bluuebunny/crossref_metadata_2025 huggingface dataset:
Consequences of daily rhythm disruption on host-parasite malaria infection dynamics
Authors: Holland Jacob G. , Prior Kimberley F. , O’Donnell Aidan J. , Reece Sarah E.
Published: August 2023

Undertaking certain activities at the time of day that maximises fitness is assumed to explain the evolution of circadian clocks. Organisms often use daily environmental cues such as light and food availability to set the timing of their clocks. These cues may be the environmental rhythms that ultimately determine fitness, act as proxies for the timing of less tractable ultimate drivers, or are used simply to maintain internal synchrony. While many pathogens/parasites undertake rhythmic activities, both the proximate and ultimate drivers of their rhythms are poorly understood. Explaining the roles of rhythms in infections offers avenues for novel interventions to interfere with parasite fitness and reduce the severity and spread of disease. Here, we perturb several rhythms in the hosts of malaria parasites to investigate why parasites align their rhythmic replication to the host’s feeding-fasting rhythm. We manipulated host rhythms governed by light, food, or both, and assessed the fitness implications for parasites, and the consequences for hosts, to test which host rhythms represent ultimate drivers of the parasite’s rhythm. We found that alignment with the host’s light-driven rhythms did not affect parasite fitness metrics. In contrast, aligning with the timing of feeding-fasting rhythms may be beneficial for the parasite, but only when the host possess a functional canonical circadian clock. Because parasites in clock-disrupted hosts align with the host’s feeding-fasting rhythms and yet derive no apparent benefit, our results suggest cue(s) from host food act as a proxy rather than being a key selective driver of the parasite’s rhythm. Alternatively, parasite rhythmicity may only be beneficial because it promotes synchrony between parasite cells and/or allows parasites to align to the biting rhythms of vectors. Our results also suggest that interventions can disrupt parasite rhythms by targeting the proxies or the selective factors driving them without impacting host health.
Evaluating models of the ageing BOLD response
Authors: Henson Richard N , Olszowy Wiktor , Tsvetanov Kamen A , Yadav Pranay S ,   CamCAN, Zeidman Peter
Published: August 2023

Neural activity cannot be directly observed using fMRI; rather it must be inferred from the hemodynamic responses that neural activity causes. Solving this inverse problem is made possible through the use of forward models, which generate predicted hemodynamic responses given hypothesised underlying neural activity. Commonly-used hemodynamic models were developed to explain data from healthy young participants; however studies of ageing and dementia are increasingly shifting the focus towards elderly populations. We evaluated the validity of a range of hemodynamic models across the healthy adult lifespan: from basis sets for the linear convolution models commonly used to analyse fMRI studies, to more advanced models including nonlinear fitting of a parameterised hemodynamic response function (HRF) and nonlinear fitting of a biophysical generative model (hemodynamic modelling, HDM). Using an exceptionally large sample of participants, and a sensorimotor task optimized for detecting the shape of the BOLD response to brief stimulation, we first characterised the effects of age on descriptive features of the response (e.g., peak amplitude and latency). We then compared these to features from more complex nonlinear models, fit to four regions of interest engaged by the task, namely left auditory cortex, bilateral visual cortex, left (contralateral) motor cortex and right (ipsilateral) motor cortex. Finally, we validated the extent to which parameter estimates from these models have predictive validity, in terms of how well they predict age in cross-validated multiple regression. We conclude that age-related differences in the BOLD response can be captured effectively by models with three free parameters. Furthermore, we show that biophysical models like the HDM have predictive validity comparable to more common models, while additionally providing insights into underlying mechanisms, which go beyond descriptive features like peak amplitude or latency, and include estimation of nonlinear effects. Here, the HDM revealed that most of the effects of age on the BOLD response could be explained by an increased rate of vasoactive signal decay and decreased transit rate of blood, rather than changes in neural activity per se. However, in the absence of other types of neural/hemodynamic data, unique interpretation of HDM parameters is difficult from fMRI data alone, and some brain regions in some tasks (e.g, ipsilateral motor cortex) can show responses that are more difficult to capture using current models.
Do working forest easements work for conservation?
Authors: Thompson Jonathan R. , Kalinin Alexey , Lee Lucy G. , Pasquarella Valerie J. , Plisinski Joshua , Sims Katharine R. E.
Published: August 2023

Conservation easements are voluntary legal agreements designed to achieve conservation goals on private land. Extensive public and private funding has been used to establish “working forest” conservation easements (WFCE) that aim to protect conservation values while maintaining commercial timber production. We use variation in the timing and location of easements to estimate the impacts of WFCEs in Maine from a 33-year time-series of forest loss and harvesting. Compared to matched controls, WFCEs reduced forest loss rates by just 0.0004% yr-1, the equivalent of 3ha yr-1, and increased the rate of harvesting by 0.37% yr-1, or 2935ha yr-1within the 839,000 ha enrolled. More recent easements contained stricter restrictions on harvest practices and these easements reduced harvest by 0.62% yr-1. Overall, WFCEs supported continued harvests, but did not appear to provide substantial ecological benefits. Future easements could be more effective if they include additional provisions for harvest restrictions and monitoring.
CAR T-cell therapy - Paving the way for sensitized kidney transplant patients
Authors: Jarmi Tambi , Luo Yan , Attieh Rose Mary , Qie Yaqing , Gadd Martha E. , Hundal Tanya , Mao Shennen , Murthy Hemant S. , Taner Burcin C. , Kharfan-Dabaja Mohamed A. , Qin Hong
Published: August 2023

Anti-HLA donor specific antibodies have been extensively documented for their critical role in kidney transplant rejection and resulting adverse outcomes. Several approaches have been employed to desensitize these patients; however, none of these explored therapeutic approaches has exhibited enduring clinical benefits. In this study, we explore a novel strategy of utilizing chimeric antigen receptor T cells (CAR T-cells) to target B cells in sensitized kidney transplant recipients. Specifically, we investigate the potential of our innovative MC10029 CAR T-cells, which are designed to recognize the B cell activating factor receptor (BAFF-R). BAFF-R is predominantly expressed on mature B cells and plays a crucial role in their survival, as well as in the promotion of autoreactive B cell. Our data revealed that sensitized patients’ B cells exhibited high levels of BAFF-R expression. We have successfully generated patient-derived MC10029 CAR T-cells from 6 sensitized patients. All these patient-derived MC10029 CAR T-cells consistently exhibited antigen-specific cytotoxicity against autologous B cells, accompanied by the release of cytotoxic granules. We have recently obtained FDA approval of an Investigational New Drug application for MC10029 CAR T-cell therapy in B-cell hematological diseases. This significant milestone paves the way for the pioneering launch of a human clinical trial, marking the first-ever application of CAR T-cell therapy in sensitized patients waiting for life-saving organ transplants.
Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2
Authors: Rajasekaran V , Harris B. T , Osborn R. T , Smillie C , Donnelly K , Bacou M , Esiri-Bloom E , Ooi L.Y , Allan M , Walker M , Reid S , Meynert A , Grimes G , Blackmur J. P , Vaughan-Shaw P. G , Law P. J , Fernandez-Rozadilla C , Tomlinson I. P , Houlston R , Myant K. B , Din F. V , Dunlop M. G. , Farrington S. M
Published: August 2023

Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, and exerts local (cis) expression quantitative trait locus (cis-eQTL) effects onPOU2AF2, COLCA1 and POU2AF3genes. However, complex linkage disequilibrium and correlated expression at the 11q23.1 locus has thus far hindered elucidation of the mechanisms by which genetic variants impart CRC risk. Here, we establish that rs3087967 is the likely causal eQTL at this locus, co-localising with expression ofPOU2AF2and CRC risk. Furthermore, we show trans-eQTL effects on 21 distant target genes, which are highly enriched for Tuft cell markers. Analysis of available scRNAseq, ChIPseq and scATACseq data implicates POU2AF2 as the primary controller of the tuft cell specific trans-genes through POU2F3-correlated genetic regulation. Immunofluorescence demonstrates that the rs3087967 risk genotype (T) is associated with lower tuft cell abundance in human colonic epithelium. CRISPR-mediated deletion of the 11q23.1 risk locus in the mouse germline exacerbated theApcMin/+mouse phenotype upon abrogation ofPou2af2expression specifically. Taken together, we implicate a key protective role of tuft cells in the large bowel and the importance of mis-regulation ofPOU2AF2as the prime tuft cell transcriptional activator at this locus.
Bacillus subtilisderived lipopeptides disrupt quorum sensing and biofilm assembly inStaphylococcus aureus
Authors: Leistikow Kyle R. , May Daniel S. , Suh Won Se , Asensio Gabriel Vargas , Currie Cameron R. , Hristova Krassimira R.
Published: August 2023

Multidrug-resistantStaphylococcus aureusis one of the most clinically important pathogens in the world with infections leading to high rates of morbidity and mortality in both humans and animals.S. aureus’ability to form biofilm protects individual cells from antibiotics and promotes the transfer of antibiotic resistance genes. Therefore, new strategies aimed to inhibit biofilm growth and disassemble mature biofilms are urgently needed. Probiotic species, namelyBacillus subtilis,are gaining interest as a potential therapeutic againstS. aureusfor their ability to reduceS. aureuscolonization and virulence. Here, we collected and screened 1123Bacillusstrains obtained from a variety of agricultural environments in search of isolates with strong antibiofilm activity against clinical multi-drug resistantS. aureus.We selected a single strain,B. subtilis6D1, based on its ability to inhibit biofilm growth, disassemble mature biofilm, and improve antibiotic sensitivity ofS. aureusbiofilms through an Agr quorum sensing interference mechanism. Biochemical and molecular networking analysis of an active organic fraction revealed multiple surfactin isoforms and an uncharacterized compound were both driving this antibiofilm activity. Furthermore, when compared against commercial HPLC grade surfactin obtained fromB. subtilis,this active fraction inhibited biofilm formation against all fourS. aureusAgr backgrounds and preventedS. aureus-induced cytotoxicity when applied to HT29 human intestinal cell lines better than the commercial standard. Our results demonstrate the mixture of compounds produced byB. subtilis6D1 can mitigateS. aureusvirulence through multiple mechanisms.

Contribution to the Field

The biofilm formation capability of bacterial pathogens, such asStaphylococcus aureus, increases these microorganisms’ virulence potential and decreases the efficacy of common antibiotic regiments. Probiotics possess a variety of strain-specific strategies to reduce biofilm formation in competing organisms, however, the mechanisms and compounds responsible for these phenomena often go uncharacterized. In this study, we identified a mixture of small probiotic-derived peptides capable of Agr quorum sensing interference as one of the mechanisms driving antibiofilm activity againstS. aureus.This collection of peptides also improved antibiotic killing and protected human gut epithelial cells fromS. aureus-induced toxicity by stimulating an adaptive immune response. We conclude that purposeful strain screening and selection efforts can be used to identify unique probiotic strains that possess specially desired mechanisms of action. This information can be used to further improve our understanding of the ways in which probiotic and probiotic-derived compounds can be applied to prevent bacterial infections in clinical and agricultural settings.
Developmental adaptation of rod photoreceptor number via photoreception in melanopsin (OPN4) retinal ganglion cells
Authors: D’Souza Shane P. , Upton Brian A. , Eldred Kiara C. , Glass Ian , Grover Kassidy , Ahmed Abdulla , Ngyuen Minh-Thanh , Gamlin Paul , Lang Richard A.
Published: August 2023

Photoreception, a form of sensory experience, is essential for normal development of the mammalian visual system. Detecting photons during development is a prerequisite for visual system function - from vision’s first synapse at the cone pedicle and maturation of retinal vascular networks, to transcriptional establishment and maturation of cell types within the visual cortex. Consistent with this theme, we find that the lighting environment regulates developmental rod photoreceptor apoptosis via OPN4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using a combination of genetics, sensory environment manipulations, and computational approaches, we establish a molecular pathway in which light-dependent glutamate release from ipRGCs is detected via a transiently expressed kainate receptor (GRIK3) in immature rods localized to the inner retina. Communication between ipRGCs and nascent inner retinal rods appears to be mediated by unusual hybrid neurites projecting from ipRGCs that sense light before eye-opening. These structures, previously referred to as outer retinal dendrites (ORDs), span the ipRGC-immature rod distance over the first postnatal week and contain the machinery for sensory detection (melanopsin, OPN4) and axonal/anterograde neurotransmitter release (Synaptophysin, and VGLUT2). Histological and computational assessment of human mid-gestation development reveal conservation of several hallmarks of an ipRGC-to-immature rod pathway, including displaced immature rods, transientGRIK3expression in the rod lineage, and the presence of ipRGCs with putative neurites projecting deep into the developing retina. Thus, this analysis defines a retinal retrograde signaling pathway that links the sensory environment to immature rods via ipRGC photoreceptors, allowing the visual system to adapt to distinct lighting environments priory to eye-opening.
An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism
Authors: Souza Adriana Jesus , Sharmin Dishary , Cook James M. , Guimarães Francisco S. , Gomes Felipe V.
Published: August 2023

Autism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAAreceptors (α5-GABAARs) SH-053-2’F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based onin uteroVPA exposure. We also evaluated if animals exposed to VPAin uteropresent changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2’F-R-CH3 could attenuate these changes.In uteroVPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2’F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2’F-R-CH3. Despite sex differences, our findings indicate α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
Genotypic variation in resource exchange, use, and production traits in the legume-rhizobia mutualism
Authors: Calvert McCall B. , Hoque Maliha , Wood Corlett W.
Published: August 2023

Mutualisms, reciprocally beneficial interaction between two or more species, are ubiquitous in nature. A common feature of mutualisms is extensive context-dependent variation in fitness outcomes. This context-dependency is hypothesized to stem from the environment’s mediation of the relative costs and benefits associated with mutualisms. However, traits related to the exchange of goods and services in mutualisms have received little attention in comparison to net fitness outcomes. In this study, we quantified the contribution of host and symbiont genotypes to variation in resource exchange, use, and production traits measured in the host using the model mutualism between legumes and nitrogen-fixing rhizobia. We predicted that plant genotype x rhizobia genotype (GxG) effects would be common to resource exchange traits because resource exchange is hypothesized to be governed by both interacting partners through bargaining. On the other hand, we predicted that plant genotype effects would dominate host resource use and production traits because these traits are only indirectly related to the exchange of resources. Consistent with our prediction for resource exchange traits, but not our prediction for resource use and production traits, we found that rhizobia genotype and GxG effects were the most common sources of variation in the traits that we measured. The results of this study complement the commonly observed phenomenon of GxG effects for fitness by showing that numerous mutualism traits also exhibit GxG variation. Furthermore, our results highlight the possibility that the exchange of resources as well as how partners use and produce traded resources can influence the evolution of mutualistic interactions. Our study lays the groundwork for future work to explore the relationship between resource exchange, use and production traits and fitness (i.e. selection) to test the competing hypotheses proposed to explain the maintenance of fitness variation in mutualisms.
The characteristics of inducible defenses influence predator-prey dynamics
Authors: Cortez Michael H. , Mila Emily , Hammill Edward
Published: August 2023

Empirical and theoretical studies suggest inducible and evolving defenses have different effects on predator-prey dynamics. However, theory for inducible defenses does not account for differences in response stimuli, reversibility, and within-generation versus transgenerational responses. We use predator-prey models to explore how these characteristics influence the effects of inducible defenses on stability and predator-prey oscillations. We find that while inducible defenses are typically stabilizing, defenses responding to any stimuli (predator density, conspecific and predator densities, predation rates, or the fitness gradient) can be destabilizing. Also, while induced defenses typically shorten predator-prey phase lags, defenses that respond to prey densities or the fitness gradient can increase the lags. Our theory helps explain why inducible defenses are less likely to be destabilizing and increase phase lags than evolving defenses: inducible defenses typically have negative feedbacks of the trait on its own dynamics whereas evolving defenses under disruptive selection can have positive feedbacks.
WITHDRAWN: Dynamic Regulation of MAVS Protein Function via Reversible Oxidation at Cys79in Response to Oxidant Stimuli
Authors: Zamorano Cuervo Natalia , Fortin Audray , Vallejo Arroyo Alejandro , Dehbidi Layla , Grandvaux Nathalie
Published: August 2023

Withdrawal statement

“The authors have withdrawn their manuscript owing to changes in the work. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.”
Both phenotypic and genotypic sex influence sex chromosome dosage compensation in a sex reversing lizard
Authors: Hanrahan Benjamin J. , Chang J King , Lister Nicholas C. , Dissanayake Duminda S.B. , Hammond Jillian M. , Reis Andre L.M. , Deveson Ira W. , Ruiz-Herrera Aurora , Patel Hardip R. , Marshall Graves Jennifer A. , Georges Arthur , Waters Paul D.
Published: August 2023

Studies of sex chromosome dosage compensation have historically focussed on therian mammals which have a conserved XY sex determination system. In contrast, lizards have sex determination systems that can differ between even closely related species that include XY and ZW systems and thermolabile systems where genetic and temperature interact to various degrees to determine sex. The eastern three-lined skink (Bassiana duperreyi) has a differentiated XY sex determination system, in which low temperature incubation during development can cause female to male sex reversal, producing XX males. This provides a unique opportunity to investigate how genotype and phenotype affect dosage compensation. We generated transcriptomes from brain and heart tissue of normal adult males and females, along with brain tissue of sex-reversed XX males. We observed partial dosage compensation between XX females and XY males in both brain and heart, with median gene expression from the X in normal males being 0.7 times that of normal females. Surprisingly, in brain of sex reversed XX males the median X chromosome output did not match that of either normal males or females, but instead was 0.89 times that of the normal XX female level. This suggests that not just genotype, but also sexual phenotype, influences gene dosage of the X chromosome. This has profound implications for our understanding of the evolution of dosage compensation.
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

Background

Regular 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.

Methods

SROI 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.

Results

The 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.

Conclusion

Compared 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 registration

ISRCTN15320670
Host behaviour driven by awareness of infection risk amplifies the chance of superspreading events
Authors: Parag Kris V , Thompson Robin N
Published: August 2023

We 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

Objective

To investigate the association between a Parkinson’s disease (PD)-specific polygenic score (PGS) and protective lifestyle factors on age at onset (AAO) in PD.

Methods

We 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.

Results

The 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).

Interpretation

In 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

Objectives

Identify workplace risk factors for SARS-Cov-2 infection, using data collected by a United Kingdom electricity-generating company.

Methods

Using 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.

Results

From 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.

Conclusions

In 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 messages

What is already known on this topic

In 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 adds

At 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 policy

The 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

BACKGROUND

Congenital 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.

METHODS

To 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.

RESULTS

The 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.

CONCLUSIONS

Our 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

DNA 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

Reliable 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

U7 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

Computational 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

Quorum 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 summary

Quorum 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

Aberrant 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

The 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

Opioids 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.
GNSS denied navigation system for the manoeuvring flying objects
Authors: Borodacz Krystian , Szczepański Cezary
Published: August 2023

Purpose

Before designing a navigation system, it is necessary to analyse possible approaches in terms of expected accuracy, existing limitations and economic justification to select the most advantageous solution. This paper aims to collect possible navigation methods that can provide correction for inertial navigation and to evaluate their suitability for use on a manoeuvring tactical missile.

Design/methodology/approach

The review of existing munitions was based on data collected from the literature and online databases. The data collected included dimensions, performance, applied navigation and guidance methods and their achievable accuracy. The requirements and limitations identified were confronted with the range of sensor parameters available on the market. Based on recent literature, navigation methods were reviewed and evaluated for applicability to inertial navigation system (INS) correction in global navigation satellite system-denied space.

Findings

The performance analysis of existing munition shows that small and relatively inexpensive micro-electro-mechanical system-type inertial sensors are required. A review of the parameters of existing devices of this type has shown that they are subject to measurement errors that do not allow them to achieve the delivery accuracy expected of precision missiles. The most promising navigation correction methods for manoeuvring flying objects have been identified.

Originality/value

The information presented in this paper is the result of the first phase of a project and presents the results of the requirements selection, initial sizing and preliminary design of the navigation system. This paper combines a review of the current state of the art in missile systems and an analysis of INS accuracy including the selection of sensor parameters.