bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenges and pitfalls of inferring microbial growth rates from lab cultures
Authors: Ghenu Ana-Hermina , Marrec Loïc , Bank Claudia
Published: June 2022

After more than 100 years of generating monoculture batch culture growth curves, microbial ecologists and evolutionary biologists still lack a reference method for inferring growth rates. Our work highlights the challenges of estimating the growth rate from growth curve data and shows that inaccurate estimates of growth rates significantly impact the estimated relative fitness, a principal quantity in evolution and ecology. First, we conducted a literature review and found which different types of methods are currently used to estimate growth rates. These methods differ in the meaning of the estimated growth rate parameter. Kinetic models estimate the intrinsic growth rate µ whereas statistical methods – both model-based and model-free – estimate the maximum per capita growth rate µmax. Using math and simulations, we show the conditions in which µmax is not a good estimator of µ. Then, we demonstrate that inaccurate absolute estimates of µ is not overcome by calculating relative values. Importantly, we find that poor approximations for µ sometimes lead to wrongly classifying a beneficial mutant as deleterious. Finally, we re-analyzed four published data-sets using most of the methods found by our literature review. We detected no single best-fitting model across all experiments within a data-set and found that the Gompertz models, which were among the most commonly used, were often among the worst fitting. Our study provides suggestions for how experimenters can improve their growth rate and associated relative fitness estimates and highlights a neglected but fundamental problem for nearly everyone who studies microbial populations in the lab.
A Causal Model of Ion Interference Enables Assessment and Correction of Ratio Compression in Multiplex Proteomics
Authors: Madern Moritz , Reiter Wolfgang , Stanek Florian , Hartl Natascha , Mechtler Karl , Hartl Markus
Published: June 2022

Multiplex proteomics using isobaric labeling tags has emerged as a powerful tool for the simultaneous relative quantification of peptides and proteins across multiple experimental conditions. However, the quantitative accuracy of the approach is largely compromised by ion interference, a phenomenon that causes fold changes to appear compressed. The degree of compression is generally unknown, and the contributing factors are poorly understood. In this study, we thoroughly characterized ion interference at the MS2 level using a defined two-proteome experimental system with known ground-truth. We discovered remarkably poor agreement between the apparent precursor purity in the isolation window and the actual level of observed reporter ion interference in MS2-scans – a discrepancy that we found resolved by considering co-fragmentation of peptide ions hidden within the spectral “noise” of the MS1 isolation window. To address this issue, we developed a regression modeling strategy to accurately predict estimates of reporter ion interference in any dataset. Finally, we demonstrate the utility of our procedure for improved fold change estimation and unbiased PTM site-to-protein normalization. All computational tools and code required to apply this method to any MS2 TMT dataset are documented and freely available.
Gene expression as phenotype - Many small-step changes leading to little long-term phenotypic evolution
Authors: Lin Pei , Lu Guang-An , Liufu Zhongqi , Zhao Yi-Xin , Ruan Yongsen , Wu Chung-I , Wen Haijun
Published: June 2022

Unlike in genotypic evolution, there are few general rules governing phenotypic evolution with one of them being the small-step evolution. More specifically, natural selection tends to favor mutations of smaller phenotypic effects than of larger ones. This postulate can be viewed as a logical extension of Fisher’s Geometric Model (FGM). Testing this FGM postulate, however, is challenging as the test would require a large number of phenotypes, each with a clear genetic basis. For such a test, we treat the expression level of each gene as a phenotype. Furthermore, a mechanism of small-step expression evolution exists, namely via the control by microRNAs (miRNAs). Each miRNA in metazoans is known to weakly repress the expression of tens or hundreds of target genes. In our analysis of mammalian and Drosophila expression data, small step evolution via miRNA regulation happens frequently in long-term evolution. However, such small-step evolution does not lead to long-term phenotypic changes which would take too many such steps to accomplish. Furthermore, target site changes often cancel themselves out by continual gains and losses. The results suggest that the FGM postulate may be most appropriate for phenotypic fine-tuning near the expression optimum. In contrast, longterm expression evolution may occasionally take large steps (e.g., mutations in transcription factors) when big environmental shift happens. In another study (Lu et al. 2021), we further show how the small-step evolution of expression phenotypes is a manifestation of miRNAs’ role in developmental canalization. In conclusion, the rules of phenotypic evolution may depend crucially on the genetics of the phenotype, rather than its metric properties.
Functional traits trade-offs define plant population stability worldwide
Authors: Conti Luisa , Valencia Enrique , Galland Thomas , Götzenberger Lars , Lepš Jan , E-Vojtkó Anna , Carmona Carlos P. , Májeková Maria , Danihelka Jiří , Dengler Jürgen , Eldridge David J. , Estiarte Marc , García-González Ricardo , Garnier Eric , Gómez Daniel , Hadincová Věra , Harrison Susan P. , Herben Tomáš , Ibáñez Ricardo , Jentsch Anke , Juergens Norbert , Kertész Miklós , Klumpp Katja , Krahulec František , Louault Frédérique , Marrs Rob H. , Ónodi Gábor , Pakeman Robin J. , Pärtel Meelis , Peco Begoña , Peñuelas Josep , Rueda Marta , Schmidt Wolfgang , Schmiedel Ute , Schuetz Martin , Skalova Hana , Šmilauer Petr , Šmilauerová Marie , Smit Christian , Song MingHua , Stock Martin , Val James , Vandvik Vigdis , Ward David , Wesche Karsten , Wiser Susan K. , Woodcock Ben A. , Young Truman P. , Yu Fei-Hai , Zobel Martin , de Bello Francesco
Published: June 2022

Ecological theory posits that temporal stability patterns in plant populations are associated with differences in species’ ecological strategies. However, empirical evidence is lacking about which traits, or trade-offs, underlie species stability, specially across different ecosystems.

To address this, we compiled a global collection of long-term permanent vegetation records (>7000 plots from 78 datasets) from a wide range of habitats and combined this with existing trait databases. We tested whether the observed inter-annual variability in species abundance (coefficient of variation) was related to multiple individual traits and multivariate axes of trait variations (PCoA axes).

We found that species with greater leaf dry matter content and seed mass were consistently more stable over time (lower variability in species abundance) although other leaf traits played a significant role as well, albeit weaker. Using multivariate axes did not improve predictions by specific traits.

Our results confirm existing theory, providing compelling empirical evidence on the importance of specific traits, which point at ecological trade-offs in different resource use and dispersal strategies, on the stability of plant populations worldwide.
Divergent evolution of early terrestrial fungi reveals the evolution of Mucormycosis pathogenicity factors
Authors: Wang Yan , Chang Ying , Ortanez Jericho , Peña Jesús F. , Carter-House Derreck , Reynolds Nicole K , Smith Matthew E , Benny Gerald , Mondo Stephen J , Salamov Asaf , Lipzen Anna , Pangilinan Jasmyn , Guo Jie , LaButti Kurt , Andreopolous William , Tritt Andrew , Keymanesh Keykhosrow , Yan Mi , Barry Kerrie , Grigoriev Igor V , Spatafora Joseph W , Stajich Jason E
Published: June 2022

Fungi have evolved over millions of years and their species diversity is predicted to be the second largest on the earth. Fungi have cross-kingdom interactions with many organisms which have mutually shaped their evolutionary trajectories. Zygomycete fungi hold a pivotal position in the fungal tree of life and provide important perspectives on the early evolution of fungi from aquatic to terrestrial environments. Phylogenomic analyses have found that zygomycete fungi diversified into two separate clades, the Mucoromycota which are frequently associated with plants and Zoopagomycota that are commonly animal-associated fungi. Genetic elements that contributed to the fitness and divergence of these lineages may have been shaped by the varied interactions these fungi have had with plants, animals, bacteria and other microbes. To investigate this, we performed comparative genomic analyses of the two clades in the context of Kingdom Fungi, benefiting from our generation of a new collection of zygomycete genomes. We identified lineage-specific genomic content which may contribute to the disparate biology observed in these zygomycetes. Our findings include the discovery of undescribed diversity in CotH, a Mucormycosis pathogenicity factor, which was found in a broad set of zygomycetes. Reconciliation analysis identified multiple duplication events and an expansion of CotH copies throughout Mucoromycotina, Mortierellomycotina, Neocallimastigomycota, and Basidiobolus lineages. A kingdom-level phylogenomic analysis also identified new evolutionary relationships within the sub-phyla of Mucoromycota and Zoopagomycota.
Phage-plasmids spread antibiotic resistance genes through infection and lysogenic conversion
Authors: Pfeifer Eugen , A. Bonnin Rémy , Rocha Eduardo P.C.
Published: June 2022

Antibiotic resistance is rapidly spreading by horizontal transfer of resistance genes in mobile genetic elements. While plasmids are key drivers of this process, very few integrative phages encode antibiotic resistance genes. Here, we find that phage-plasmids, elements that are both phages and plasmids, often carry antibiotic resistance genes. We found 60 phage-plasmids with 184 antibiotic resistance genes, including broad-spectrum-cephalosporins, carbapenems, aminoglycosides, fluoroquinolones and colistin. These genes are in a few hotspots, seem to have been co-translocated with transposable elements, and are often in class I integrons, which had not been previously found in phages. We tried to induce six phage-plasmids with resistance genes (including four with resistance integrons) and succeeded in five cases. Other phage-plasmids and integrative prophages were co-induced in these experiments. As a proof of principle, we focused on a P1-like element encoding an extended spectrum β-lactamase, blaCTX-M-55. After induction, we confirmed that it’s capable to infect and convert four other E. coli strains. Its re-induction led to further conversion of a sensitive strain, confirming it’s a fully functional phage. This study shows that phage-plasmids carry a large diversity of clinically relevant antibiotic resistance genes that they transfer across bacteria. As plasmids, these elements seem very plastic and capable of acquiring genes from other plasmids. As phages, they may provide novel paths of transfer for resistance genes, because they can infect bacteria distant in time and space from the original host. As a matter of alarm, they may also eventually mediate transfer to other types of phages.

Importance

Dissemination of antimicrobial resistances is a major threat to global health. Here, we show that a group of temperate bacterial viruses (=phages), termed phage-plasmids, commonly encode different and multiple types of resistance genes of high clinical importance, often in integrons. This is unexpected since phages typically do not carry resistance genes and, hence, do not confer their hosts with resistance upon infection and genome integration. Our experiments with phage-plasmids isolated from clinical settings confirmed they infect sensitive strains, rendering them antibiotic resistant. The spread of antibiotic resistance genes by phage-plasmids is worrisome because it dispenses cell-to-cell contact, necessary for the canonical plasmid transfer (=conjugation). Furthermore, their integrons are now genetic platforms for the acquisition of novel resistance genes.
Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis
Authors: Dressel Nicole , Natusch Loreen , Munz Clara M. , Ramon Santiago Costas , Morcos Mina N.F. , Loff Anja , Hiller Björn , Lesche Mathias , Dahl Andreas , Luksch Hella , Rösen-Wolff Angela , Roers Axel , Behrendt Rayk , Gerbaulet Alexander
Published: June 2022

Cell-intrinsic response patterns control risks arising from genome-damage, preventing malignant transformation. The DNA sensor cyclic-GMP-AMP synthase (cGAS) has emerged as a new principle detecting genome damage, as it can be triggered by aberrant self-DNA. Stimulator of interferon genes (STING)-activation downstream of cGAS can drive cells into senescence or cell death and induces antiproliferative type I interferon (IFN) and pro-apoptotic tumor necrosis factor responses. Herein, we investigated how DNA damage-driven activation of cGAS/STING signaling impacts on hematopoiesis. Defective ribonucleotide excision repair (RER) in the hematopoietic system caused chromosomal instability as well as robust activation of the cGAS/STING/IFN axis, and compromised hematopoietic stem cell function, resulting in cytopenia and ultimately leukemia. Whereas loss of p53 largely rescued RER-deficient hematopoiesis at the cost of further accelerated leukemogenesis, the additional inactivation of cGAS, STING or type I IFN signaling had no detectable effect on blood cell generation and leukemia development. Moreover, cGAS-deficient hematopoiesis showed unaltered responses to spontaneous or acute DNA damage. Our data demonstrate that the cGAS/STING pathway is dispensable for the hematopoietic system coping with chronic or acute DNA damage and does not protect against leukemic transformation in the absence of RER.
The HERV-K(HML-2) Transcriptome in Non-Diseased Tissue
Authors: Burn Aidan , Roy Farrah , Freeman Michael , Coffin John M
Published: June 2022

Human endogenous retrovirus (HERV) transcripts are known to be highly expressed in cancers, yet their activity in non-diseased tissue is largely unknown. Using the GTEx RNA-seq dataset from normal tissue sampled at autopsy, we characterized individual expression of the recent HERV-K(HML-2) provirus group across 13,000 different samples of 54 different tissues from 948 individuals. HML-2 transcripts could be identified in every tissue sampled, and were elevated in the cerebellum, pituitary, testis, and thyroid. 37 different individual proviruses were expressed in one or more tissues, representing all three LTR5 subgroups. 9 proviruses were identified as having LTR-driven transcription, 7 of which belonged to the most recent LTR5HS subgroup. Proviruses of different subgroups displayed a bias in tissue expression which may be associated with differences in transcription factor binding sites in their LTRs. Provirus expression was greater in evolutionarily older proviruses with an earliest shared ancestor of gorilla or older. HML-2 expression was significantly affected by biological sex in one tissue, while age and timing of death (Hardy score) had little effect. Proviruses containing intact gag, pro and env ORFs were expressed in the dataset, with almost every tissue measured potentially expressing at least one intact ORF (gag).
Structure and Flexibility of the Yeast NuA4 Histone Acetyltransferase Complex
Authors: Zukin Stefan A. , Marunde Matthew R. , Popova Irina K. , Nogales Eva , Patel Avinash B.
Published: June 2022

The NuA4 protein complex acetylates histones H4 and H2A to activate both transcription and DNA repair. We report the 3.0 Å-resolution cryo-electron microscopy structure of the central hub of NuA4, which flexibly tethers the HAT and TINTIN modules. The hub contains the large Tra1 subunit and a core that includes Swc4, Arp4, Act1, Eaf1 and the C-terminal region of Epl1. Eaf1 stands out as the primary scaffolding factor that interacts with the Tra1, Sw4 and Epl1 subunits and contributes the conserved HSA helix to the Arp module. Using nucleosome binding assays, we find that the HAT module, which is anchored to the core through Epl1, recognizes H3K4me3 nucleosomes with hyperacetylated H3 tails, while the TINTIN module, anchored to the core via Eaf1, recognizes nucleosomes that have hyperacetylated H2A and H4 tails. Together with the known interaction of Tra1 with site-specific transcription factors, our data suggests a model in which Tra1 recruits NuA4 to specific genomic sites then allowing the flexible HAT and TINTIN modules to select nearby nucleosomes for acetylation.
Mitochondrial interactome remodeling in aging mouse skeletal muscle associated with functional decline
Authors: Bakhtina Anna A. , Pharaoh Gavin , Keller Andrew D. , Stuppard Rudy , Marcinek David J. , Bruce James E.
Published: June 2022

Genomic, transcriptomic, and proteomic approaches have been employed to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors in addition to abundance levels, such as modifications, localization, conformation, and protein-protein interactions. We have applied new robust quantitative chemical cross-linking technologies to uncover changes muscle mitochondrial interactome contributing to functional decline in aging. Statistically significant age-related changes in protein cross-link levels relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid beta-oxidation and TCA enzymes were observed. These changes showed remarkable correlation with measured CI based respiration differences within the same young-old animal pairs, indicating these cross-link levels offer new molecular insight on commonly observed age-related phenotypic differences. Overall, these system-wide quantitative mitochondrial interactome data provide the first molecular-level insight on ETS complex and substrate utilization enzyme remodeling that occur during age-related mitochondrial dysfunction. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies making this dataset a unique resource for many additional in-depth molecular studies that are needed to better understand complex molecular changes that occur with aging.
Diverse thermosensory receptors and neurons mediate the neural coding of oral cooling in the mouse trigeminothalamic tract
Authors: Li Jinrong , Lemon Christian H.
Published: June 2022

Different sets of peripheral and medullary trigeminal neurons respond across a cooling gradient applied to intraoral skin. Here we applied electrophysiology to anesthetized mice to study if different types of cool-driven trigeminothalamic neurons convey oral cooling information to the thalamus. We monitored spiking responses to oral stimulation with cold (≤13°C), cool (21°C to 28°C), neutral (35°C), and warm/hot (≥40°C) water in single trigeminal nucleus caudalis (Vc) neurons physiologically tested for projections to the thalamus. We also recorded oral thermal responses from Vc neurons in mice gene deficient for the cooling and menthol receptor TRPM8 to study afferent mechanisms of central oral thermosensory activity. We found that thalamic-projecting Vc neurons that respond to oral cooling comprise heterogeneous cell types. These cell types showed unique temporal response kinetics across cool and cold temperatures, with tuning to select ranges of a cooling gradient. The combined thermal activity of multiple, differently tuned types of trigeminothalamic cooling neurons offered greater contrast between cold, cool, and warm temperatures in multivariate analysis than the responses of the individual neural types alone, agreeing with a neural population code for cooling information. Compared to control, TRPM8 deficient mice demonstrated a loss of Vc neurons tuned to mild oral cooling, but maintained Vc cells responsive to intense cold. Notably, distinctions between Vc population responses to mild cool and warm temperatures were impaired in TRPM8 deficient mice, suggesting a role for TRPM8 in oral warmth recognition. Diverse receptors and neurons mediate oral cooling signals carried by the trigeminothalamic pathway.
Culture-Independent Detection and Identification of Leptospira Serovars
Authors: Matthias Michael A. , Lubar Aristea A. , Lanka Acharige Shalka S. , Chaiboonma Kira L. , Pilau Nicholas N. , Marroquin Alan S. , Jayasundara Dinesha , Agampodi Suneth , Vinetz Joseph M.
Published: June 2022

Pathogenic Leptospira, the causative agents of leptospirosis, comprise >200 serotypes (called serovars). Most have a restricted reservoir-host range, and some, e.g., serovar Copenhageni, are cosmopolitan and of public health importance owing to their propensity to produce severe, fatal disease in humans. Available serotyping approaches—such as multi-locus sequence typing, core genome sequence typing, pulsed-field gel electrophoresis, and the cross-agglutination absorption test—are tedious and expensive, and require isolation of the organisms in culture media—a protracted and incredibly inefficient process— precluding their use in prospective studies or outbreak investigations. The unavailability of culture-independent assays capable of distinguishing Leptospira serotypes remains a crucial gap in the field. Here, we have developed a simple yet specific real-time qPCR assay—targeting a Leptospira-unique gene encoding a putative polysaccharide flippase—that provides intra-species, serotype-defining (i.e., epidemiologically useful) information, and improves upon the sensitivity of preferred lipL32-based qPCR-based diagnostic tests. The assay, dubbed RAgI (“rage one”), is rapid and affordable, and reliably and specifically detects group I pathogenic Leptospira in culture, serum and urine, with no detectable off-target amplification—even of the genetically related but low virulence group II pathogenic (formerly “intermediate”) or non-pathogenic Leptospira. It retained 100% diagnostic specificity when tested against difficult sample types, including field-collected dog urine-samples and environmental samples containing varied and complex microbial species-consortia. And holds considerable promise in the clinical setting, and for routine epidemiological and environmental surveillance studies.
SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient
Authors: Shapira Guy , Weiner Chen , Sorek Abramovich Reut , Gutwein Odit , Rainy Nir , Benveniste-Levkovitz Patricia , Gordon Ezra , Bar Chaim Adina , Shomron Noam
Published: June 2022

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies.

Highlights

SARS-CoV-2 undergoes rapid evolution in an immunocompromised, chronically infected cancer patient, overcoming neutralization by two monoclonal antibody cocktail treatments

Receptor binding domain (RBD) mutations emerging after monoclonal antibody treatment enable effective escape from neutralization in the absence of adaptive immunity

Some emerging mutations are predicted to disrupt immunomodulatory viral proteins, including prevention of ORF8 homodimerization, mis-localization of ORF3a in host cells and alteration of the host-suppressive function of NSP1
Omega-3 supplements in the prevention and treatment of youth depression and anxiety: A scoping review
Authors: Reily Natalie M. , Tang Samantha , Negrone Ashlee , Gan Daniel Z. Q. , Sheanoda Veronica , Christensen Helen
Published: June 2022

Introduction

Emerging evidence suggests that omega-3 supplements may be efficacious in reducing symptoms of depression and anxiety in adults, particularly as an adjunct to antidepressant medication. However, research on its efficacy in young people is limited. Thus, this scoping review aimed to summarise existing evidence on the efficacy of omega-3 supplementation in treating depression and anxiety in young people aged 14-24.

Method

Four databases (Cochrane CENTRAL, EmBASE, PsycINFO and PubMed) were searched from inception to 4th August 2021. Eligible peer-reviewed studies were empirical studies which examined the efficacy of omega-3 supplements in preventing/treating anxiety and/or depression in young people aged 14-24. Risk of bias was assessed for randomised studies using the Cochrane Risk of Bias Tool. Selected grey literature databases were also searched, with eligible sources assessed for quality. A group of stakeholders consisting of young people with lived experience of anxiety/depression, parents/carers and mental health professionals informed the research questions and data interpretation. Findings were summarised using narrative synthesis.

Results

17 empirical studies (N = 1240 participants) meeting inclusion criteria were identified. Studies varied in treatment and participant characteristics. In general, the data did not support the view that omega-3 supplements were efficacious in improving symptoms of anxiety or depression. In contrast, most grey literature sources recommended the use of omega-3 supplements despite the lack of supporting evidence.

Discussion

Evidence for efficacy of omega-3 supplementation in reducing symptoms of depression and anxiety was inconclusive. More research is needed to identify potential mechanisms and moderators of the effect of omega-3 supplements on depression and anxiety symptoms in young people.
An Economic Evaluation of a virtual Covid Ward in Leicester, Leicestershire, and Rutland
Authors: Swift Jim , O’Kelly Noel , Barker Chris , Woodward Alex , Ghosh Sudip
Published: June 2022

Objective

The objective of this study was to demonstrate the impact of a virtual Covid—19 ward on NHS resource use.

Methods

Different methods were used to derive comparators for the observational data on acute length of stay versus the actual lengths of stay of 310 patients on acute wards and differences estimated. The resource use associated with delivering care in the virtual ward were collected on an ongoing basis.

Results

The virtual ward delivered estimated health care system savings of 1,103 bed days, £529,719 in net financial savings across two key groups of patients; those who had been on oxygen and required weaning off it while within the virtual ward and those not requiring oxygen therapy with less severe acute Covid disease. The costs of the intervention were 9.7% of the estimated gross savings and the mean net saving per patient was £1,709 in the base case without including the savings associated with a likely reduction in re-admissions. The 30-day re-admission rate was 2.9%, which was substantially beneath alternative comparative data. The mean cost of the intervention was £184.38 per patient.

Conclusion

The virtual ward delivered significant financial savings in both groups of patients, did so with a high degree of confidence, whilst doing so at a very low absolute and relative cost.
BNT162b2 effectiveness against Delta & Omicron variants in teens by dosing interval and duration
Authors: Ionescu Iulia G. , Skowronski Danuta M. , Sauvageau Chantal , Chuang Erica , Ouakki Manale , Kim Shinhye , De Serres Gaston
Published: June 2022

Background and Objectives

Two- and three-dose BNT162b2 (Pfizer-BioNTech) mRNA vaccine effectiveness (VE) against SARS-CoV-2 infection, including Delta and Omicron variants, was assessed among adolescents in two Canadian provinces where first and second doses were spaced longer than the manufacturer-specified 3-week interval.

Methods

Test-negative design estimated VE against laboratory-confirmed SARS-CoV-2 infection among adolescents 12-17 years old in Quebec and British Columbia, Canada between September 5, 2021 (epi-week 36), and April 30, 2022 (epi-week 17). Delta-dominant and Omicron-dominant periods spanned epi-weeks 36-47 and 51-17, respectively. VE was assessed from 14 days and explored by interval between first and second doses, time since second dose, and with administration of a third dose.

Results

Median first-second dosing-interval was ∼8 weeks and second-third dosing-interval was ∼28-31 weeks. Median follow-up post-second-dose was ∼10-11 weeks for Delta-dominant and ∼21-22 weeks for Omicron-dominant periods, and ∼3-9 weeks post-third dose. VE against Delta was ≥90% to at least the 5th month post-second dose. VE against Omicron declined from ∼65-75% at weeks to ≤50% by the 3rd month post-vaccination, restored to ∼60-65% shortly following a third dose. VE exceeded 90% against Delta regardless of dosing-interval but appeared improved against Omicron with ≥8 weeks between first and second doses.

Conclusion

In adolescents, two BNT162b2 doses provided strong and sustained protection against Delta but reduced and rapidly-waning VE against Omicron. Longer interval between first and second doses and a third dose improved Omicron protection. Updated vaccine antigens, increased doses and/or dosing-intervals may be needed to improve adolescent VE against immunological-escape variants.
An Occupational Health Survey for Port Employees in Shenzhen and A Dataset Management System based on R
Authors: Wang Jinlin , Mo Chunbao , Huang Yuehong , Lin Dafeng , Situ Jie , Zhang Ming , Zhang Naixing
Published: June 2022

Background

Port employees is a huge occupational group in industrial economy but the occupational health problem does not receive enough attention and the relative data is still deficient. Hence, the aim of the study was to survey the occupational health condition for port employees and to construct a relative dataset.

Method

A cross-sectional study was implemented among the population in a Shenzhen port, they were required to undergo occupational physical examination and questionnaires to learn about physical condition and other information. Description analysis were used to describe the data, and missing value analysis and Cronbach’s alpha coefficient were utilized to evaluated the data quality. And management system based on Shiny was constructed to manage and analyze the dataset.

Result

A total of 5245 participants involved in this study, 3211 of them received occupational physical examinations, 3946 participants received the questionnaire, and 1912 received the both. Quality analysis suggested that the total missing rate of these three datasets were 10.76%, 0% and 4.78%, respectively. And the total Cronbach’s alpha confidence of Effort-Reward Imbalance Questionnaire and National Health Literacy Monitoring Questionnaire was 0.808. Furthermore, a dataset management system with preview overview, selection, output and summary functions was constructed.

Conclusion

Occupational Health Survey for Port Employees is a reliable survey and it’s system can be used to manage and analyze the dataset, however, further optimization and improvement are still required.
Combining Machine Learning with Cox models for identifying risk factors for incident post-menopausal breast cancer in the UK Biobank
Authors: Liu Xiaonan , Morelli Davide , Littlejohns Thomas J , Clifton David A , Clifton Lei
Published: June 2022

1.

Breast cancer is the most common cancer in women. A better understanding of risk factors plays a central role in disease prediction and prevention. We aimed to identify potential novel risk factors for breast cancer among post-menopausal women, with pre-specified interest in the role of polygenic risk scores (PRS) for risk prediction.

We designed an analysis pipeline combining both machine learning (ML) and classical statistical models with emphasis on necessary statistical considerations (e.g. collinearity, missing data). Extreme gradient boosting (XGBoost) machine with Shapley (SHAP) feature importance measures were used for risk factor discovery among ∼1.7k features in 104,313 post-menopausal women from the UK Biobank cohort. Cox models were constructed subsequently for in-depth investigation.

Both PRS were significant risk factors when fitted simultaneously in both ML and Cox models (p< 0.001). ML analyses identified 11 (excluding the two PRS) novel predictors, among which five were confirmed by the Cox models: plasma urea (HR=0.95, 95% CI 0.92−0.98,p< 0.001) and plasma phosphate (HR=0.67, 95% CI 0.52−0.88,p= 0.003) were inversely associated with risk of developing post-menopausal breast cancer, whereas basal metabolic rate (HR=1.15, 95% CI 1.08−1.22,p< 0.001), red blood cell count (HR=1.20, 95% CI 1.08−1.34,p= 0.001), and creatinine in urine (HR=1.05, 95% CI 1.01−1.09,p= 0.008) were positively associated.

Our final Cox model demonstrated a slight improvement in risk discrimination when adding novel features to a simpler Cox model containing PRS and the established risk factors (Harrell’s C-index = 0.670 vs 0.665).
Cardiovascular disease and subsequent risk of psychiatric disorders: a nationwide sibling-controlled study
Authors: Shen Qing , Song Huan , Aspelund Thor , Yu Jingru , Lu Donghao , Jakobsdóttir Jóhanna , Bergstedt Jacob , Yi Lu , Sullivan Patrick F. , Sjölander Arvid , Ye Weimin , Fall Katja , Fang Fang , Valdimarsdóttir Unnur
Published: June 2022

Background

The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while inadequate control of familial factors and comorbidities has halted causal inferences.

Methods

We identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden while no history of psychiatric disorders, and 910 178 full siblings of these patients and 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox regression to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls.

Results

The median age at diagnosis was 60 years for patients with cardiovascular disease and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with cardiovascular disease, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after cardiovascular diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of cardiovascular disease. We observed similar associations in the population comparison. Cardiovascular patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at increased risk of subsequent cardiovascular death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67).

Conclusions

Patients diagnosed with cardiovascular disease are at an elevated risk for subsequent psychiatric disorders independent of familial factors and comorbid conditions. Cardiovascular patients with comorbid psychiatric disorders are at increased risk of cardiovascular mortality suggesting that surveillance and treatment of psychiatric comorbidities should be considered as an integral part of clinical management of newly diagnosed patients with cardiovascular disease.

Funding

this work was supported by the EU Horizon 2020 Research and Innovation Action Grant (CoMorMent, Grant nr. 847776 to UV, PFS and FF), Grant of Excellence, Icelandic Research Fund (grant no. 163362-051 to UV), ERC Consolidator Grant (StressGene, grant no: 726413 to UV), Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS) and US NIMH R01 MH123724 (to PFS).
Human PRPS1 filaments stabilize allosteric sites to regulate activity
Authors: Hvorecny Kelli L. , Hargett Kenzee A. , Quispe Joel , Kollman Justin M.
Published: June 2022

The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here, we determine structures of PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.
Changing word meanings in biomedical literature reveal pandemics and new technologies
Authors: Nicholson David N. , Alquaddoomi Faisal , Rubinetti Vincent , Greene Casey S.
Published: June 2022

While we often think of words as having a fixed meaning that we use to describe a changing world, words are also dynamic and changing. Scientific research can also be remarkably fast-moving, with new concepts or approaches rapidly gaining mind share. We examined scientific writing, both preprint and pre-publication peer-reviewed text, to identify terms that have changed and examine their use. One particular challenge that we faced was that the shift from closed to open access publishing meant that the size of available corpora changed by over an order of magnitude in the last two decades. We developed an approach to evaluate semantic shift by accounting for both intra- and inter-year variability using multiple integrated models. Using this strategy and examining year-by-year changes revealed thousands of change points in both corpora. We found change points for tokens including ‘cas9’, ‘pandemic’, and ‘sars’ among many others. The consistent change-points between pre-publication peer-reviewed and preprinted text were largely related to the COVID-19 pandemic. We developed a web app for exploration (https://greenelab.github.io/word-lapse/) that enables users to investigate individual terms. To our knowledge, this analysis is the first to examine semantic shift in biomedical preprints and pre-publication peer-reviewed text, and it lays the foundation for future work to examine how terms acquire new meaning and the extent to which that process is encouraged or discouraged by peer review.
Patterns of interdivision time correlations reveal hidden cell cycle factors
Authors: Hughes Fern A. , Barr Alexis R. , Thomas Philipp
Published: June 2022

The time taken for cells to complete a round of cell division is a stochastic process controlled, in part, by intracellular factors. These factors can be inherited across cellular generations which gives rise to, often non-intuitive, correlation patterns in cell cycle timing between cells of different family relationships on lineage trees. Here, we formulate a framework of hidden inherited factors affecting the cell cycle that unifies known cell cycle control models and reveals three distinct interdivision time correlation patterns: aperiodic, alternator and oscillator. We use Bayesian inference with single-cell datasets of cell division in bacteria, mammalian and cancer cells, to identify the inheritance motifs that underlie these datasets. From our inference, we find that interdivision time correlation patterns do not identify a single cell cycle model but generally admit a broad posterior distribution of possible mechanisms. Despite this unidentifiability, we observe that the inferred patterns reveal interpretable inheritance dynamics and hidden rhythmicity of cell cycle factors. This reveals that cell cycle factors are commonly driven by circadian rhythms, but their period may differ in cancer. Our quantitative analysis thus reveals that correlation patterns are an emergent phenomenon that impact cell proliferation and these patterns may be altered in disease.
Use of statins and other lipid-modifying agents across pregnancy – a nationwide drug utilization study of 822 071 pregnancies in Norway in 2005-2018
Authors: Christensen Jacob J. , Bogsrud Martin P. , Holven Kirsten B. , Retterstøl Kjetil , Veierød Marit B. , Nordeng Hedvig
Published: June 2022

Background

Statins are becoming more widely used among women of reproductive age; however, nationwide data on statin use across pregnancy is scarce. We therefore aimed to describe the drug utilization patterns for statins and other lipid-modifying agents (LMAs) before, during, and after pregnancy, for all pregnancies in Norway from 2005 to 2018.

Methods

We linked individual-level data from four nationwide electronic health care registries in Norway and characterized the prescription fills of statins and other LMAs across pregnancy. We also examined trends in pregnancy-related LMA use, and characterized women using statins and other LMAs on parameters of health status and co-morbidity.

Results

In total 822 071 pregnancies for 503 723 women were included. The number of statin prescription fills decreased rapidly during first trimester and returned to pre-pregnancy levels about one year postpartum. Pregnancy-related statin use increased from 2005 (approx. 0.11 % of all pregnancies) to 2018 (approx. 0.29 % of all pregnancies); however, in total, few statin prescriptions were filled within any trimester of pregnancy (n = 331, 0.04 % of all pregnancies). Statin use was more common in women with higher age, higher weight, smoking, and comorbidities such as hypertension and diabetes mellitus; also, statin users often had co-medication pertinent to these conditions.

Conclusions

Although statins and other LMAs were increasingly being used around the time of pregnancy among women in Norway, drug use was mostly discontinued during first trimester. Our results suggest that pregnancy-related statin use should be monitored, and that drug safety analyses for maternal and offspring health outcomes are needed.
DNA Methylation Age Acceleration, Type 2 Diabetes, and its Complications: Cross-sectional and Longitudinal Data from the Berlin Aging Study II (BASE-II)
Authors: Vetter Valentin Max , Spieker Johanne , Sommerer Yasmine , Buchmann Nikolaus , Kalies Christian Humberto , Regitz-Zagrosek Vera , Bertram Lars , Demuth Ilja
Published: June 2022

Patients with diabetes mellitus are at risk for micro- and macrovascular complications that are responsible for a substantial part of the individual health burden and socio-economic costs. Therefore, implementable risk scores are needed to improve targeted prevention for patients that are particularly susceptible to complications. The “epigenetic clock” estimates an individual’s biological age using DNA methylation profiles and was previously shown to be associated with morbidity and mortality.

In this study, we examine older adults of the BASE-II study that were reexamined on average 7.4 years after baseline assessment as part of the GendAge study. For DNA methylation age (DNAmA) estimation we used the 7-CpG clock which was available for two timepoints (n=1,071 at follow-up). In addition, we determined epigenetic age using Horvath’s clock, Hannum’s clock, PhenoAge and GrimAge which were available at follow-up only (n=1,067). The deviation of DNAmA from chronological age, DNA methylation age acceleration (DNAmAA), was calculated as residuals of a leukocyte cell count adjusted linear regression analysis. Diabetes associated complications were assessed with the Diabetes Complications Severity Index (DCSI).

Cross-sectionally, a statistically significant association between oral glucose tolerance test results and Hannum (ß=0.8, SE=0.3, p=0.02, n=762) and PhenoAge DNAmAA (ß=0.8, SE=0.3, p=0.003, n=762) was found. PhenoAge was also associated with fasting glucose (ß=0.3, SE=0.1, p=0.013, n=966). In contrast, we observed no cross-sectional association after covariate adjustment between DNAmAA and a diagnosis of diabetes mellitus with any of the five clocks employed. This was true for longitudinal analyses with the 7-CpG clock as well. However, longitudinal analyses showed that every year in the 7-CpG-based DNAmAA estimate at baseline increased the risk for developing of one or more additional complications or worsening of an already existing complication during the follow-up period by 11% in male participants with diabetes mellitus type 2. This association persisted after adjustment for DCSI at baseline, chronological age, smoking, alcohol, diabetes medication, and BMI (OR =1.11, p=0.045, n=56). No statistically significant association was found in the subgroup of women or when the whole dataset was analyzed (p>0.05).

Although our findings still need to be independently validated, the 7-CpG clock appears to be a promising biomarker which is informative about the individual risk for diabetic complications independent of age, sex, lifestyle factors, or complications at baseline.