bluuebunny/crossref_metadata_2025 huggingface dataset:
Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability inDrosophila melanogaster
Authors: Ertl Henry A. , Bayala Erick X. , Siddiq Mohammad A. , Wittkopp Patricia J.
Published: April 2024

Pioneer factors are critical for gene regulation and development because they bind chromatin and make DNA more accessible for binding by other transcription factors. The pioneer factor Grainy head (Grh) is present across metazoans and has been shown to retain a role in epithelium development in fruit flies, nematodes, and mice despite extensive divergence in both amino acid sequence and length. Here, we investigate the evolution of Grh function by comparing the effects of the fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) Grh orthologs on chromatin accessibility, gene expression, embryonic development, and viability in transgenicD. melanogaster. We found that theCaenorhabditis elegansortholog rescued cuticle development but not full embryonic viability inDrosophila melanogaster grhnull mutants. At the molecular level, theC. elegansortholog only partially rescued chromatin accessibility and gene expression. Divergence in the disordered N-terminus of the Grh protein contributes to these differences in embryonic viability and molecular phenotypes. These data show how pioneer factors can diverge in sequence and function at the molecular level while retaining conserved developmental functions at the organismal level.

SUMMARY STATEMENT

Despite divergence in a disordered region that affects function at both molecular and organismal levels, theCaenorhabditis elegansGrainy head (Grh) protein rescued cuticle morphology inD. melanogasterembryos.
Assessing Cognitive Functions Remotely Using a Music-Game-Like Program
Authors: Perron Maxime , Imran Ashna , Alain Rebecca , Alain Claude , Sakaki Yayoi
Published: April 2024

There is a growing need to develop ways of assessing cognitive functions remotely and providing interventions using a web-based approach. The Ipsilon Test is a music-based cognitive assessment and training tablet application. On each trial, it presents simplified musical notation with colours, spatial cues, and gestural references so that users can translate spatial information into motor actions by tapping on the screen. In this study, we examined the correlation between the performance of a group of healthy older adults on the Ipsilon test and standard measures of cognitive function—a total of 30 participants aged 58 and over were recruited for the study. Before and after one week of training using the web-based program Ipsilon, all participants completed an online version of the Montreal Cognitive Assessment (MoCA) and the visual Stroop task. Of the participants recruited, 22 participants completed the Ipsilon training and cognitive testing. In our sample, performance on the Ipsilon test was generally high, with all participants scoring above the chance level. Importantly, we found a correlation between Ipsilon test performance and pre-Ipsilon MoCA scores. In addition, participants who scored higher on the Ipsilon test also showed improvement in the visual Stroop task after Ipsilon training, particularly in the ability to inhibit irrelevant information. These results suggest the Ipsilon test is a practical web-based cognitive assessment and training tool. Future research will explore its relationship with other cognitive tests and its diagnostic power for differentiating individuals with normal cognition from those with cognitive disorders.
Flynotyper 2.0: An updated tool for rapid quantitative assessment ofDrosophilaeye phenotypes
Authors: Ray Johnathan , Banerjee Deepro , Wang Qingyu , Girirajan Santhosh
Published: April 2024

About two-thirds of the genes in theDrosophila melanogastergenome are also involved in its eye development, making theDrosophilaeye an ideal system for genetic studies. We previously developed Flynotyper, a software that uses image processing operations to identify and quantify the degree of roughness by measuring disorderliness of ommatidial arrangement in the fly eye. This software has enabled researchers to quantify morphological defects of thousands of eye images caused by genetic perturbations. Here, we present Flynotyper 2.0, a software that has an updated computer vision library, improved performance, and a streamlined pipeline for high-throughput analysis of multiple eye images. We also tested several batches ofDrosophilaeye images to ensure robustness and reproducibility of the updated Flynotyper 2.0 software.

Availability and implementation

The source code for Flynotyper 2.0 can be downloaded and installed fromhttps://github.com/girirajanlab/flynotyper-desktop-application.
Role of Mutual Information Profile Shifts in Assessing the Pathogenicity of Mutations on Protein Functions: The Case of Pyrin Variants Associated with Familial Mediterranean Fever
Authors: Hacisuleyman Aysima , Gul Ahmet , Erman Burak
Published: April 2024

This paper presents a novel method to assess the pathogenicity of Pyrin protein mutations by using mutual information (MI) as a measure to quantify the correlation between residue motions or fluctuations and associated changes affecting the phenotype. The concept of MI profile shift is presented to quantify changes in MI upon mutation, revealing insights into residue-residue interactions at critical positions. We apply this method to the Pyrin protein variants, which are associated with an autosomal recessively inherited disease called familial Mediterranean fever (FMF) since the available tools do not help predict the pathogenicity of the most penetrant variants. We demonstrate the utility of MI profile shifts in assessing the effects of mutations on protein stability, function, and disease phenotype. The importance of MI shifts, for the pyrin example the negative shifts, as indicators of severe functional effects is emphasized, along with exploring potential compensatory mechanisms indicated by positive MI shifts, which are otherwise random and inconsequential. The paper also discusses challenges in relating MI profile changes to disease severity and advocates for comprehensive analysis considering genetic, environmental, and stochastic factors. Overall, this study provides insights into the molecular mechanisms underlying the pathogenesis of FMF and offers a framework for identifying potential therapeutic targets based on MI profile changes induced by mutations.
Parallel Trends in an Unparalleled Pandemic Difference-in-differences for infectious disease policy evaluation
Authors: Feng Shuo , Bilinski Alyssa
Published: April 2024

Researchers frequently employ difference-in-differences (DiD) to study the impact of public health interventions on infectious disease outcomes. DiD assumes that treatment and non-experimental comparison groups would have moved in parallel in expectation, absent the intervention (“parallel trends assumption”). However, the plausibility of parallel trends assumption in the context of infectious disease transmission is not well-understood. Our work bridges this gap by formalizing epidemiological assumptions required for common DiD specifications, positing an underlying Susceptible-Infectious-Recovered (SIR) data-generating process. We demonstrate that popular specifications can encode strict epidemiological assumptions. For example, DiD modeling incident case numbers or rates as outcomes will produce biased treatment effect estimates unless untreated potential outcomes for treatment and comparison groups come from a data-generating process with the same initial infection and equal transmission rates at each time step. Applying a log transformation or modeling log growth allows for different initial infection rates under an “infinite susceptible population” assumption, but invokes conditions on transmission parameters. We then propose alternative DiD specifications based on epidemiological parameters – the effective reproduction number and the effective contact rate – that are both more robust to differences between treatment and comparison groups and can be extended to complex transmission dynamics. With minimal power difference incidence and log incidence models, we recommend a default of the more robust log specification. Our alternative specifications have lower power than incidence or log incidence models, but have higher power than log growth models. We illustrate implications of our work by re-analyzing published studies of COVID-19 mask policies.

Significance Statement

Difference-in-differences is a popular observational study design for policy evaluation. However, it may not perform well when modeling infectious disease outcomes. Although many COVID-19 DiD studies in the medical literature have used incident case numbers or rates as the outcome variable, we demonstrate that this and other common model specifications may encode strict epidemiological assumptions as a result of non-linear infectious disease transmission. We unpack the assumptions embedded in popular DiD specifications assuming a Susceptible-Infected-Recovered data-generating process and propose more robust alternatives, modeling the effective reproduction number and effective contact rate.
Factors shaping vaginal microbiota long-term community dynamics in young adult women
Authors: Kamiya Tsukushi , Tessandier Nicolas , Elie Baptiste , Bernat Claire , Boué Vanina , Grasset Sophie , Groc Soraya , Rahmoun Massilva , Selinger Christian , Humphrys Michael S. , Bonneau Marine , Graf Christelle , Foulongne Vincent , Reynes Jacques , Tribout Vincent , Segondy Michel , Boulle Nathalie , Ravel Jacques , Murall Carmen Lía , Alizon Samuel
Published: April 2024

The vaginal microbiota is known to affect women’s health. Yet, there is a notable paucity of high-resolution follow-up studies lasting several months, which would be required to interrogate the long-term dynamics and associations with demographic and behavioural covariates. Here, we present a high-resolution longitudinal cohort of 125 women followed for a median duration of 8.6 months, providing 11 samples per woman. Using a hierarchical Bayesian Markov model, we characterised the patterns of vaginal microbiota community persistence and transition, simultaneously estimated the impact of 16 covariates and quantified individual variability among women. We showed that ‘optimal’ (Community State Type (CST) I, II, and V) and ‘sub-optimal’ (CST III) communities are more stable over time than ‘non-optimal’ (CST IV) ones. Furthermore, we found that some covariates — most notably alcohol consumption — impacted the probability of shifting from one CST to another. We performed counterfactual simulations to confirm that alterations of key covariates, such as alcohol consumption, could shape the prevalence of different microbiota communities in the population. Finally, our analyses indicated that there is a relatively canalised pathway leading to the deterioration of vaginal microbiota communities, whereas the paths to recovery can be highly individualised among women. In addition to providing one of the first insights into vaginal microbiota dynamics over a year, our study showcases a novel application of a hierarchical Bayesian Markov model to clinical cohort data with many covariates. Our findings pave the way for an improved mechanistic understanding of microbial dynamics in the vaginal environment and the development of novel preventative and therapeutic strategies to improve vaginal health.
Telehealth versus face-to-face delivery of speech language pathology services: a systematic review and meta-analysis
Authors: Scott Anna Mae , Clark Justin , Cardona Magnolia , Atkins Tiffany , Peiris Ruwani , Greenwood Hannah , Wenke Rachel , Cardell Elizabeth , Glasziou Paul
Published: April 2024

Background

There is an increasing demand for the provision of speech language pathology (SLP) services via telehealth. Therefore, we systematically reviewed randomized controlled trials comparing telehealth to face-to-face provision of SLP services.

Methods

We searched Medline, Embase, and Cochrane, clinical trial registries, and conducted a citation analysis to identify trials. We included randomized trials comparing similar care delivered live via telehealth (phone or video), to face-to-face. Primary outcomes included: % syllables stuttered (%SS) (for individuals who stutter); change in sound pressure levels monologue (for individuals with Parkinson’s disease); and key function scores (for other areas). Where data were sufficient, mean differences were calculated.

Results

Nine randomized controlled trials were included; 8 evaluated video and 1 evaluated phone telehealth. Risk of bias was generally low or unclear, excepting blinding. There were no significant differences at any time-point up to 18 months for %SS (mean difference, MD 0.1, 95% CI –0.4 to 0.6, p=0.70). For people with Parkinson’s disease, there was no difference between groups in change in sound pressure levels (monologue) (MD 0.6, 95% CI –1.2 to 2.5, p=0.49). Four trials investigated interventions for speech sound disorder, voice disorder, and post-stroke dysphagia and aphasia; they found no differences between telehealth service delivery and face-to-face delivery.

Conclusions

Evidence suggests that the telehealth provision of SLP services may be a viable alternative to their provision face-to-face, particularly to people who stutter and people with Parkinson’s disease. The key limitation is the small number of randomized controlled trials, as well as evidence on the quality of life, well-being and satisfaction, and economic outcomes.
Disability patterns in multiple sclerosis: a meta-analysis on PIRA and RAW in the real world context
Authors: Prosperini Luca , Ruggieri Serena , Haggiag Shalom , Tortorella Carla , Gasperini Claudio
Published: April 2024

Background

The confirmed disability accrual (CDA) due to multiple sclerosis (MS) is driven by two factors: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). However, accurate estimations of these phenomena in the real-world setting are lacking. This study aims at summarizing current evidence on RAW and PIRA, including associated factors, through a quantitative synthesis of real-world studies.

Methods

Scientific databases were searched to identify real-world studies published until December 31, 2023, reporting how many patients experienced RAW and PIRA (events of interest). Random-effects meta-analyses, subgroup analyses and meta-regression models were ran to provide pooled estimates of RAW and PIRA events, and to identify their potential moderators (PROSPERO registration: CRD42024503895).

Results

Eighteen articles met the eligibility criteria, with a pooled sample size of 52,667 patients followed for 2.4 to 12.1 years (415,825 patient-years). Pooled event rates for RAW and PIRA were 1.6 and 3.1 per 100 patient-years, respectively. Less RAW events were found in patient cohorts under high-efficacy disease-modifying treatments (β=–0.031, p=0.007), while PIRA events were directly related to older age (β=0.397, p=0.027), predicting ≥6 PIRA events per 100 patient-years at an age ≥54 years. Additionally, we found significant differences in PIRA event rates according to the criteria adopted to define CDA.

Discussion

PIRA accounts for most CDA events in the real-world setting, even at the earlier disease stages, whereas RAW represents a less frequent phenomenon, likely due to effective treatments. However, the detection and statistical analysis of PIRA outcomes pose challenges, raising the risk of biased interpretation.

What is already known on this topic

Irreversible accumulation of disability in multiple sclerosis stems from two distinct yet not mutually exclusive phenomena: relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA).

What this study adds

In this meta-analysis including data of 52,667 patients followed for 2.4 to 12.1 years, the pooled event rates were 1.6 and 3.1 per 100 patient-years for RAW and PIRA, respectively. High-efficacy treatment strongly suppresses RAW but not PIRA, which is instead associated with age and definition criteria.

How this study might affect research, practice or policy

Although PIRA accounts for most disability events in MS, its detection in real-world setting is necessarily inaccurate and its statistical analysis is challenging.
NeoCoMM: Neocortical Computational Microscale Model
Authors: Al Harrach M. , Yochum M. , Wendling F.
Published: April 2024

The Neocortical Computational Microscale model (NeoCoMM) is a unique neurophysiologically-inspired software. It offers a friendly graphical user interface that allows for the simulation of the intracellular and extracellular neural activity of a neocortical column. This software provides a realistic framework that can portray the neural activity and underlying cellular mechanisms related to different brain pathologies such as epilepsy. NeoCoMM is capable of (1) simulating the cortical tissue of three different species, (2) visualizing individual cell responses to external stimulation, (3) visualizing the corresponding local field potential, (4) studying the impact of the recording electrode features on simulated signals, and (5) testing various physiological and pathological hypotheses. While NeoCoMM was primarily developed for simulating epileptiform activity, it can also generate healthy brain rhythms or be adapted to other brain disorders.
Modeling CSF circulation and the glymphatic system during infusion using subject specific intracranial pressures and brain geometries
Authors: Dreyer Lars Willas , Eklund Anders , Rognes Marie Elisabeth , Malm Jan , Qvarlander Sara , Støverud Karen-Helene , Mardal Kent-Andre , Vinje Vegard
Published: April 2024

Background

Infusion testing is an established method for assessing CSF resistance in patients with idiopathic normal pressure hydrocephalus (iNPH). To what extent the increased resistance is related to the glymphatic system is an open question. Here we introduce a computational model that includes the glymphatic system and enables us to determine the importance of 1) brain geometry, 2) intracranial pressure and 3) physiological parameters on the outcome of and response to an infusion test.

Methods

We implemented a seven-compartment multiple network porous medium model with subject specific geometries from MR images. The model consists of the arterial, capillary and venous blood vessels, their corresponding perivascular spaces, and the extracellular space (ECS). Both subject specific brain geometries and subject specific infusion tests were used in the modeling of both healthy adults and iNPH patients. Furthermore, we performed a systematic study of the effect of variations in model parameters.

Results

Both the iNPH group and the control group reached a similar steady state solution when subject specific geometries under identical boundary conditions was used in simulation. The difference in terms of average fluid pressure and velocity between the iNPH and control groups, was found to be less than 6 % during all stages of infusion in all compartments. With subject specific boundary conditions, the largest computed difference was a 75 % greater fluid speed in the arterial perivascular space (PVS) in the iNPH group compared to the control group. Changes to material parameters changed fluid speeds by several orders of magnitude in some scenarios. A considerable amount of the CSF pass through the glymphatic pathway in our models during infusion, i.e., 28% and 38% in the healthy and iNPH patients, respectively.

Conclusions

Using computational models, we have found the relative importance of subject specific geometries to be less important than individual differences in terms of fluid pressure and flow rate during infusion. Model parameters such as permeabilities and inter-compartment transfer parameters are uncertain but important and have large impact on the simulation results. The computations predicts that a considerable amount of the infused volume pass through the brain either through the perivascular spaces or the extracellular space.
Spatiotemporal binding of cyclophilin A and CPSF6 to capsid regulates HIV-1 nuclear entry and integration
Authors: Ingram Zachary , Kline Christopher , Hughson Alexandra K. , Singh Parmit K. , Fischer Hannah L. , Sowd Gregory A. , Watkins Simon C. , Kane Melissa , Engelman Alan N. , Ambrose Zandrea
Published: April 2024

Human immunodeficiency virus type 1 (HIV-1) capsid, which is the target of the antiviral lenacapavir, protects the viral genome and binds multiple host proteins to influence intracellular trafficking, nuclear import, and integration. Previously, we showed that capsid binding to cleavage and polyadenylation specificity factor 6 (CPSF6) in the cytoplasm is competitively inhibited by cyclophilin A (CypA) binding and regulates capsid trafficking, nuclear import, and infection. Here we determined that a capsid mutant with increased CypA binding affinity had significantly reduced nuclear entry and mislocalized integration. However, disruption of CypA binding to the mutant capsid restored nuclear entry, integration, and infection in a CPSF6-dependent manner. Furthermore, relocalization of CypA expression from the cell cytoplasm to the nucleus failed to restore mutant HIV-1 infection. Our results clarify that sequential binding of CypA and CPSF6 to HIV-1 capsid is required for optimal nuclear entry and integration targeting, informing antiretroviral therapies that contain lenacapavir.
Purified diets containing high levels of soluble fiber and grain-based diets promote similar gastrointestinal morphometry yet distinct microbial communities
Authors: Glenny Elaine M. , Liu Jintong , Skinner Harlyn G. , McFarlane Tori L. , Reed Kylie K. , Weninger Alyssa , Djukic Zorka , Pellizzon Michael A. , Carroll Ian M.
Published: April 2024

Grain-based diets (GBDs) are widely used in rodent studies but their utility is limited due to batch-to-batch variability resulting from inconsistent ingredients. Purified diets (PDs) are composed of only known and refined ingredients and offer a solution to the constraints of GBDs. However, unlike GBDs, PDs commonly used as control diets typically contain little to no soluble fiber. We therefore sought to identify a combination of fibers in PDs that best recapitulates the gastrointestinal morphometry and intestinal microbial composition of mice fed GBDs. Adult male mice (n=30) were randomly assigned to one of six diets—two GBDs and four PDs with varying insoluble and soluble fiber composition—for 28 days. 16S rRNA gene sequencing was used to compare microbial profiles across different gastrointestinal (GI) niches and diets. Gut microbiotas and cecal weights were distinct between mice fed the two GBDs, indicating that GBDs are unreliable controls in diet-based studies. Unexpectedly, intestinal microbial richness decreased as the amount of soluble fiber in the PDs increased and the addition of multiple soluble fibers did not rescue this effect. Mice fed PDs with high soluble fiber content (≥ 75% of dietary fiber was soluble fiber) best recapitulated GI morphometry of mice fed GBDs, but intestinal microbial communities were distinct between PD- and GBD-fed mice. Although supplementing PDs with soluble fiber improved GI morphometry, further research to determine the optimal mixture of soluble and insoluble fibers is required to more closely mirror the intestinal microbial diversity observed in mice fed GBDs.

Importance

Dietary fibers are essential for maintaining gut health. Insoluble fibers aid in fecal bulking and water retention while soluble fiber is a fermentative substrate for intestinal microbial communities. GBDs are commonly used in preclinical research but the variability in ingredients across batches impedes reproducibility. PDs, which are composed of highly refined ingredients, pose a potential solution but the most widely used low-fat control PDs contain no soluble fiber. This study intended to identify a PD with a combination of fibers that promotes murine gut health and microbial diversity. A PD with optimal fiber composition would aid in the standardization and reproducibility of studies investigating intestinal physiology and the gut microbiota.
Plasmodium falciparumprotein phosphatase PP7 is required for early ring-stage development
Authors: Patel Avnish , Fréville Aline , Rey Joshua A. , Flynn Helen R. , Koussis Konstantinos , Skehel Mark J. , Blackman Michael J. , Baker David A.
Published: April 2024

We previously reported that thePlasmodium falciparumputative serine/threonine protein phosphatase 7 (PP7) is a high confidence substrate of the cAMP-dependent protein kinase (PKA). Here we explore the function of PP7 in asexualP. falciparumblood stage parasites. We show that conditional disruption of PP7 leads to a severe growth arrest. We show that PP7 is a calcium-dependent phosphatase which interacts with calmodulin and calcium-dependent protein kinase 1 (CDPK1), consistent with a role in calcium signalling. Notably, PP7 was found to be dispensable for erythrocyte invasion, but was crucial for ring-stage development, with PP7-null parasites arresting shortly following invasion and showing no transition to ameboid forms. Phosphoproteomic analysis revealed that PP7 may regulate certain PKAc substrates. Its interaction with calmodulin and CDPK1 further emphasise a role in calcium signalling, while its impact on early ring development and PKAc substrate phosphorylation underscores its importance in parasite development.
Advancing 90-day mortality and anastomotic leakage predictions after oesophagectomy for cancer using explainable AI (XAI)
Authors: Djerf Sebastian , Åkesson Oscar , Nilsson Magnus , Lindblad Mats , Hedberg Jakob , Johansson Jan , Frigyesi Attila
Published: April 2024

Oesophagectomy for cancer of the oesophagus carries significant morbidity and mortality. Ninety-day mortality and anastomosis leakage are critical early postoperative problems traditionally analysed through logistic regression. In this study, we challenge traditional logistic regression models to predict results with new explainable AI (XAI) models. We used the Swedish National Quality Register for Oesophageal and Gastric Cancer (NREV) to perform traditional multivariable logistic regression and XAI. The 90-day mortality was 6.0%, while anastomosis leakage was present in 12.4%. The XAI models yielded an area under the curve (AUC) of 0.91 for 90-day mortality (as compared with 0.84 for logistic regression). For anastomosis leakage, the AUC was 0.84 using XAI (0.74 using logistic regression). We show that age (mortality increases sharply after 55 years) and body mass index (BMI) (lowest mortality for BMI 30 kg/m2) are important survival factors. Additionally, we show that surgery time (minimum anastomosis leakage for a surgery time of 200 min to sharply increase to a maximum at 375 min) and BMI (the lower the BMI, the less anastomosis leakage) are important factors for anastomosis leakage. The surgical understanding of anastomosis leakage and mortality after oesophagectomy is advanced by judiciously applying XAI to structured data. Our nationwide oesophagectomy data contains significant nonlinear relationships. With the help of XAI, we extract personalised knowledge, bringing oesophagus surgery one step closer to personalised medicine.
North American Pharmacist Licensure Examination Absolute Failures Warrant Monitoring of Colleges and Schools of Pharmacy
Authors: Pezzuto John M. , Shcherbakova Natalia , Pesaturo Kimberly A.
Published: April 2024

Over the past three years, 7,978 graduates of pharmacy programs have failed the North American Pharmacist Licensure Examination (NAPLEX) on the first attempt. At present, the ACPE monitors programs with a passage rate of ≥2 standard deviations (SD) below the national mean pass rate. In 2023, this would lead to monitoring seven programs that produced 140 failures out of the total of 2,472 failures (i.e., 5.7%). In our view, this is neither equitable nor demonstrative of sufficient accountability. Analysis of failure counts among the 144 programs reported by NABP demonstrates a distribution curve highly skewed to the right. After evaluating average failure counts across all the programs, we suggest that schools with absolute failures ≥2 SD higher than the average number of failures of all programs should be flagged for monitoring. Based on the 2023 data, this corresponds to ≥35 failures/program. This threshold would flag 18 programs and 36.5% of the total failures. Of the seven programs that will be monitored based on the current Accreditation Council for Pharmacy Education criteria, only one would be captured by the ≥35 failure method of selection with the remaining six contributing only 85 total failures to the pool. Thus, if both criteria were to be applied, i.e., ≥35 failures and of ≥2 standard deviations below the national mean pass rate, a total of 24 programs would be monitored (16.6% of the 144 programs), that contribute 987 (39.9%) of the total failures.
Attitudes towards the regulation and provision of abortion among healthcare professionals in Britain; cross sectional survey data from the SACHA study
Authors: Wellings Kaye , Scott Rachel , Sheldon Sally , Wellings Kaye , Palmer Melissa , Meiksin Rebecca , Shaw Jill , cameron sharon , Reiter Jennifer , French Rebecca
Published: April 2024

Abstract Objectives: Therapeutic, regulatory and technological changes have contributed to new directions in abortion care. We aimed to gather views of healthcare professionals on current and future regulation and provision of abortion in Britain. Design: Cross sectional, stratified cluster sample survey with additional free text comments. Setting: Healthcare settings in Britain Participants: Healthcare professionals (nurses, doctors, midwives, pharmacists) working in a range of healthcare services, including dedicated abortion services. Measures: Knowledge of and attitudes towards the regulation and provision of abortion. Results: 771 healthcare professionals from all areas of Britain responded to the survey. Support for abortion being the choice of a woman was high, more than nine in ten saw it as such and a clear majority favoured abortion being treated as a health rather than a legal issue. Only 6.2% saw abortion at any gestational age as contrary to their personal beliefs and a similarly small minority (6.7%) were against abortion after 12 weeks gestation. One in five of all healthcare professionals and a third of those aged under 30 were unaware that the law in Britain requires two doctors to authorise an abortion. Free text comments revealed opposition to the need for this legal requirement. Support for an extended role for nurses in abortion care was high; two thirds (65.3%) agreed that nurses should be able to prescribe abortion medication. Little more than a third of all healthcare professionals (37%) agreed that abortion should be standard practice in their service; the proportion was highest among those in sexual and reproductive health services (58.4%) and lowest among those in general practice (18.7%). Conclusions: Health care professionals in Britain are generally supportive of abortion being treated in the same way as other health issues and would be likely to support any moves to decriminalise abortion.
Hybrid humoral immune response of Pacific Islanders to BNT162b2 vaccination and Delta/Omicron infection: a cohort study
Authors: Inizan Catherine , Courtot Adrien , Sturmach Chloé , Griffon Anne-Fleur , Biron Antoine , Bruel Timothée , Enouf Vincent , Demaneuf Thibaut , Munier Sandie , Schwartz Olivier , Gourinat Ann-Claire , Médevielle Georges , Jouan Marc , van der Werf Sylvie , Madec Yoann , Albert-Dunais Valérie , Dupont-Rouzeyrol Myrielle
Published: April 2024

Background

Pacific Islanders are underrepresented in vaccine efficacy trials. Few studies describe their immune response to COVID-19 vaccination. Yet, this characterization is crucial to re-enforce vaccination strategies adapted to Pacific Islanders singularities.

Methods

We evaluated the humoral immune response of 585 adults self-declaring as Melanesians, Europeans, Polynesians or belonging to other communities to Pfizer BNT162b2 vaccine. Anti-Spike and anti-Nucleoprotein IgG levels, capacity to neutralize SARS-CoV-2 variants and capacity to mediate Antibody-Dependent Cellular Cytotoxicity (ADCC) were assessed across communities at one and three months post-second dose or one and six months post-third dose.

Results

61.3% of the sera tested contained anti-Nucleoprotein antibodies, evidencing mostly a hybrid immunity resulting from vaccination and SARS-CoV-2 infection. Anti-Spike IgG levels and capacity to mediate Omicron neutralization and ADCC were equivalent across the four ethnic communities at one-month post-immunization, during follow-up and at six months post-third dose, regardless of the infection status. Obese individuals (BMI>30 kg/m²) had significantly higher anti-Spike IgG levels at one-month post-immunization (+0.26 (0.04; 0.48) AU in LuLISA assay,pvalue = 0.017). Odds of Omicron neutralization at six months after the third dose decreased significantly in the 40-64 years and ≥65 years groups (OR (95% CI) 0.48 (0.24-0.90) and 0.29 (0.14-0.58) respectively,p-value = 0.003).

Conclusions

Our study evidenced Pacific Islander’s robust humoral immune response to Pfizer BNT162b2 vaccine, which is pivotal to re-enforce vaccination deployment in a population at risk for severe COVID-19 (clinicaltrials.gov:NCT05135585).

summary

Ethnicity has little impact on Pacific Islanders’ hybrid humoral immune response to BNT162b2 vaccination and SARS-CoV-2 infection. Anti-Spike IgG levels, capacity to neutralize Omicron variants and capacity to mediate Antibody-Dependent Cellular Cytotoxicity are equivalent across Pacific communities following BNT162b2 vaccination.
Corporate activities that influence population health: A scoping review and qualitative synthesis to develop the HEALTH-CORP typology
Authors: Burgess Raquel , Nyhan Kate , Freudenberg Nicholas , Ransome Yusuf
Published: April 2024

Introduction

The concept of the commercial determinants of health (CDH) is used to study the actions (and associated structures) of commercial entities that influence population health and health equity. The aim of this study was to develop a typology that describes the diverse set of activities through which corporations influence population health and health equity across industries.

Methods

We conducted a scoping review of articles using CDH terms (n=116) that discuss corporate activities that can influence population health and health equity across 16 industries. We used the qualitative constant comparison method to build a typology called the Corporate Influences on Population Health (HEALTH-CORP) typology.

Results

The HEALTH-CORP typology identifies 70 corporate activities that can influence health across industries and categorizes them into seven domains of corporate influence (e.g., political practices, employment practices). We present a model that situates these domains based on their proximity to health outcomes and identify five population groups (e.g., workers, local communities) to consider when evaluating corporate health impacts.

Discussion

The HEALTH-CORP typology facilitates an understanding of the diverse set of corporate activities that can influence population health and the population groups affected by these activities. We discuss the utility of these contributions in terms of identifying interventions to address the CDH and advancing efforts to measure and monitor the CDH. We also leverage our findings to identify key gaps in CDH literature and suggest avenues for future research.
Accessibility of care and experiential quality of care for adults with hypertension in rural Burkina Faso: results from a cross-sectional household survey
Authors: Lacey Stephanie , Odland Maria Lisa , Sié Ali , Harling Guy , Bärnighausen Till , Geldsetzer Pascal , Hirschhorn Lisa R , Davies Justine I
Published: April 2024

Providing quality healthcare is essential to reduce the future burden of cardiovascular disease. We assessed the quality of hypertension care in Burkina Faso using the Institute of Medicine (IOM) Quality Domains of effectiveness, timeliness of access, patient-centredness and equitability of care.

We performed an analysis of cross-sectional household survey data collected from a population-representative sample of 4000 adults ≥40 years in Nouna, Burkina Faso in 2018. For people with hypertension, effectiveness was assessed through the construction of care cascades describing the proportion who were screened, diagnosed, treated, and achieved hypertension control; timeliness was defined as access to care within the last 3 months. Patient-centredness was described using experiential quality process and outcome measures (dichotomised as higher [score above the median] or lower quality [score below and including the median]; a shared understanding and decision-making variable (SUDM) was also described. Equity was assessed for effectiveness, timeliness, and patient-centredness in multivariable analyses, including socio-demographic factors. In total, 1006 participants with hypertension were included. Hypertension prevalence was 34.8%, with 62.3% having previously been screened, 42.9% diagnosed, 15.0% treated, and 6.8% having controlled disease; 26.8% had accessed care within the last three months. Overall, 61.8% of participants had a positive view of the health service. Clarity of communication and opinion of medical provider knowledge were the best-rated experiential quality process variables, with 40.1% and 39.7% of participantś responses indicating higher quality care respectively. The mean SUDM score was 68.5 (±10.8) out of 100.0. Regarding equity, screening was higher in females, adults with any education, those who were married or cohabiting, and those in the higher wealth quintiles. There were no associations seen between SUDM and participant characteristics.

Although prevalence of hypertension was high in this population, quality of care was not commensurate, with room for improvement in all four of the IOM Domains assessed.
Kidney collecting duct cell type composition is regulated by Notch signaling via modulation of mTORC1
Authors: deRiso Jennifer , Mukherjee Malini , Janga Madhusudhana , Simmons Alicia , Kareta Michael , Tao Jianning , Chandrasekar Indra , Surendran Kameswaran
Published: April 2024

The plasticity and diversity of cell types with specialized functions likely defines the capacity of multicellular organisms to adapt to physiologic stressors. The kidney collecting ducts contribute to water, electrolyte, and pH homeostasis and are composed of mature intermingled epithelial cell types that are susceptible to transdifferentiate. The conversion of kidney collecting duct principal cells to intercalated cells is actively inhibited by Notch signaling to ensure urine concentrating capability. Here we identify Hes1, a target of Notch signaling, allows for maintenance of functionally distinct epithelial cell types within the same microenvironment by regulating mechanistic target of rapamycin complex 1 (mTORC1) activity. Hes1 directly represses the expression ofinsulin receptor substrate 1(Irs1), an upstream component of mTOR pathway and suppresses mTORC1 activity in principal cells. Genetic inactivation oftuberous sclerosis complex 2(Tsc2) to increase mTORC1 activity in mature principal cells is sufficient to promote acquisition of intercalated cell properties, while inhibition of mTORC1 in adult kidney epithelia suppresses intercalated cell properties. Considering that mTORC1 integrates environmental cues, the linkage of functionally distinct epithelial cell types to mTORC1 activity levels likely allows for cell plasticity to be regulated by physiologic and metabolic signals and the ability to sense/transduce these signals.
Whole genome sequencing and comparative genomic studies ofPriestia filamentosaJURBA-X for its drought-tolerance, plant-growth promotion, and fluorescent characteristics
Authors: Murthy Sneha , Govardhana Mallu , Satyan Kumudini Belur , Sharma Gaurav
Published: April 2024

Priestia filamentosaJURBA-X is a nonmotile, endospore-forming, and Gram-positive bacterium isolated from a rhizosphere soil sample of groundnut fields in Andhra Pradesh, India, during summer. JURBA-X exhibits chains of filamentous morphology with vibrant yellow fluorescence. It shows tolerance to drought stress, phosphate solubilization, siderophore production, and antibacterial activity. 16s rRNA and single-copy orthologous DNA gyrase subunit B-based phylogenies suggested its closeness withPriestia filamentosaspp., leading to its classification asP. filamentosaJURBA-X. The whole genome was assembled into 5,113,908 bp, distributed across 55 contigs with a GC content of 36.59% and 5,352 protein-coding genes. Genome-genome distance and average nucleotide identity confirmed its designation as a novel strain withinP. filamentosa.Assignment of genes/proteins in diverse functions such as drought tolerance, plant growth promotion (PGP), lantibiotics, polyketides, vitamin synthesis, siderophores production, and phosphate solubilization highlight its potential utilization in agriculture as a PGPR and industrial production of antimicrobial agent, vitamins, and biopolymers. Our research concluded that the fluorescence exhibited by JURBA-X is potentially attributed to the production of resistomycin, which might have been horizontally transferred fromStreptomyces resistomycificusas inferred by the homology of resistomycin (rem) biosynthesis cluster genes.
Structure of thePseudomonas aeruginosaPAO1 Type IV pilus
Authors: Ochner Hannah , Böhning Jan , Wang Zhexin , Tarafder Abul K. , Caspy Ido , Bharat Tanmay A. M.
Published: April 2024

Type IV pili (T4Ps), which are abundant in many bacterial and archaeal species, have been shown to play important roles in both surface sensing and twitching motility, with implications for adhesion, biofilm formation and pathogenicity. While Type IV pilus (T4P) structures from other organisms have been previously solved, a high-resolution structure of the native, fully assembled T4P ofPseudomonas aeruginosa,one of the major human pathogens, is not available. Here, we report a 3.2 Å-resolution structure of theP. aeruginosaPAO1 T4P determined by electron cryomicroscopy (cryo-EM). PilA subunits constituting the T4P exhibit a classical pilin fold featuring an extended N-terminal α-helix linked to a C-terminal globular β-sheet-containing domain, which are packed tightly along the pilus. The N-terminal helices constitute the pilus core where they stabilise the tubular assembly via hydrophobic interactions. The α-helical core of the pilus is surrounded by the C-terminal globular domain of PilA that coats the outer surface of the pilus, mediating interactions with the surrounding environment. Comparison of theP. aeruginosaT4P with T4P structures from other organisms, both at the level of the pilin subunits and the fully assembled pili, allows us to enumerate key differences, and detect common architectural principles in this abundant class of prokaryotic filaments. This study provides a structural framework for understanding the molecular and cell biology of these important cellular appendages mediating interaction of prokaryotes to surfaces.
The chemoreceptor controlling the Wsp-like transduction pathway inHalomonas titanicaeKHS3 binds purine derivatives
Authors: Ramos Ricciuti Fernando E. , Seitz M. Karina Herrera , Gasperotti Ana F. , Boyko Alexandra , Jung Kirsten , Bellinzoni Marco , Lisa María-Natalia , Studdert Claudia A.
Published: April 2024

The chemosensory pathwayHtChe2 from the marine bacteriumHalomonas titanicaeKHS3 controls the activity of a diguanylate cyclase. Constitutive activation of the pathway results in colony morphology alterations and increased ability to form biofilm. Such characteristics resemble the behaviour of the Wsp pathway ofPseudomonas. In this work we investigate the specificity of Htc10, the only chemoreceptor coded within theHtChe2 gene cluster. Thermal shift analyses performed with the Htc10 ligand-binding domain led to the identification of purine derivatives as ligands. This ligand-binding domain was crystallized in the presence of guanine or hypoxanthine and its structure was solved by X-ray protein crystallography. The sensor domain adopts a double-cache folding, with ligands bound to the membrane-distal pocket. A high-resolution structure of the occupied guanine-binding pocket allowed the identification of the involved residues. These residues were validated by site directed mutagenesis and thermal shift or isothermal calorimetry analyses of the protein variants. The dissociation constants for guanine or hypoxanthine of the intact domain were in the low micromolar range. To our knowledge, this is the first description of binding specificity for a chemoreceptor that controls the activity of an associated diguanylate cyclase, and opens the way for dynamic studies of the signalling behaviour of this kind of sensory complex. A comparison between Htc10 and the functionally equivalent WspA receptor fromPseudomonasrevealed no significant sequence similarities. In contrast, highly conserved Htc10-like receptors were found in distant bacteria carryingHtChe2-like clusters.
Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes
Authors: Wong Siu-Shing , Monteiro Joao M. , Chang Chia-Chun , Peng Min , Mohamad Nada , Steinacker Thomas L. , Saurya Saroj , Wainman Alan , Raff Jordan W.
Published: April 2024

Mitotic centrosomes form when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, yet it can assemble and disassemble within minutes, leading to much debate about its physical nature. Here we show thatDrosophilaSpd-2 fluxes out from centrioles, recruiting Polo and Aurora A to catalyse the assembly of a solid-like Cnn-scaffold and a more liquid-like TACC-scaffold, respectively. Both scaffolds can assemble and recruit PCM proteins independently, but both are required for proper centrosome assembly, with the Cnn-scaffold providing mechanical strength, and the TACC-scaffold locally concentrating centriole and centrosome proteins. Recruiting Spd-2, but not Cnn or TACC, to the surface of synthetic beads injected into early embryos reconstitutes several aspects of mitotic centrosome assembly on the bead surface, and this depends on the ability of Spd-2 to recruit Polo and AurA. Thus, Spd-2 molecules flux out from the centriole recruiting Polo and AurA to promote the assembly of two scaffolds with distinct properties to support mitotic centrosome assembly in flies.
Modelling dynamic host-pathway interactions at the genome scale
Authors: Merzbacher Charlotte , Aodha Oisin Mac , Oyarzún Diego A.
Published: April 2024

Pathway engineering offers a promising avenue for sustainable chemical production. The design of efficient production systems requires understanding complex host-pathway interactions that shape the metabolic phenotype. While genome-scale metabolic models are widespread tools for studying static host-pathway interactions, it remains a challenge to predict dynamic effects such as metabolite accumulation or enzyme overexpression during the course of fermentation. Here, we propose a novel strategy to integrate kinetic pathway models with genome-scale metabolic models of the production host. Our method enables the simulation of the local nonlinear dynamics of pathway enzymes and metabolites, informed by the global metabolic state of the host as predicted by Flux Balance Analysis (FBA). To reduce computational costs, we make extensive use of surrogate machine learning models to replace FBA calculations, achieving simulation speed-ups of at least two orders of magnitude. Through case studies on two production pathways inEscherichia coli, we demonstrate the consistency of our simulations and the ability to predict metabolite dynamics under genetic perturbations and various carbon sources. We showcase the utility of our method for screening dynamic control circuits through large-scale parameter sampling and mixed-integer optimization. Our work links together genome-scale and kinetic models into a comprehensive framework for computational strain design.