bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tackling the Pangenome Dilemma Requires the Concerted Analysis of Multiple Population Genetic Processes
Authors: Baumdicker Franz , Kupczok Anne 
Published: April 2023

Abstract
The pangenome is the set of all genes present in a prokaryotic population. Most pangenomes contain many accessory genes of low and intermediate frequencies. Different population genetics processes contribute to the shape of these pangenomes, namely selection and fitness-independent processes such as gene transfer, gene loss, and migration. However, their relative importance is unknown and highly debated. Here, we argue that the debate around prokaryotic pangenomes arose due to the imprecise application of population genetics models. Most importantly, two different processes of horizontal gene transfer act on prokaryotic populations, which are frequently confused, despite their fundamentally different behavior. Genes acquired from distantly related organisms (termed here acquiring gene transfer) are most comparable to mutation in nucleotide sequences. In contrast, gene gain within the population (termed here spreading gene transfer) has an effect on gene frequencies that is identical to the effect of positive selection on single genes. We thus show that selection and fitness-independent population genetic processes affecting pangenomes are indistinguishable at the level of single gene dynamics. Nevertheless, population genetics processes are fundamentally different when considering the joint distribution of all accessory genes across individuals of a population. We propose that, to understand to which degree the different processes shaped pangenome diversity, the development of comprehensive models and simulation tools is mandatory. Furthermore, we need to identify summary statistics and measurable features that can distinguish between the processes, where considering the joint distribution of accessory genes across individuals of a population will be particularly relevant.
Therapeutic Potential of Human Intestinal Organoids in Tissue Repair Approaches in Inflammatory Bowel Diseases
Authors: Rutherford Duncan , Ho Gwo-Tzer 
Published: April 2023

Abstract
Inflammatory bowel diseases (IBDs) are chronic immune-mediated conditions characterized by significant gut tissue damage due to uncontrolled inflammation. Anti-inflammatory treatments have improved, but there are no current prorepair approaches. Organoids have developed into a powerful experimental platform to study mechanisms of human diseases. Here, we specifically focus on its role as a direct tissue repair modality in IBD. We discuss the scientific rationale for this, recent parallel advances in scientific technologies (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 and metabolic programming), and in addition, the clinical IBD context in which this therapeutic approach is tractable. Finally, we review the translational roadmap for the application of organoids and the need for this as a novel direction in IBD.
Residential Clustering of Coronavirus Disease 2019 Cases and Efficiency of Building-Wide Compulsory Testing Notices as a Transmission Control Measure in Hong Kong
Authors: Young Benjamin R , Yang Bingyi , Wu Peng , Adam Dillon C , Wong Jessica Y , Ho Faith , Gao Huizhi , Lau Eric H Y , Leung Gabriel M , Cowling Benjamin J 
Published: April 2023

Abstract
We described the frequency of residential case clusters and the efficiency of compulsory testing in identifying cases using buildings targeted in compulsory testing and locally infected coronavirus disease 2019 (COVID-19) cases matched by residence in Hong Kong. Most of the buildings (4246 of 7688, 55.2%) with COVID-19 cases identified had only 1 reported case, and 13% of the daily reported cases were detected through compulsory testing. Compulsory testing notices could be essential in attempting to eliminate infections (“zero COVID”) and have an impact early in an epidemic, but they appear to be relatively inefficient in response to sustained community transmission.
Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Delta and Omicron Infection and Infectiousness Within Households in the Netherlands Between July 2021 and August 2022
Authors: Hoeve Christina E , de Gier Brechje , Huiberts Anne J , de Melker Hester E , Hahné Susan J M , van den Hof Susan , Knol Mirjam J 
Published: April 2023

Abstract

Background
We aimed to estimate vaccine effectiveness against infection (VE-infection) and against further transmission (VE-infectiousness) in a household setting during Delta and Omicron. Knowing these effects can aid policy makers in deciding which groups to prioritize for vaccination.

Methods
Participants with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test were asked about coronavirus disease 2019 (COVID-19) vaccination status and SARS-CoV-2 testing of their household members 1 month later. VE-infection and VE-infectiousness were estimated using generalized estimating equation logistic regression adjusting for age, vaccination status, calendar week, and household size.

Results
A total of 3399 questionnaires concerning 4105 household members were included. During the Delta period, VE-infection and VE-infectiousness of primary series were 47% (95% confidence interval [CI], −27% to 78%) and 70% (95% CI, 28% to 87%), respectively. During the Omicron period, VE-infection was −36% (95% CI, −88% to 1%) for primary series and −28% (95% CI, −77% to 7%) for booster vaccination. VE-infectiousness was 45% (95% CI, −14% to 74%) for primary series and 64% (95% CI, 31% to 82%) for booster vaccination.

Conclusions
Our study shows that COVID-19 vaccination is effective against infection with SARS-CoV-2 Delta and against infectiousness of SARS-CoV-2 Delta and Omicron. Estimation of VE against infection with SARS-CoV-2 Omicron was limited by several factors. Our results support booster vaccination for those in close contact with vulnerable people to prevent transmission.
Regional and national antimicrobial stewardship activities: a survey from the Joint Programming Initiative on Antimicrobial Resistance—Primary Care Antibiotic Audit and Feedback Network (JPIAMR-PAAN)
Authors: Michalsen Benedikte Olsen , Xu Alice X T , Alderson Sarah L , Bjerrum Lars , Brehaut Jamie , Bucher Heiner C , Clarkson Janet , Duncan Eilidh , Grimshaw Jeremy , Gunnarsson Ronny , Høye Sigurd , Ivers Noah , Lecky Donna M , Lindbæk Morten , Llor Carl , Lundgren Pia Touboul , O’connor Denise , Pulcini Celiné , Ramsay Craig , Sundvall Pär-Daniel , Verheij Theo , Schwartz Kevin L ,   JPIAMR-PAAN, Acampora Anna , Alderson Sarah L , Coello Pablo Alonso , Altiner Attila , Bjerrum Lars , Brehaut Jamie , Brown Benjamin , Bucher Heiner C , Butler Chris , Cavazzuti Laura , Clarkson Janet , Davoli Marina , De Sutter An , Martino Mirko Di , Duncan Eilidh , Francis Nick , Grilli Roberto , Grimshaw Jeremy , Gunnarsson Ronny , Hallsworth Michael , Hemkens Lars , Hoye Sigurd , Ivers Noah , Khan Tasneem , Lecky Donna M , Lindbaek Morten , Linder Jeff , Little Paul , Llor Carl , Lorencatto Fabiano , O’connor Denise , Pulcini Celine , Ramsay Craig , Saulle Rosella , Schwartz Kevin L , Simon Maia , Sundvall Pär-Daniel , Taljaard Monica , Lundgren Pia Touboul , Vellinga Akke , Verbakel Jan , Verheij Theo 
Published: April 2023

Abstract

Background
Antibiotic overuse and misuse in primary care are common, highlighting the importance of antimicrobial stewardship (AMS) efforts in this setting. Audit and feedback (A&F) interventions can improve professional practice and performance in some settings.

Objectives and methods
To leverage the expertise from international members of the Joint Programming Initiative on Antimicrobial Resistance – Primary care Antibiotic Audit and feedback Network (JPIAMR-PAAN). Network members all have experience of designing and delivering A&F interventions to reduce inappropriate antibiotic prescribing in primary care settings. We aim to introduce the network and explore ongoing A&F activities in member regions. An online survey was administered to all network members to collect regional information.

Results
Fifteen respondents from 11 countries provided information on A&F activities in their country, and national/regional antibiotic stewardship programmes or policies. Most countries use electronic medical records as the primary data source, antibiotic appropriateness as the main outcome of feedback, and target GPs as the prescribers of interest. Funding sources varied across countries, which could influence the frequency and quality of A&F interventions. Nine out of 11 countries reported having a national antibiotic stewardship programme or policy, which aim to provide systematic support to ongoing AMS efforts and aid sustainability.

Conclusions
The survey identified gaps and opportunities for AMS efforts that include A&F across member countries in Europe, Canada and Australia. JPIAMR-PAAN will continue to leverage its members to produce best practice resources and toolkits for antibiotic A&F interventions in primary care settings and identify research priorities.
Manifold lifting: scaling Markov chain Monte Carlo to the vanishing noise regime
Authors: Au Khai Xiang , Graham Matthew M , Thiery Alexandre H 
Published: April 2023

Abstract
Standard Markov chain Monte Carlo methods struggle to explore distributions that concentrate in the neighbourhood of low-dimensional submanifolds. This pathology naturally occurs in Bayesian inference settings when there is a high signal-to-noise ratio in the observational data but the model is inherently over-parametrised or nonidentifiable. In this paper, we propose a strategy that transforms the original sampling problem into the task of exploring a distribution supported on a manifold embedded in a higher-dimensional space; in contrast to the original posterior this lifted distribution remains diffuse in the limit of vanishing observation noise. We employ a constrained Hamiltonian Monte Carlo method, which exploits the geometry of this lifted distribution, to perform efficient approximate inference. We demonstrate in numerical experiments that, contrarily to competing approaches, the sampling efficiency of our proposed methodology does not degenerate as the target distribution to be explored concentrates near low-dimensional submanifolds. Python code reproducing the results is available at https://doi.org/10.5281/zenodo.6551654.
MUCE: Bayesian hierarchical modelling for the design and analysis of phase 1b multiple expansion cohort trials
Authors: Lyu Jiaying , Zhou Tianjian , Yuan Shijie , Guo Wentian , Ji Yuan 
Published: April 2023

AbstractWe propose a multiple cohort expansion (MUCE) approach as a design or analysis method for phase 1b multiple expansion cohort trials, which are novel first-in-human studies conducted following phase 1a dose escalation. In a phase 1b expansion cohort trial, one or more doses of a new investigational drug identified from phase 1a are tested for initial antitumour activities in patients with different indications (cancer types and/or biomarker status). Each dose–indication combination defines an arm, and patients are enrolled in parallel cohorts to all the arms. The MUCE design is based on a class of Bayesian hierarchical models that adaptively borrow information across arms. Specifically, we employ a latent probit model that allows for different degrees of borrowing across doses and indications. Statistical inference is directly based on the posterior probability of each arm being efficacious, facilitating the decision making that decides which arm to select for further testing. The MUCE design also incorporates interim looks, based on which the nonpromising arms will be stopped early due to futility. Through simulation studies, we show that MUCE exhibits superior operating characteristics. We also compare the performance of MUCE with that of Simon’s two-stage design and some existing Bayesian designs for multiarm trials. To our knowledge, MUCE is the first Bayesian method for phase 1b expansion cohort trials with multiple doses and indications.
The DNA replication initiation protein DnaD recognises a specific strand of the Bacillus subtilis chromosome origin
Authors: Winterhalter Charles , Pelliciari Simone , Stevens Daniel , Fenyk Stepan , Marchand Elie , Cronin Nora B , Soultanas Panos , Costa Tiago R D , Ilangovan Aravindan , Murray Heath 
Published: April 2023

Abstract
Genome replication is a fundamental biological activity shared by all organisms. Chromosomal replication proceeds bidirectionally from origins, requiring the loading of two helicases, one for each replisome. However, the molecular mechanisms underpinning helicase loading at bacterial chromosome origins (oriC) are unclear. Here we investigated the essential DNA replication initiation protein DnaD in the model organism Bacillus subtilis. A set of DnaD residues required for ssDNA binding was identified, and photo-crosslinking revealed that this ssDNA binding region interacts preferentially with one strand of oriC. Biochemical and genetic data support the model that DnaD recognizes a new single-stranded DNA (ssDNA) motif located in oriC, the DnaD Recognition Element (DRE). Considered with single particle cryo-electron microscopy (cryo-EM) imaging of DnaD, we propose that the location of the DRE within oriC orchestrates strand-specific recruitment of helicase during DNA replication initiation. These findings significantly advance our mechanistic understanding of bidirectional replication from a bacterial chromosome origin.
CSNK2B modulates IRF1 binding to functional DNA elements and promotes basal and agonist-induced antiviral signaling
Authors: Matsumoto Moe , Modliszewski Jennifer L , Shinozaki Kotomi , Maezawa Reona , Perez Vincent M , Ishikawa Yuki , Suzuki Ryosuke , McKnight Kevin L , Masaki Takahiro , Hirai-Yuki Asuka , Kohara Michinori , Lemon Stanley M , Selitsky Sara R , Yamane Daisuke 
Published: April 2023

Abstract
Interferon regulatory factor 1 (IRF1) is a critical component of cell-intrinsic innate immunity that regulates both constitutive and induced antiviral defenses. Due to its short half-life, IRF1 function is generally considered to be regulated by its synthesis. However, how IRF1 activity is controlled post-translationally has remained poorly characterized. Here, we employed a proteomics approach to identify proteins interacting with IRF1, and found that CSNK2B, a regulatory subunit of casein kinase 2, interacts directly with IRF1 and constitutively modulates its transcriptional activity. Genome-wide CUT&RUN analysis of IRF1 binding loci revealed that CSNK2B acts generally to enhance the binding of IRF1 to chromatin, thereby enhancing transcription of key antiviral genes, such as PLAAT4 (also known as RARRES3/RIG1/TIG3). On the other hand, depleting CSNK2B triggered abnormal accumulation of IRF1 at AFAP1 loci, thereby down-regulating transcription of AFAP1, revealing contrary effects of CSNK2B on IRF1 binding at different loci. AFAP1 encodes an actin crosslinking factor that mediates Src activation. Importantly, CSNK2B was also found to mediate phosphorylation-dependent activation of AFAP1-Src signaling and exert suppressive effects against flaviviruses, including dengue virus. These findings reveal a previously unappreciated mode of IRF1 regulation and identify important effector genes mediating multiple cellular functions governed by CSNK2B and IRF1.
Not4-dependent targeting of MMF1 mRNA to mitochondria limits its expression via ribosome pausing, Egd1 ubiquitination, Caf130, no-go-decay and autophagy
Authors: Chen Siyu , Allen George , Panasenko Olesya O , Collart Martine A 
Published: April 2023

Abstract
The Ccr4–Not complex is a conserved multi protein complex with diverse roles in the mRNA life cycle. Recently we determined that the Not1 and Not4 subunits of Ccr4–Not inversely regulate mRNA solubility and thereby impact dynamics of co-translation events. One mRNA whose solubility is limited by Not4 is MMF1 encoding a mitochondrial matrix protein. In this work we uncover a mechanism that limits MMF1 overexpression and depends upon its co-translational targeting to the mitochondria. We have named this mechanism Mito-ENCay. This mechanism relies on Not4 promoting ribosome pausing during MMF1 translation, and hence the co-translational docking of the MMF1 mRNA to mitochondria via the mitochondrial targeting sequence of the Mmf1 nascent chain, the Egd1 chaperone, the Om14 mitochondrial outer membrane protein and the co-translational import machinery. Besides co-translational Mitochondrial targeting, Mito-ENCay depends upon Egd1 ubiquitination by Not4, the Caf130 subunit of the Ccr4–Not complex, the mitochondrial outer membrane protein Cis1, autophagy and no-go-decay.
Depositing centromere repeats induces heritable intragenic heterochromatin establishment and spreading in Arabidopsis
Authors: Liu Zhang-Wei , Liu Jie , Liu Fengquan , Zhong Xuehua 
Published: April 2023

Abstract
Stable transmission of non-DNA-sequence-based epigenetic information contributes to heritable phenotypic variants and thus to biological diversity. While studies on spontaneous natural epigenome variants have revealed an association of epialleles with a wide range of biological traits in both plants and animals, the function, transmission mechanism, and stability of an epiallele over generations in a locus-specific manner remain poorly investigated. Here, we invented a DNA sequence deposition strategy to generate a locus-specific epiallele by depositing CEN180 satellite repeats into a euchromatic target locus in Arabidopsis. Using CRISPR/Cas9-mediated knock-in system, we demonstrated that depositing CEN180 repeats can induce heterochromatin nucleation accompanied by DNA methylation, H3K9me2, and changes in the nucleosome occupancy at the insertion sites. Interestingly, both DNA methylation and H3K9me2 are restricted within the depositing sites and depletion of an H3K9me2 demethylase IBM1 enables the outward heterochromatin propagation into the neighboring regions, leading to inheritable target gene silencing to persist for at least five generations. Together, these results demonstrate the promise of employing a cis-engineering system for the creation of stable and site-specific epialleles and provide important insights into functional epigenome studies and locus-specific transgenerational epigenetic inheritance.
Political Parties and Civility in Parliament: The Case of Australia from 1901 to 2020
Authors: Martínez Arranz Alfonso , Zech Steven T , Bonotti Matteo 
Published: April 2023

Abstract
Incivility in parliaments is always prominently displayed in media reports, often with the implicit or explicit commentary that the situation is getting worse. This paper processes and analyses the records of verbal interactions in the Australian Parliament for over 100 years to provide a first approximation on the evolution of civility. It provides a framework for understanding the multidimensional nature of civility that examines both ‘politeness’ and ‘argumentation’, with the latter grounded in notions of public-mindedness. The analysis focuses on the interactions between parties of the orators and the party in power, the chamber of utterance, and the year. The results indicate that instances of impoliteness have increased since the 1970s but only modestly and remain highly infrequent. Minor parties, particularly those representing right-wing and Green politics are more likely to use dismissive or offensive language than the dominant centre-left and centre-right parties, although direct insults and swearwords are the particular remits of right-wing ‘system-wrecker’ parties. All these minor parties, nonetheless, also display higher levels of argumentation in their interventions. This combination of aggressive language and increased argumentation highlights the pressures on minor parties to convey their points in a forceful way, a challenge that is particularly pressing in two-party systems like the Australian one.
OA03 Harnessing quantitative proteomics to identify biomarkers of treatment response to etanercept in patients with rheumatoid arthritis
Authors: Ling Stephanie F , Yap Chuan Fu , Nair Nisha , Bluett James , Morgan Ann W , Isaacs John D , Wilson Anthony G , Hyrich Kimme L , Barton Anne , Plant Darren 
Published: April 2023

Abstract

Background/Aims
Tumour necrosis factor inhibitors (TNFi) are commonly prescribed to treat rheumatoid arthritis (RA), but response to TNFi is not universal and there are no validated pre-treatment biomarkers of treatment response at present. Proteins have many features that make them ideal potential biomarkers, as they carry out diverse biological processes, interact with drugs and can reflect post-translational modifications. This study aimed to identify protein biomarkers associated with response to TNFi in patients with RA.

Methods
Participants were recruited from a UK-based prospective multi-centre study of patients fulfilling either the 1987 ACR or 2010 ACR/EULAR classification for RA starting biologic treatment for the first time. Quantitative proteomics was performed using Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) in sera from study participants before and after three months of treatment with the TNFi etanercept. Linear regression models were used to study the association between protein levels and the composite 28-joint count Disease Activity Score (DAS28) and its sub-components, adjusting for baseline covariates including age, biological sex disease duration and baseline DAS28. Sub-network analysis was carried out using the DIAMOnD algorithm, followed by functional enrichment analysis.

Results
Of the total 180 participants recruited, 134 (74.44%) were female, with a median age of 56.90 years and median pre-treatment DAS28 of 5.9. Eight individual proteins were found to be significantly associated with RA clinical outcome measures (see Table). Sub-network analysis identified the ontological theme with the strongest association as being positive regulation of response to endoplasmic reticulum (ER) stress (-log10(P) ∼ 7).

Conclusion
This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response and identified ER stress as an underlying pathway. The ER stress pathway has been previously reported to contribute to RA pathogenesis via synoviocyte proliferation and stimulation of pro-inflammatory cytokine production.
Disclosure
S.F. Ling: None. C. Yap: None. N. Nair: None. J. Bluett: None. A.W. Morgan: None. J.D. Isaacs: None. A.G. Wilson: None. K.L. Hyrich: None. A. Barton: None. D. Plant: None.