bluuebunny/crossref_metadata_2025_split huggingface dataset:
RCT-based Social Return on Investment (SROI) of a home exercise programme for people with early dementia comparing in-person and blended delivery before and during the COVID-19 pandemic
Authors: Doungsong Kodchawan , Hartfiel Ned , Gladman John , Harwood Rowan H , Edwards Rhiannon Tudor 
Published: August 2023

AbstractBackgroundRegular exercise and community engagement may slow the rate of function loss for people with dementia. However, the evidence is uncertain regarding the cost-effectiveness and social return on investment (SROI) of home exercise with community referral for people with dementia. This study aimed to compare the social value generated from the in-person PrAISED programme delivered before March 2020 with a blended PrAISED programme delivered after March 2020.MethodsSROI analysis was conducted alongside a randomised controlled trial (RCT). Of 205 patient participants and their carers who completed cost data, 61 completed an in-person programme before March 2020. Due to COVID-19 pandemic restrictions, 144 patient participants completed a blended programme consisting of a combination of in-person visits, phone calls and video conferencing with multidisciplinary team (MDT) members.SROI analysis compared in-person and blended delivery formats. Five relevant and material outcomes were identified: three outcomes for patient participants (fear of falling, health-related quality of life, and social connection); one outcome for carer participants (carer strain index), and one outcome for the NHS (health service resource use). Data were collected at baseline and a 12-month follow-up.ResultsThe in-person PrAISED programme generated SROI ratios ranging from £0.58 to £2.33 for every £1 invested. In-person PrAISED patient participants gained social value from improved health-related quality of life, social connection, and less fear of falling. In-person PrAISED carer participants acquired social value from less carer strain. The NHS gained benefit from less health care service resource use. However, the blended PrAISED programme generated lower SROI ratios ranging from a negative ratio to £0.08: £1.ConclusionCompared with the blended programme, the PrAISED in-person programme generated higher SROI ratios for people with early dementia. During the COVID-19 pandemic and its restrictions, a blended delivery of the programme and the curtailment of community activities resulted in lower SROI ratios during this period. An in-person PrAISED intervention with community referral is likely to provide better value for money than a blended one with limited community referral, despite the greater costs of the former.Trial registrationISRCTN15320670
Host behaviour driven by awareness of infection risk amplifies the chance of superspreading events
Authors: Parag Kris V , Thompson Robin N 
Published: August 2023

AbstractWe demonstrate that heterogeneity in the perceived risks associated with infection within host populations amplifies the chances of superspreading during the crucial early stages of an epidemic. Under this behavioural model, individuals less concerned about the dangers from infection are more likely to be infected and attend larger-sized (riskier) events. For directly transmitted diseases such as COVID-19, this leads to infections being introduced at rates above the population prevalence to the events most conducive to superspreading. We develop an interpretable computational framework for evaluating within-event risks and derive a small-scale reproduction number measuring how the infections generated at an event depend on transmission heterogeneities and the number of introductions. This quantifies how event-scale patterns relate to population-level characteristics and generalises previous frameworks. As event duration and size grow, our reproduction number converges to the basic reproduction number. We illustrate that even moderate levels of heterogeneity in the perceived risks from infection substantially increase the likelihood of disproportionately large clusters of infections occurring at larger events, despite fixed overall disease prevalence. We show why collecting data linking host behaviour and event attendance is essential for accurately assessing the risk posed by an invading pathogen in the emerging stages of an outbreak.
The combined effect of lifestyle factors and polygenic scores on age at onset in Parkinson’s disease
Authors: Gabbert Carolin , Blöbaum Leonie , Lüth Theresa , König Inke R. , Caliebe Amke , Koch Sebastian , Laabs Björn-Hergen , Klein Christine , Trinh Joanne 
Published: August 2023

AbstractObjectiveTo investigate the association between a Parkinson’s disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD.MethodsWe included data from 4375 patients with idiopathic PD, 167 patients withGBA1-PD, and 3091 healthy controls of European ancestry from AMP-PD, PPMI, and Fox Insight cohorts. The PGS was calculated based on a previously proposed composition of 1805 variants. The association between PGS and lifestyle factors (i.e., coffee, tobacco, and aspirin) on AAO was assessed with linear and Cox proportional hazards models.ResultsThe PGS showed a negative association with AAO (β=-1.07, p=6x10-7). The use of one, two, or three of the protective lifestyle factors showed a reduction in the hazard ratio by 21% (p=0.0001), 45% (p<2x10-16), and 55% (p<2x10-16), respectively, compared to no use. An additive effect of aspirin (β=7.61, p=8x10-7) and PGS (β=-1.63, p=0.0112) was found for AAO without an interaction (p=0.9789) in the linear regressions, and similar effects were seen for tobacco. Aspirin is shown to be a better predictor of AAO (R2=0.1740) compared to coffee and tobacco use (R2=0.0243, R2=0.0295) or the PGS (R2=0.0141). In contrast, no association between aspirin and AAO was found inGBA1-PD (p>0.05).InterpretationIn our cohort, coffee, tobacco, aspirin, and PGS are independent predictors of PD AAO. Additionally, lifestyle factors seem to have a greater influence on AAO than common genetic risk variants with aspirin presenting the largest effect. External validation of our findings is needed.
Risk factors for SARS-Cov-2 infection at a United Kingdom electricity-generating company: a test-negative design case-control study
Authors: Rutter Charlotte E , Van Tongeren Martie , Fletcher Tony , Rhodes Sarah A , Chen Yiqun , Hall Ian , Warren Nick , Pearce Neil 
Published: August 2023

AbstractObjectivesIdentify workplace risk factors for SARS-Cov-2 infection, using data collected by a United Kingdom electricity-generating company.MethodsUsing a test-negative design case-control study we estimated the odds ratios (OR) of infection by job category, site, test reason, sex, vaccination status, vulnerability, site outage, and site COVID-19 weekly risk rating, adjusting for age, test date and test type.ResultsFrom an original 80,077 COVID-19 tests, there were 70,646 included in the final analysis. Most exclusions were due to being visitor tests (5,030) or tests after an individual first tested positive (2,968).Women were less likely to test positive than men (OR=0.71; 95% confidence interval=0.58-0.86). Test reason was strongly associated with positivity and although not a cause of infection itself, due to differing test regimes by area it was a strong confounder for other variables. Compared to routine tests, tests due to symptoms were highest risk (94.99; 78.29-115.24), followed by close contact (16.73; 13.80-20.29) and broader-defined work contact 2.66 (1.99-3.56). After adjustment, we found little difference in risk by job category, but some differences by site with three sites showing substantially lower risks, and one site showing higher risks in the final model.ConclusionsIn general, infection risk was not associated with job category. Vulnerable individuals were at slightly lower risk, tests during outages were higher risk, vaccination showed no evidence of an effect on testing positive, and site COVID-19 risk rating did not show an ordered trend in positivity rates.Key messagesWhat is already known on this topicIn the United Kingdom, there is now a considerable body of evidence showing occupational differences in Covid-19 infection and severity, but with understandable focus on high-risk industries like healthcare.Less is known about differences in risk of COVID-19 infection in other industries that do not involve directly working with the general public, in particular, there is relatively little evidence on the risks of transmission in the electricity-generating industry.What this study addsAt this company, infection risk was not associated with job category after adjusting for test reason; however women were less likely to test positive than men and the risk was higher when there was a power outage, requiring more staff to visit the site in person.How this study might affect research, practice or policyThe site risk rating showed a consistent (but modest) dose-response with infection risk, indicating that such risk rating may be useful for identifying “high risk” sites.This analysis demonstrates the importance of adjusting for both date of and reason for test, when prevalence and testing protocols differ over time.
Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients
Authors: Baird Daniel A. , Mubeen Hira , Doganli Canan , Miltenburg Jasmijn B. , Thomsen Oskar Kaaber , Ali Zafar , Naveed Tahir , Rehman Asif ur , Baig Shahid Mahmood , Christensen Søren Tvorup , Farooq Muhammad , Larsen Lars Allan 
Published: August 2023

AbstractBACKGROUNDCongenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a significant CHD risk factor in Asian populations, because Asian populations have a high degree of consanguineous marriages, which increases the risk of CHD. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology.METHODSTo obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patient’s malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patient’s coding genome by whole exome sequencing.RESULTSThe patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P<2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P<5.4e-04) and the 23 candidate disease genes (P<5.2e-04). Functional investigation ofADCY6in cell- and zebrafish-models verified its role in heart development.CONCLUSIONSOur results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.
A ubiquitous mobile genetic element disarms a bacterial antagonist of the gut microbiota
Authors: Sheahan Madeline L. , Coyne Michael J. , Flores Katia , Garcia-Bayona Leonor , Chatzidaki-Livanis Maria , Sundararajan Anitha , Holst Andrea Q. , Barquera Blanca , Comstock Laurie E. 
Published: August 2023

AbstractDNA transfer is ubiquitous in the gut microbiota, especially among species of Bacteroidales.In silicoanalyses have revealed hundreds of mobile genetic elements shared between these species, yet little is known about the phenotypes they encode, their effects on fitness, or pleiotropic consequences for the recipient’s genome. Here, we show that acquisition of a ubiquitous integrative and conjugative element encoding an antagonistic system shuts down the native contact-dependent antagonistic system ofBacteroides fragilis. Despite inactivating the native antagonism system, mobile element acquisition increases fitness of theB. fragilistransconjugant over its progenitor by arming it with a new weapon. This DNA transfer causes the strain to change allegiances so that it no longer targets ecosystem members containing the same element yet is armed for communal defense.
An Allee-based Distributed Algorithm for Microbial Whole-Cell Sensors
Authors: Cravo Fabricio , Függer Matthias , Nowak Thomas 
Published: August 2023

AbstractReliable detection of substances present at potentially low concentrations is a problem common to many biomedical applications. Complementary to well-established enzyme-, antibody-antigen-, and sequencing-based approaches, so-called microbial whole-cell sensors, i.e., synthetically engineered microbial cells that sense and report substances, have been proposed as alternatives. Typically these cells operate independently: a cell reports an analyte upon local detection.In this work, we analyze a distributed algorithm for microbial whole-cell sensors, where cells communicate to coordinate if an analyte has been detected. The algorithm, inspired by the Allee effect in biological populations, causes cells to alternate between a logical 0 and 1 state in response to reacting with the particle of interest. When the cells in the logical 1 state exceed a threshold, the algorithm converts the remaining cells to the logical 1 state, representing an easily-detectable output signal. We validate the algorithm through mathematical analysis and simulations, demonstrating that it works correctly even in noisy cellular environments.
Novel function of U7 snRNA in the repression of HERV1/LTR12s and lincRNAs in human cells
Authors: Plewka Patrycja , Szczesniak Michał W. , Pasieka Robert , Stepien Agata , Wanowska Elzbieta , Makalowska Izabela , Raczynska Katarzyna Dorota 
Published: August 2023

ABSTRACTU7 snRNA is part of U7 snRNP, a complex required for the 3’end processing of replication-dependent histone pre-mRNAs in the S phase of the cell cycle. During this maturation event, the 5’ region of U7 snRNA hybridizes with the highly complementary sequence present in the 3’UTR of histone pre-mRNAs, called histone downstream element, HDE. This base-pair interaction triggers subsequent reactions that eventually result in cleavage and release of mature histone transcripts. Intriguingly, U7 snRNP is constitutively expressed throughout the cell cycle and in nondividing cells, suggesting another function of U7 snRNA/snRNP in cells.Here, we show that several human endogenous retroviruses (HERVs) are significantly upregulated in HEK293T cells with U7 snRNA knockdown. They predominantly belong to the LTR12 class. Interestingly, some of them are located within long intergenic noncoding RNAs (lincRNAs), which in turn are upregulated in U7 snRNA knockdown cells as well. Significantly, both these HERV1/LTR12s and lincRNAs contain two or more sequence motifs that perfectly match the 5’ end of U7 snRNA, which we called HDE-like motifs. We confirmed that mutations within the HDE-like motifs abrogate U7 snRNA regulatory function and stimulate the expression of selected lincRNAs. Furthermore, we demonstrate that U7 snRNA inhibits HERV1/LTR12 and lincRNA expression at the transcription level. We propose a mechanism in which U7 snRNA hampers binding/activity of NF-Y transcription factor to CCAAT motifs that are frequently found in LTRs as well as in a close proximity to HDE-like motifs.The expression of many HERV1/LTR12s and lincRNAs regulated by U7 snRNA seems to be tissue specific, therefore, we suggest that U7 snRNA plays a protective role in keeping deleterious genetic elements in silence in selected types of cells.
Rationally seeded computational protein design
Authors: Albanese Katherine I. , Petrenas Rokas , Pirro Fabio , Naudin Elise A. , Borucu Ufuk , Dawson William M. , Arne Scott D. , Leggett Graham J. , Weiner Orion D. , Oliver Thomas A. A. , Woolfson Derek N. 
Published: August 2023

AbstractComputational protein design is advancing rapidly. Here we describe efficient routes to two families of α-helical-barrel proteins with central channels that bind small molecules. The designs are seeded by the sequences and structures of definedde novooligomeric barrel-forming peptides. Adjacent helices are connected using computational loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix-turn-helix-turn-helix motifs that are packed onto the barrels computationally. Throughout these pipelines, residues that define open states of the barrels are maintained. This minimises sequence sampling and accelerates routes to successful designs. For each of 6 targets, just 2 – 6 synthetic genes are made for expression inE. coli. On average, 80% express to give soluble monomeric proteins that are characterized fully, including high-resolution structures for most targets that match the seed structures and design models with high accuracy.
Inhibition of PQS signaling by the Pf bacteriophage protein PfsE enhances viral replication inPseudomonas aeruginosa
Authors: Schwartzkopf Caleb M. , Taylor Véronique L. , Groleau Marie-Christine , Faith Dominick R. , Schmidt Amelia K. , Lamma Tyrza L. , Brooks Diane M. , Déziel Eric , Maxwell Karen L. , Secor Patrick R. 
Published: August 2023

AbstractQuorum sensing, a bacterial signaling system that coordinates group behaviors as a function of cell density, plays an important role in regulating viral (phage) defense mechanisms in bacteria. The opportunistic pathogenPseudomonas aeruginosais a model system for the study of quorum sensing.P. aeruginosais also frequently infected by Pf prophages that integrate into the host chromosome. Upon induction, Pf phages suppress host quorum sensing systems; however, the physiological relevance and mechanism of suppression are unknown. Here, we identify the Pf phage protein PfsE as an inhibitor ofPseudomonasQuinolone Signal (PQS) quorum sensing. PfsE binds to the host protein PqsA, which is essential for the biosynthesis of the PQS signaling molecule. Inhibition of PqsA increases the replication efficiency of Pf virions when infecting a new host and when the Pf prophage switches from lysogenic replication to active virion replication. In addition to inhibiting PQS signaling, our prior work demonstrates that PfsE also binds to PilC and inhibits type IV pili extension, protectingP. aeruginosafrom infection by type IV pili-dependent phages. Overall, this work suggests that the simultaneous inhibition of PQS signaling and type IV pili by PfsE may be a viral strategy to suppress host defenses to promote Pf replication while at the same time protecting the susceptible host from competing phages.Abbreviated summaryQuorum sensing regulates phage defense inPseudomonas aeruginosa. The Pf phage protein PfsE inhibits PQS-mediated quorum sensing by binding to the host enzyme PqsA, while also protecting against type IV pili-dependent phage infection. This dual inhibition strategy promotes Pf replication and safeguards the host from competing phages.
Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease
Authors: Lambert Jordi , Oc Sebnem , Worssam Matthew D , Häußler Daniel , Figg Nichola L , Baxter Ruby , Foote Kirsty , Finigan Alison , Mahbubani Krishnaa T , Bennett Martin R , Krüger Achim , Spivakov Mikhail , Jørgensen Helle F 
Published: August 2023

AbstractAberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation are hallmarks of vascular diseases causing heart attack and stroke. To elucidate molecular determinants governing VSMC proliferation, we reconstructed gene regulatory networks from single cell transcriptomics and epigenetic profiling. We find progressive activation of enhancers at disease-relevant loci in VSMCs that don’t respond to injury and proliferation-predisposed cells. Our analysis suggests that while many transcription factors are shared, their target loci differ between VSMC states. Comparison of rewiring between VSMC subsets andin silicoperturbation analysis prioritised novel regulators, including RUNX1 and the network target TIMP1. We experimentally validated that the pioneer factor RUNX1 increased VSMC responsiveness and show that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signalling. Both RUNX1 and the TIMP1-CD74 axis were expressed in hVSMCs, at low frequency in normal arteries and increased in disease, suggesting clinical significance and potential as novel vascular disease targets.
High-Fidelity, Hyper-Accurate, and Evolved Mutants Rewire Atomic Level Communication in CRISPR-Cas9
Authors: Skeens Erin , Sinha Souvik , Ahsan Mohd , D’Ordine Alexandra M. , Jogl Gerwald , Palermo Giulia , Lisi George P. 
Published: August 2023

ABSTRACTThe Cas9-HF1, HypaCas9, and evoCas9 variants of the Cas9 endonuclease are critical tools to mitigate off-target effects in the application of CRISPR-Cas9 technology. The mechanisms by which mutations in the Rec3 domain mediate specificity in these variants are poorly understood. Here, solution NMR and molecular dynamics simulations establish the structural and dynamic effects of high-specificity mutations in Rec3, and how they propagate the allosteric signal of Cas9. We reveal conserved structural changes and peculiar dynamic differences at regions of Rec3 that interface with the RNA:DNA hybrid, transducing chemical signals from Rec3 to the catalytic HNH domain. The variants remodel the communication sourcing from the Rec3 α-helix 37, previously shown to sense target DNA complementarity, either directly or allosterically. This mechanism increases communication between the DNA mismatch recognition helix and the HNH active site, shedding light on the structure and dynamics underlying Cas9 specificity and providing insight for future engineering principles.
Computational Drug Design of Novel Agonists of the μ-Opioid Receptor to Inhibit Pain Signaling
Authors: Daoud Nancy , Mateos Diego Lopez , Riley Mary A. , Siegel Justin B. 
Published: August 2023

ABSTRACTOpioids such as Morphine, Codeine, Hydrocodone, and Oxycodone target the μ-opioid receptor, a G-protein-coupled receptor (GPCR), blocking the transmission of nociceptive signals. In this study, four opioids were analyzed for ADMET properties and molecular interactions with a GPCR crystal structure (PDB ID: 8EF6). This aided in the computational design of two novel drug candidates with improved docking scores and ADMET properties when compared to Hydrocodone. Homology analysis indicated that aMus musculus(house mouse) animal model could be used in the preclinical studies of these drug candidates in the development of safer and more effective opioid drugs for pain management with reduced side effects.