bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractHuman 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

ABSTRACTGrain-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.ImportanceDietary 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

AbstractWe 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

AbstractOesophagectomy 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

AbstractOver 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.
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

SummaryBackgroundPacific 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.MethodsWe 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.Results61.3% 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).ConclusionsOur 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).summaryEthnicity 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

IntroductionThe 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.MethodsWe 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.ResultsThe 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.DiscussionThe 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

AbstractProviding 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

AbstractThe 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

AbstractPriestia 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

AbstractType 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

AbstractThe 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.