeling and unsupervised machine learning to delineate white matter fiber covariance networks comprised of structurally similar areas of white matter in a cross-sectional sample of 939 youth aged 8-22 years. We then evaluated associations between fiber covariance network structural properties with both age and executive function using generalized additive models. The identified fiber covariance networks aligned with the known architecture of white matter while simultaneously capturing novel spatial patterns of coordinated maturation. Fiber covariance networks showed heterochronous increases in fiber density and cross section that generally followed hierarchically organized temporal patterns of cortical development, with the greatest increases in unimodal sensorimotor networks and the most prolonged increases in superior and anterior transmodal networks. Notably, we found that executive function was associated with structural features of limbic and association networks. Taken together, this study delineates data-driven patterns of white matter network development that support cognition and align with major axes of brain maturation.
A versatile CRISPR-based system for lineage tracing in living plants
Authors: Donà Mattia , Bradamante Gabriele , Bogojevic Zorana , Gutzat Ruben , Streubel Susanna , Mosiolek Magdalena , Dolan Liam , Scheid Ortrun Mittelsten
Published: February 2023

Individual cells give rise to diverse cell lineages during the development of multicellular organisms. Understanding the contribution of these lineages to mature organisms is a central question of developmental biology. Several techniques to document cell lineages have been used, from marking single cells with mutations that express a visible marker to generating molecular bar codes by CRISPR-induced mutations and subsequent single-cell analysis. Here, we exploit the mutagenic activity of CRISPR to allow lineage tracing within living plants. Cas9-induced mutations are directed to correct a frameshift mutation that restores expression of a nuclear fluorescent protein, labelling the initial cell and all progenitor cells with a strong signal without modifying other phenotypes of the plants. Spatial and temporal control of Cas9 activity can be achieved using tissue-specific and/or inducible promoters. We provide proof of principle for the function of lineage tracing in two model plants. The conserved features of the components and the versatile cloning system, allowing for easy exchange of promoters, are expected to make the system widely applicable.

SIGNIFICANCE STATEMENT

By targeting Cas9 in a tissue- and time-specific way to correct a frameshift mutation, resulting in fluorescence labelling of nuclei, we generated a method forin vivovisual lineage tracing in two model plants. The versatile cloning system makes the system widely applicable in other plants.
Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala
Authors: Grogans Shannon Elizabeth , Hur Juyoen , Barstead Matthew G , Anderson Allegra S , Islam Samiha , Kim Hyung Cho , Kuhn Manuel , Tillman Rachael M , Fox Andrew S , Smith Jason F , DeYoung Kathryn A , Shackman Alexander J
Published: February 2023

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are non-fungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing mechanistic research.
Metaphor - A workflow for streamlined assembly and binning of metagenomes
Authors: Salazar Vinícius W. , Shaban Babak , del Mar Quiroga Maria , Turnbull Robert , Tescari Edoardo , Marcelino Vanessa Rossetto , Verbruggen Heroen , Lê Cao Kim-Anh
Published: February 2023

Recent advances in bioinformatics and high-throughput sequencing have enabled the large-scale recovery of genomes from metagenomes. This has the potential to bring important insights as researchers can bypass cultivation and analyse genomes sourced directly from environmental samples. There are, however, technical challenges associated with this process, most notably the complexity of computational workflows required to process metagenomic data, which include dozens of bioinformatics software tools, each with their own set of customisable parameters that affect the final output of the workflow. At the core of these workflows are the processes of assembly - combining the short input reads into longer, contiguous fragments (contigs), and binning - clustering these contigs into individual genome bins. Both processes can be done for each sample separately or by pooling together multiple samples to leverage information from a combination of samples. Here we present Metaphor, a fully-automated workflow for genome-resolved metagenomics (GRM). Metaphor differs from existing GRM workflows by offering flexible approaches for the assembly and binning of the input data, and by combining multiple binning algorithms with a bin refinement step to achieve high quality genome bins. Moreover, Metaphor generates reports to evaluate the performance of the workflow. We showcase the functionality of Metaphor on different synthetic datasets, and the impact of available assembly and binning strategies on the final results. The workflow is freely available athttps://github.com/vinisalazar/metaphor.

Author summary

We present Metaphor, a user-friendly, automated workflow for the recovery of genomes from metagenomes. Our tool offers flexible options for assembling and binning metagenomic contigs, that may be adjusted according to the characteristics of the input data and available computational resources, and a combination of binning algorithms, which improves the quantity and quality of resulting genome bins. We showcase the performance of Metaphor on synthetic benchmarking datasets and discuss the implication of methodological decisions regarding the strategy for assembling and binning metagenomic contigs.
Seroprevalence of IgG Antibody against SARS-CoV-2 Nucleocapsid protein and Associated Risk Factors
Authors: Chowdhury Yeamin Farabi , Hossen Faruk , Islam S. M. Rashadul , Hossain Md. Saddam , Mahtab-Ul-Islam Kazi , Chowdhury Sumaiya Islam , Hasan Md. Rakibul , Tasnim Nishat , Sultana Sharmin , Shaikh Md. Aftab Ali , Karim Md. Rezaul
Published: February 2023

Estimation of antibody development against SARS-CoV-2 is essential means for understanding the immune response against the virus. We reported IgG antibody development status against Nucleocapsid protein of the virus and compared with lifestyle (health and food habits), co-existing diseases, vaccination and COVID-19 infection status. ELISA (Enzyme Linked Immunosorbent Assay) was performed to assess IgG antibodies targeted against the Nucleocapsid protein of SARS-CoV-2 in participants (n=500). In this seroprevalence study, serological data were estimated for a period of 10 months in the participants who were aged 10 years and above. Sociodemographic and risk factors related data were collected through a written questionnaire and chi-square test was performed to determine the association with seropositivity. The overall seroprevalence of anti-SARS-CoV-2 antibodies among the study subjects was 47.8%. Estimates were highest among the participants of 21-40 years old (55.1%), and lowest in older aged (>60 years) participants (39.5%). Among the Sinopharm vaccinated individuals 81.8% had developed anti-Nucleocapsid antibody. Physical exercise and existence of comorbidities like hypertension and diabetes were the distinguishing factors between seropositive and seronegative individuals. Seropositivity rate largely varied among symptomatic (67%) and asymptomatic (33.1%) COVID-19 infected participants. The findings suggest that residents of Dhaka city had a higher prevalence of anti-nucleocapsid antibody in the second year of the pandemic. This indicates the improvement of immunological status among the population. Finally, the study emphasizes on maintaining active and healthy lifestyle to improve immunity. However, the absence of IgG antibodies in many cases of COVID-19 infected individuals suggests that antibodies wane with time.

Key messages

The overall seroprevalence of anti-Nucleocapsid IgG among the study subjects was determined to be 47.8%.

Age, regular physical exercise, existence of comorbidities were the identified parameters associated with seroprevalence.

This study observed lower prevalence of Anti-Nucleocapsid antibody among asymptomatic cases of COVID-19 infected individuals compared to symptomatic cases.
Unipept Desktop 2.0: construction of targeted reference protein databases for proteogenomics analyses
Authors: Verschaffelt Pieter , Tanca Alessandro , Abbondio Marcello , Van Den Bossche Tim , Vande Moortele Tibo , Dawyndt Peter , Martens Lennart , Mesuere Bart
Published: February 2023

Unipept Desktop 2.0 is the most recent iteration of the Unipept Desktop tool that adds support for the analysis of proteogenomics datasets. Unipept Desktop now supports the automatic construction of targeted protein reference databases that only contain proteins associated with a predetermined list of taxa. This improves both the taxonomic and functional resolution of a metaproteomic analysis and yields several technical advantages. By limiting the proteins present in a reference database, it is now also possible to perform (meta)proteogenomics analyses. Since the protein reference database now lives on the user’s local machine, they have complete control over the database used during an analysis. Data does no longer need to be transmitted over the internet, decreasing the time required for an analysis and better safeguarding privacy sensitive data. As a proof of concept, we present a case study in which a human gut metaproteome dataset is analyzed with Unipept Desktop 2.0 using different targeted databases based on matched 16S rRNA gene sequencing data.
ImmuneMirror: a Machine Learning-based Integrative Pipeline and Web Server for Neoantigen Prediction
Authors: Chuwdhury Gulam Sarwar , Guo Yunshan , Chiang Chi-Leung , Lam Ka-On , Kam Ngar-Woon , Liu Zhonghua , Dai Wei
Published: February 2023

Neoantigens are derived from tumors but are absent in normal tissues. Emerging evidence suggests that neoantigens can stimulate tumor-specific T-cell-mediated antitumor immune responses, and neoantigens are potential immunotherapy targets. We developed ImmuneMirror as a stand-alone open-source pipeline (https://github.com/weidai2/ImmuneMirror/) and a web server (http://immunemirror.hku.hk/App/) incorporating a balanced random forest model for neoantigen prediction and prioritization; the model was trained and tested using known immunogenic neopeptides collected from 19 published studies. The area under the curve (AUC) of our model was 0.87. We utilized ImmuneMirror in gastrointestinal tract cancers and discovered a subgroup of microsatellite instability-high (MSI-H) colorectal cancer (CRC) patients with a low neoantigen load but a high tumor mutation burden (TMB>10 mutations per Mbp). Although the efficacy of PD-1 blockade has been demonstrated in advanced MSI-H patients, almost half of such patients do not respond well. Our study may identify MSI-H patients who do not benefit from this treatment. Additionally, the neopeptide YMCNSSCMGV-TP53G245V, derived from a hotspot mutation restricted by HLA-A02, was identified as an actionable target in esophageal squamous cell carcinoma (ESCC). This is the largest study to comprehensively evaluate neoantigen prediction models using experimentally validated neopeptides. Our results demonstrate the reliability and effectiveness of ImmuneMirror for neoantigen prediction.
An RNA to rule them all: Critical steps in Lassa virus ribonucleoparticle assembly and recruitment
Authors: Sänger Lennart , Williams Harry M. , Yu Dingquan , Vogel Dominik , Kosinski Jan , Rosenthal Maria , Uetrecht Charlotte
Published: February 2023

Lassa virus is a negative-strand RNA virus with only four structural proteins that causes periodic outbreaks in West Africa. The nucleoprotein (NP) encapsidates the viral genome, forming the ribonucleoprotein complexes (RNPs) together with the viral RNA and the L protein. RNPs have to be continuously restructured during viral genome replication and transcription. The Z protein is important for membrane recruitment of RNPs, viral particle assembly and budding, and has also been shown to interact with the L protein. However, the interaction of NP, viral RNA and Z is poorly understood. Here, we characterize the interactions between Lassa virus NP, Z and RNA using structural mass spectrometry. We identify the presence of RNA as the driver for disassembly of ring-like NP trimers, a storage form, into monomers to subsequently form higher order RNA-bound NP assemblies. We locate the interaction site of Z and NP and demonstrate that while NP binds Z independently of the presence of RNA, this interaction is pH-dependent. These data improve our understanding of RNP assembly, recruitment and release in Lassa virus.
Condensate formation of the human RNA-binding protein SMAUG1 is controlled by its intrinsically disordered regions and interactions with 14-3-3 proteins
Authors: Fehilly John , Carey Olivia , O’Leary Eoghan Thomas , O’Shea Stephen , Juda Klaudia , Fitzel Rahel , Selvaraj Pooja , Lindsay Andrew J. , Mészáros Bálint , Dean Kellie
Published: February 2023

SMAUG1 is a human RNA-binding protein that is known to be dysregulated in a wide range of diseases. It is evolutionarily conserved and has been shown to form condensates containing translationally repressed RNAs. This indicates that condensation is central to proper SMAUG1 function; however, the factors governing condensation are largely unknown. In this work, we show that SMAUG1 drives the formation of liquid-like condensates in cells through its non-conventional C-terminal prion-like disordered region. We use biochemical assays to show that this liquid-liquid phase separation is independent of RNA binding and does not depend on other large, disordered regions that potentially harbor several binding sites for partner proteins. Using a combination of computational predictions, structural modeling,in vitroand in cell measurements, we also show that SMAUG1-driven condensation is negatively regulated by direct interactions with members of the 14-3-3 protein family. These interactions are mediated by four distinct phospho-regulated short linear motifs embedded in the disordered regions of SMAUG1, working synergistically. Interactions between SMAUG1 and 14-3-3 proteins drive the dissolution of condensates, alter the dynamics of the condensed state, and are likely to be intertwined with currently unknown regulatory mechanisms. Our results provide information on how SMAUG1 phase separation is regulated and the first known instance of 14-3-3 proteins being able to completely dissolve condensates by directly interacting with a phase separation driver, which might be a general mechanism in cells to regulate biological condensation.

Graphical abstract

Highlights

SMAUG1 is a human RNA-binding protein capable of condensation with unknown regulation

A prion-like domain of SMAUG1 drives condensation via liquid-liquid phase separation

SMAUG1 interacts with 14-3-3 proteins via four phospho-regulated short linear motifs

14-3-3 interactions change the dynamics of SMAUG1 condensates, promoting their dissolution

This is the first described regulatory mechanism for SMAUG1-driven condensation
Telomerase reverse transcriptase (TERT)-expressing cells mark a novel stem cell population in the adult mouse brain
Authors: Jensen Gabriel S. , Beaulieu Ashleigh N. , Curtis Caroline D. , Passarelli Joshua , Blaszkiewicz Magdalena , Thomas Seth , Morin Trevor , Willows Jake W. , Greco Callie W. , Brennan Ciara J. , Aniapam Christopher , Caron Lydia , Alves Michele J. , Lynes Matthew D. , Carlone Diana L. , Breault David T. , Townsend Kristy L.
Published: February 2023

Telomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (ASC) in numerous adult murine and human tissues, but has never been explored in the adult brain. Here, we demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent ASCs that are localized to numerous classical neuro/gliogenic niches (including the ventricular-subventricular zone, hypothalamus, and olfactory bulb), as well as more recently described regions of adult brain plasticity such as the meninges and choroid plexus. Using a direct-reporter mouse line, we found that TERT+ cells expressed known neural stem cell markers such as Nestin and Sox2, but not markers of committed stem/progenitor cells, nor markers of mature neuronal or glial cells. TERT+ ASCs rarely expressed the proliferation marker Ki67, andin vitroTERT+ cells lost TERT expression when activated by growth factors, together indicating a quiescent phenotype similar to what has been observed in other tissues. When cultured, TERT+ cells behaved like neural stem cells by forming neurospheres, which could proliferate and become more metabolically active once stimulated by growth factors. TERT+ cells were observed in numerous brain niches, particularly near the ventricles and cerebrospinal fluid barriers, but notably, TERT+ cells were never observed in the hippocampus. Lineage tracing of TERT+ cells in adult transgenic mice (mTERTrtTA::oTET-Cre::RosamTmG) revealed large-scale expansion of TERT+ progeny and differentiation to diverse cell types in multiple brain regions. For example, lineage-traced cells expressed markers of mature neurons, oligodendrocytes, astrocytes, ependymal cells, and choroid epithelial cells, thus demonstrating the striking multipotency of this stem cell population in basal tissue turnover of the adult brain. Together, these data demonstrate that TERT+ cells represent a novel population of multipotent stem cells that contribute to basal plasticity and regeneration in the adult mouse brain.

Graphical Abstract
A kinetic dichotomy between mitochondrial and nuclear gene expression drives OXPHOS biogenesis
Authors: McShane Erik , Couvillion Mary , Ietswaart Robert , Prakash Gyan , Smalec Brendan M. , Soto Iliana , Baxter-Koenigs Autum R. , Choquet Karine , Churchman L. Stirling
Published: February 2023

Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared to nuclear mRNAs, mt-mRNAs were produced 700-fold higher, degraded 5-fold faster, and accumulated to 170-fold higher levels. Quantitative modeling and depletion of mitochondrial factors, LRPPRC and FASTKD5, identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.
Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes
Authors: Shah Anit , Huck Ian , Duncan Kaylia , Gansemer Erica R. , Apte Udayan , Stamnes Mark A. , Rutkowski D. Thomas
Published: February 2023

In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identityin vitroenhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.
Cell state transition analysis identifies interventions that improve control ofM. tuberculosisinfection by susceptible macrophages
Authors: Yabaji Shivraj M. , Rukhlenko Oleksii S. , Chatterjee Sujoy , Bhattacharya Bidisha , Wood Emily , Kasaikina Marina , Kholodenko Boris , Gimelbrant Alexander A. , Kramnik Igor
Published: February 2023

Understanding cell state transitions and purposefully controlling them to improve therapies is a longstanding challenge in biological research and medicine. Here, we identify a transcriptional signature that distinguishes activated macrophages from TB-susceptible and TB-resistant mice. We then apply the cSTAR (cell State Transition Assessment and Regulation) approach to data from screening-by-RNA sequencing to identify chemical perturbations that shift the. transcriptional state of the TB-susceptible macrophages towards that of TB-resistant cells. Finally, we demonstrate that the compounds identified with this approach enhance resistance of the TB-susceptible mouse macrophages to virulentM. tuberculosis.
Interrogating the function of bicistronic translational control elements to improve consistency of gene expression
Authors: Jansen Zachary , Reilly Sophia R. , Lieber-Kotz Matan , Li Andrew Z. , Wei Qiyao , Kulhanek Devon L. , Gilmour Andrew R. , Thyer Ross
Published: February 2023

Context independent gene expression is required for genetic circuits to maintain consistent and predicable behavior. Previous efforts to develop context independent translation have leveraged the helicase activity of translating ribosomes via bicistronic design translational control elements (BCDs) located within an efficiently translated leader peptide. We have developed a series of bicistronic translational control elements with strengths that span several orders of magnitude, maintain consistent expression levels across diverse sequence contexts, and are agnostic to common ligation sequences used in modular cloning systems. We have used this series of BCDs to investigate several features of this design, including the spacing of the start and stop codons, the nucleotide identity upstream of the start codon, and factors affecting translation of the leader peptide. To demonstrate the flexibility of this architecture and their value as a generic modular expression control cassette for synthetic biology, we have developed a set of robust BCDs for use in severalRhodococcusspecies.
TidyGEO: Preparing analysis-ready datasets from Gene Expression Omnibus
Authors: Mecham Avery , Stephenson Ashlie , Quinteros Badi I. , Salmons Grace , Piccolo Stephen R.
Published: February 2023

TidyGEO is a Web-based tool for downloading, tidying, and reformatting data series from Gene Expression Omnibus (GEO). As a freely accessible repository with data from over 4 million biological samples across more than 4,000 organisms, GEO provides diverse opportunities for secondary research. Transcriptomic data are most common in GEO, but other measurement types are also prevalent, including DNA methylation levels, genotypes, and chromatin-accessibility profiles. GEO’s diversity and expansiveness present opportunities and challenges. Although scientists may find assay data relevant to a given research question, most analyses require sample annotations, such as a sample’s treatment group, disease subtype, or age. In GEO, such annotations are stored alongside assay data in delimited, text-based files. However, the structure and semantics of the annotations vary widely from one series to another, and many annotations are not useful for analysis purposes. Thus, every GEO series must be tidied before it can be analyzed. Manual approaches may be used, but these are error prone and take time away from other research tasks. Custom computer scripts can be written, but many scientists lack the computational expertise to create such scripts. To address these challenges, we created TidyGEO, which supports essential data-cleaning tasks for sample-level annotations, such as selecting informative columns, renaming columns, splitting or merging columns, standardizing data values, and filtering samples. Additionally, users can integrate annotations with assay data, restructure assay data, and generate code that enables others to reproduce these steps. The source code for TidyGEO is athttps://github.com/srp33/TidyGEO.