bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare workers’ compliance with COVID-19 preventive and control measures at De Martino Hospital, Mogadishu, Somalia
Authors: Janay Abdullahi Ibrahim , Kilic Bulent , Unal Belgin
Published: March 2024

Background and objectives

Healthcare workers are a high-risk group for COVID-19 and protecting them is crucial for healthcare delivery. Limited studies have explored compliance with infection prevention and control (IPC) practices among Somali healthcare workers. This study aimed to determine compliance with IPC practices among healthcare workers in De Martino Public Hospital, Somalia.

Materials and methods

A cross-sectional study was conducted at De Martino Public Hospital, Mogadishu, Somalia from August to October 2022, with the participation of 204 healthcare workers (response rate = %97). Compliance was assessed using responses to 25 questions on a five-point Likert-type scale, and the median score of 20 was used to dichotomize compliance scores. A chi-square test and logistic regression analysis were performed to check the associations between healthcare workers’ sociodemographic information, related factors to IPC, work conditions and practices on COVID-19, and IPC compliance during healthcare interventions using SPSS 23 version.

Results

In total, 58.3% of the participants had good compliance with IPC. There were significant associations between IPC compliance and the type of healthcare worker (doctors and doctor assistants: 72.3%, nurses and paramedical staff: 67.3%, non-clinical staff: 5.7%, p<0.01). After adjusting for potential confounding factors, compared to non-clinical staff, doctors and doctor assistants (OR: 12.11, 95% CI: 2.23-65.84) nurses and paramedical staff (OR: 21.38, 95% CI: 4.23 - 108.01) had higher compliance with infection prevention and control measures. There were no significant associations between compliance and gender, marital status, vaccination status, or smoking (p>0.05 for all).

Conclusions

Inadequate compliance with COVID-19 IPC measures was observed among hospital workers. Prioritizing awareness campaigns and behavior change interventions, especially among non-clinical staff, is crucial for effective COVID-19 infection prevention and control within the hospital.
Cost-effectiveness of end-game strategies against sleeping sickness across the Democratic Republic of Congo
Authors: Antillon Marina , Huang Ching-I , Sutherland Samuel A. , Crump Ronald E. , Brown Paul E. , Bessell Paul R. , Crowley Emily H. , Snĳders Rian , Hope Andrew , Tirados Iñaki , Dunkley Sophie , Verlé Paul , Lebuki Junior , Shampa Chansy , Miaka Erick Mwamba , Tediosi Fabrizio , Rock Kat S.
Published: March 2024

Gambiensehuman African trypanosomiasis (gHAT) is marked for elimination of transmission (EoT) by 2030. We examined the cost-effectiveness (CE) of EoT in the Democratic Republic of Congo, which has the highest global gHAT burden. In 165 health zones (HZs), we modelled the transmission dynamics, health outcomes, and economic costs of six strategies during 2024–40, including the cessation of activities after case reporting reduces to zero. Uncertainty in CE was assessed within the net monetary framework, which presents the optimal strategies at a range of willingness-to-pay (WTP) values, denominated in costs per disability-adjusted life-year averted. We assessed the optimal strategy for CE and EoT in each health zone separately, but we present results by health zone as well as aggregated by coordination and for the whole country. Status quo strategies, CE strategies (WTP=$500), and strategies with a high probability of EoT by 2030 are predicted to yield EoT by 2030 in 117 HZs, 130 HZs, and 138 HZs respectively, at a cost by 2040 of $171M (95% PI:$89.5M— 283M), $177M (95% PI: $97.9M—289M), $216M (95% PI: $119M–355M). A more lenient timeline of EoT by 2040 could lead to EoT in 153 HZs at a cost of $199M (95% PI: $109M–$327M), leaving 12 HZs shy of the goal. Costs would have to be front-loaded; in 2024, status quo strategies would cost $16.1M (95% PI: $8.44M—23.8M), minimum costs strategies would cost $17.0M (95% PI: $9.31M-–24.9M), and elimination strategies would cost $25.6M (95% PI: $15.8M—36.6M). Investing in EoT by 2030 is predicted to reduce 74% of gHAT deaths from 10,601 (95% PI: 1063—36,124) with status quo strategies to 2654 (95% PI: 301—9454).
Cardiac Ultrasonic Tissue Characterization in Myocardial Infarction Based on Deep Transfer Learning and Radiomics Features
Authors: Jamthikar Ankush D. , Hathaway Quincy A , Maganti Kameswari , Hamirani Yasmin , Bokhari Sabahat , Yanamala Naveena , Sengupta Partho P.
Published: March 2024

Objective

Acute myocardial infarction (MI) alters cardiomyocyte geometry and architecture, leading to changes in the acoustic properties of the myocardium. This study examines ultrasomics — a novel cardiac ultrasound-based radiomics technique to extract high-throughput pixel-level information from images—for identifying infarcted myocardium.

Methodology

A retrospective multicenter cohort of 380 participants was split into two groups: a model development cohort (n=296; 101 MI cases, 195 controls) and an external validation cohort (n=84; 40 MI cases, 44 controls). Handcrafted and transfer learning-derived deep ultrasomics features were extracted from 2-chamber and 4-chamber echocardiographic views and ML models were built to detect patients with MI and infarcted myocardium within individual views. Myocardial infarct localization via texture features was determined using Shapley additive explanations. All the ML models were trained using 10-fold cross-validation and assessed on an external test dataset, using the area under the curve (AUC).

Results

The ML model, leveraging segment-level handcrafted ultrasomics features identified MI with AUCs of 0.93 (95% CI: 0.97-0.97) and 0.83 (95% CI: 0.74-0.89) at the patient-level and view-level, respectively. A model combining handcrafted and deep ultrasomics provided incremental information over deep ultrasomics alone (AUC: 0.79, 95% CI: 0.71-0.85 vs. 0.75, 95% CI: 0.66-0.82). Using a view-level ultrasomic model we identified texture features that effectively discriminated between infarcted and non-infarcted segments (p<0.001) and facilitated parametric visualization of infarcted myocardium.

Conclusion

This pilot study highlights the potential of cardiac ultrasomics in distinguishing healthy and infarcted myocardium and opens new opportunities for advancing myocardial tissue characterization using echocardiography.
Top-funded digital health companies offering lifestyle interventions for dementia prevention: Company overview and evidence analysis
Authors: Vinay Rasita , Probst Jonas , Huynh Panitda , Schlögl Mathias , Kowatsch Tobias , Nißen Marcia
Published: March 2024

Background and objective

Dementia prevention has been recognized as a top priority by public health authorities due to the lack of disease modifying treatments. In this regard, digital dementia-preventive lifestyle services (DDLS) emerge as potentially pivotal services, aiming to address modifiable risk factors on a large scale. This study aims to identify the top-funded companies offering DDLS globally and evaluate their clinical evidence to gain insights into the current state of the global service landscape.

Methods

A systematic screening of two financial databases (Pitchbook and Crunchbase) was conducted. Corresponding published clinical evidence was collected through a systematic literature review and analyzed regarding study purpose, results, quality of results, and level of clinical evidence.

Findings

The ten top-funded companies offering DDLS received a total funding of EUR 128.52 million, of which three companies collected more than 75%. Clinical evidence was limited due to only nine eligible publications, small clinical subject groups, the absence of longitudinal study designs, and no direct evidence of dementia prevention.

Conclusion

The study highlights the need for a more rigorous evaluation of DDLS effectiveness in today’s market. It serves as a starting point for further research in digital dementia prevention.
Pharmaceutical Repurposing Strategies for Metabolic Disorders: Insights from Mendelian Randomization Studies
Authors: Zhang Shixuan , Hu Xiaoxi , Hou Dandan , Sun Xiaoru , Sun Dayan
Published: March 2024

Metabolic disorders (MDs) are a group of medical conditions that impact the metabolism. These complex processes may have common characteristics among various diseases, thereby suggesting the potential of drug repurposing. Employing Mendelian Randomization (MR), we constructed a causal network between 2,478 targetable drug-gene expressions (eQTLs) and 30 broadly reported metabolic disorders. Our study identified 499 drug target genes significantly associated with 27 metabolic disorders (|MR coefficient| > 0.2). Pathway enrichment analysis of drug target genes indicates that regulation of response stimulus may serve as a common pathway across 14 diseases. Based on 53 commonly used clinical drugs for 18 diseases, we elucidated novel therapeutic mechanisms of some drugs, such as the potential of Valproic Acid to treat Schizophrenia by affecting key genes in Alcoholism,SLC29A1, andHDAC4. Furthermore, we identified potential for drug repurposing in four diseases, with Manic Episode and Type 1 Diabetes sharing four novel drugs: Cannabidiol, Doxorubicin, Genistein, and Propylthiouracil. Additionally, we predicted 189 potential therapeutic drugs affecting the causal genes of diseases. Overall, we established a causal network between metabolic disorders and drug target genes, explored possible pathways for drug action on disease treatment, and proposed drug repurposing strategies for four diseases.

Highlights

To the best of our understanding, the manuscript we have submitted delineates the inaugural drug-gene causal network tailored for Metabolic Disorders (MDs), covering an array of 30 diseases.

This investigation unveils potential novel drug mechanisms aimed at treating MDs, marking a pioneering exploration in this domain.

We introduce strategies for the repurposing of drugs targeting four specific MDs, suggesting innovative approaches to treatment.

The findings are presented through an easily navigable web interface, enabling thorough examination by users (https://quantlifebits.shinyapps.io/mrmetabopharm/).
Exploring Motor Imagery as a Therapeutic Intervention for Parkinson’s Disease Patients: A Scoping Review
Authors: Michel Maxime , Terragno Elena , Bereau Matthieu , Magnin Eloi , Gueugneau Nicolas , Soares Antonio Vinicius , Sagawa Yoshimasa
Published: March 2024

Background

Motor Imagery (MI) has emerged as a promising therapeutic approach in the rehabilitation of individuals with Parkinson’s Disease (PD). MI entails mentally rehearsing motor actions without physically executing them. This cognitive process has garnered attention due to its potential benefits in aiding motor function recovery in PD patients. Its role in complementing traditional treatment approaches is likely to reverberate throughout clinical practice. This study strives to provide a comprehensive examination several MI protocols designed for individuals with PD. The focus was to underscore the outcomes observed across motor symptoms, balance, gait, and quality of life.

Methods

A literature search was carried out in the following databases: Medline, Embase, Cochrane, and PEDro, from the first publication to February 2024. Study with at least one keyword in relation to PD and MI in the title were included.

Results

Of the 262 studies 53 were included. Twelve RCTs with a mean PEDro score of 6.6/10 and 41 descriptive and non-RCT studies. Among the RCTs, there were almost exclusively MI on balance, gait, and lower limbs exercise. They found an 85.2% improvement for the experimental group on the TUG with a cognitive task (p<0.02), 5.8% on the TUG (p<0.05), a 5.1% improvement in walking speed (p<0.05), other variables did not show significant improvement. For the descriptive and non-RCTs studies, there were various tasks and outcomes for the lower and upper limbs. It was shown that there was no difference in execution time in MI between patients with PD and HS, while in ME patients with PD were slower. For the upper limb, several tasks were proposed, such as thumb opposition, joystick movements and writing tasks with variable results. RCTs were more focused on balance, lower limb and walking, there was no specific outcome for the upper limb and speech. The heterogeneity of the tasks and outcomes across all included studies is also a limitation.

Conclusion

To summarize, the current research on walking disorders in PD shows promise, but further investigations are crucial, particularly with an emphasis on upper limb function and speech. A need exists for studies with larger sample sizes, utilizing precise methodologies, and specifically targeting these areas to enhance our comprehension of the potential advantages of MI in the context of comprehensive PD rehabilitation.
Pre-exposure prophylaxis (PrEP) knowledge, use, and discontinuation among Lake Victoria fisherfolk in Uganda: a cross-sectional population-based study
Authors: Ntabadde Kauthrah , Kagaayi Joseph , Ssempijja Victor , Feng Xinyi , Kairania Robert , Lubwama Joseph , Ssekubugu Robert , Yeh Ping Teresa , Ssekasanvu Joseph , Tobian Aaron A R , Kennedy Caitlin E. , Mills Lisa A. , Alamo Stella , Kreniske Philip , Santelli John , Nelson Lisa J. , Reynolds Steven J. , Chang Larry William , Nakigozi Gertrude , Grabowski M. Kate
Published: March 2024

Background

There are limited population-level data on the pre-exposure prophylaxis (PrEP) care continuum in eastern Africa. Here, we assessed the PrEP care continuum following PrEP rollout in a Ugandan community with ∼40% HIV seroprevalence.

Methods

We used cross-sectional population-based data collected between September 3 and December 19, 2018 from a Lake Victoria fishing community in southern Uganda to measure levels of self-reported PrEP knowledge, ever use, and discontinuation following 2017 PrEP rollout via a U.S. President’s Emergency Plan for AIDS Relief (PEPFAR)-supported phased implementation program. Our analysis included HIV-seronegative persons reporting having ever received an HIV test result. We examined associations between demographic, behavioral, and health utilization factors with each outcome using age-adjusted modified Poisson regression.

Results

There were 1,401 HIV-seronegative participants, of whom 1,363 (97.3%) reported ever receiving an HIV test result. Median age was 29 years (IQR: 23-36), and 42.3% (n=577) were women. Most (85.5%; n=1,166) participants reported PrEP knowledge, but few (14.5%; n=197) reported ever using PrEP. Among 375 (47.7%) men and 169 (29.3%) women PrEP-eligible at time of survey, 18.9% (n=71) and 27.8% (n=47) reported ever using PrEP, respectively. Over half (52.3%, n=103) of those who had ever used PrEP, self-reported current use.

Conclusion

In this Lake Victoria fishing community, there were low levels of PrEP use despite high levels of PrEP awareness and eligibility, particularly among men. Efforts that enhance awareness of HIV risk and increase PrEP accessibility may help increase PrEP use among HIV-seronegative persons in African settings with high HIV burden.
Characterizing the genetic architecture of drug response using gene-context interaction methods
Authors: Sadowski Michal , Thompson Mike , Mefford Joel , Haldar Tanushree , Oni-Orisan Akinyemi , Border Richard , Pazokitoroudi Ali , Ayroles Julien F. , Sankararaman Sriram , Dahl Andy , Zaitlen Noah
Published: March 2024

Identifying the factors responsible for variability of treatment response is a central objective of clinical research. Specially designed pharmacogenomic studies have identified a handful of individual mutations modulating the effect of specific drugs. However, the extent to which drug response variability is driven by genetics is largely unknown, partly due to the small sample sizes of prospective pharmacogenomic trials. In this work, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks coupled with electronic health records. Our framework leverages concepts from gene-environment interaction testing, including novel interaction models at the level of genes, polygenic scores (PGS), and genome-wide heritability. We quantified the heritability of response to statins, metformin, warfarin, and methotrexate in 342,257 UK Biobank participants. Our results show that genetic variation modifies the primary effect of statins on LDL cholesterol (9% heritable) as well as its side effects on hemoglobin A1c and blood glucose (10% and 11% heritable, respectively). Next, we identified dozens of specific genes that modify drug response, which we then replicated in a retrospective pharmacogenomic study. Finally, we found that PGS accuracy varies up to 2-fold depending on treatment status, showing that the current approach of building PGS using mostly healthy individuals is likely to underperform in clinical contexts. Together, our results provide a framework for characterizing the genetic architecture of drug response using cross-sectional data.
Patients with COVID-19 Infection and Stroke have Higher than Expected Mortality, Regardless of the Primary Presentation
Authors: Liu Jintong , Fu Eric , Gillette Riley , Wohlauer Max
Published: March 2024

Background

COVID-19 infection is associated with thrombotic events; however, this phenomenon is poorly understood. Few studies have reported the association between COVID-19 and stroke in the hospital setting.

Methods

We retrospectively reviewed and characterized all patients who presented to a single, quaternary medical center between March and December 2020 (N=603). COVID-19 positive patients who developed ischemic or hemorrhagic stroke were included in the analysis (N=66). This cohort was compared with patients who were COVID-19 negative at the time of stroke presentation in the same period (N=537). Statistical significance was evaluated using Pearson’s Chi squared test with Yates’ continuity correction and linear model ANOVA.

Results

Sixty-six patients had COVID-19 and Stroke. Of these patients, 22 (33.4%) patients initially presented with stroke and 44 (66.7%) initially presented with COVID-19. Patients who presented with COVID-19 and had a stroke during their hospitalization (COVID-first) had worse outcomes than patients presenting to the hospital with stroke whose COVID test became positive later in the hospitalization (stroke-first). Patients who presented with COVID-19 and had a stroke during their hospitalization had an increased rate of acute renal failure (48.9% vs 19.0%, p=0.021) and need for ventilation (60.0% vs 28.6%, p=0.017). Further, in the COVID-first cohort, the use of heparin prior to the stroke event was not associated with mortality or type of stroke (ischemic or hemorrhagic).

Conclusion

In the early pandemic, patients with COVID-19 infection and stroke had a higher mortality rate compared to COVID-19 negative patients with stroke. Among patients with both COVID-19 and stroke, patients presenting with COVID-19 first had worse outcomes than patients presenting with stroke first. The use of heparin prior to the stroke event was not associated with mortality or type of stroke.
Shape dynamics and migration of branched cells on complex networks
Authors: Liu Jiayi , Boix-Campos Javier , Ron Jonathan E. , Kux Johan M. , Oremek Magdalena E.M. , Rossi Adriano G. , Gov Nir S. , Sáez Pablo J.
Published: March 2024

Migrating cells often face microenvironmental constraints that force them to extend multiple, often highly dynamic, protrusions, that compete to choose the new direction. However, the analy-sis of how cells coordinate shape dynamics during this directional decision-making process has been restricted to single junctions. Here, we present a theoretical model and the corresponding experimen-tal proof of concept usingin vivoandin vitrolive-cell microscopy and a neuronal network-based image analysis pipeline, to explore the shape and migration dynamics of highly bifurcated cells during spontaneous random migration. We found that macrophages and endothelial cells display different migration regimes in a hexagonal adhesive network, despite sharing a mesenchymal migra-tory strategy. Macrophages moved faster and presented larger changes in cell length in comparison to endothelial cells. The theoretical model describes the behavior of both cells during directional decision-making, and it reveals a trade-off between exploration for directional cues and long-range migration efficiency, showing the fine tune regulation of shape dynamics in complex geometries.

Teaser

Highly branched cells require precise control of their shape dynamics to ensure microenvironment exploration while keeping their motility.
IL-8 Instructs Macrophage Identity in Lateral Ventricle Contacting Glioblastoma
Authors: Medina Stephanie , Brockman Asa A. , Cross Claire E. , Hayes Madeline J. , Mobley Bret C. , Mistry Akshitkumar M. , Chotai Silky , Weaver Kyle D. , Thompson Reid , Chambless Lola B. , Ihrie Rebecca A , Irish Jonathan Michael
Published: March 2024

Adult IDH-wildtype glioblastoma (GBM) is a highly aggressive brain tumor with no established immunotherapy or targeted therapy. Recently, CD32+HLA-DRhimacrophages were discovered to have displaced resident microglia in GBM tumors that contact the lateral ventricle stem cell niche. Since these lateral ventricle contacting GBM tumors have especially poor outcomes, identifying the origin and role of these CD32+macrophages is likely critical to developing successful GBM immunotherapies. Here, we identify these CD32+cells as M_IL-8 macrophages and establish that IL-8 is sufficient and necessary for tumor cells to instruct healthy macrophages into CD32+M_IL-8 M2 macrophages. Using a set of 73 GBM tumors, IL-8 protein is shown to be present in GBM tumor cellsin vivoand especially common in tumors contacting the lateral ventricle. Finally, inex vivoexperiments with conditioned medium from primary human tumor cells, inhibitory antibodies to IL-8 blocked the generation of CD32+M_IL-8 cells. These results provide a mechanistic origin for CD32+macrophages that predominate in the microenvironment of the most aggressive GBM tumors. IL-8 and CD32+macrophages should now be explored as targets in combination with GBM immunotherapies, especially for patients whose tumors present with radiographic contact with the ventricular subventricular zone stem cell niche.
Tumor Stroma Content Regulates Penetration and Efficacy of Tumor-targeting Bacteria
Authors: Zhan Y. , Burkel B. , Leaman E. J. , Ponik S. M. , Behkam B.
Published: March 2024

Bacteria-based cancer therapy (BBCT) strains grow selectively in primary tumors and metastases, colonize solid tumors independent of genetics, and kill cells resistant to standard molecular therapy. Clinical trials of BBCT in solid tumors have not reported any survival advantage yet, partly due to the limited bacterial colonization. Collagen, abundant in primary and metastatic solid tumors, has a well-known role in hindering intratumoral penetration of therapeutics. Nevertheless, the effect of collagen content on the intratumoral penetration and antitumor efficacy of BBCT is rarely unexplored. We hypothesized that the presence of collagen limits the penetration and, thereby, the antitumor effects of tumor-selectiveSalmonella. Typhimurium VNP20009 cheY+. We tested our hypothesis in low and high collagen content tumor spheroid models of triple-negative murine breast cancer. We found that high collagen content significantly hinders bacteria transport in tumors, reducing bacteria penetration and distribution by ∼7-fold. The higher penetration of bacteria in low collagen-content tumors led to an overwhelming antitumor effect (∼73% increase in cell death), whereas only a 28% increase in cell death was seen in the high collagen-content tumors. Our mathematical modeling of intratumoral bacterial colonization delineates the role of growth and diffusivity, suggesting an order of magnitude lower diffusivity in the high collagen-content tumors dominates the observed outcomes. Finally, our single-cell resolution analysis reveals a strong spatial correlation between bacterial spatial localization and collagen content, further corroborating that collagen acts as a barrier to bacterial penetration despiteS. Typhimurium VNP20009 cheY+motility. Understanding the effect of collagen on BBCT performance could lead to engineering more efficacious BBCT strains capable of overcoming this barrier to colonization of primary tumors and metastases.
Long-term co-circulation of multiple arboviruses in southeast Australia revealed by xeno-monitoring and metatranscriptomics
Authors: Julia S. P. Vieira Carla , Onn Michael B. , Shivas Martin A. , Shearman Damien , Darbro Jonathan M. , Graham Melissa , Freitas Lucas , van den Hurk Andrew F. , Frentiu Francesca D. , Wallau Gabriel L. , Devine Gregor J.
Published: March 2024

Arbovirus surveillance of wild-caught mosquitoes is an affordable and sensitive means of monitoring virus transmission dynamics at various spatial-temporal scales, and emergence and re-emergence during epidemic and interepidemic periods. A variety of molecular diagnostics for arbovirus screening of mosquitoes (known as xeno-monitoring) are available, but most provide limited information about virus diversity. PCR-based screening coupled with metatranscriptomics is an increasingly affordable and sensitive pipeline for integrating complete viral genome sequencing into surveillance programs. This enables large-scale, high-throughput arbovirus screening from diverse samples. We collected mosquitoes in CO2-baited light traps from five urban parks in Brisbane from March 2021 to May 2022. Mosquito pools of ≤200 specimens were screened for alphaviruses and flaviviruses using virus genus-specific primers and reverse transcription quantitative PCR (qRT-PCR). A subset of virus-positive samples was then processed using a mosquito-specific ribosomal RNA depletion method and then sequenced on the Illumina NextSeq. Overall, 54,670 mosquitoes, representing 26 species were screened in 382 pools. Thirty detections of arboviruses were made in 28 pools. Twenty of these positive pools were further characterised using meta-transcriptomics generating 18 full-length genomes. These full-length sequences belonged to four medically relevant arboviruses: Barmah Forest, Ross River, Sindbis-like and Stratford viruses. Phylogenetic and evolutionary analyses revealed the evolutionary progression of arbovirus lineages over the last 100 years, highlighting long-distance dispersal across the Australian continent and continuous circulation characterised by constant turnover of virus lineages.
Identification of a proteolysis regulator for an essential enzyme inMycobacterium tuberculosis
Authors: Kahne Shoshanna C. , Yoo Jin Hee , Chen James , Nakedi Kehilwe , Iyer Lakshminarayan M. , Putzel Gregory , Samhadaneh Nora M. , Pironti Alejandro , Aravind L. , Ekiert Damian C. , Bhabha Gira , Rhee Kyu Y. , Darwin K. Heran
Published: March 2024

InMycobacterium tuberculosisproteins that are post-translationally modified with Pup, a prokaryotic ubiquitin-like protein, can be degraded by proteasomes. While pupylation is reversible, mechanisms regulating substrate specificity have not been identified. Here, we identify the first depupylation regulators: CoaX, a pseudokinase, and pantothenate, an essential, central metabolite. In a ΔcoaXmutant, pantothenate synthesis enzymes were more abundant, including PanB, a substrate of the Pup-proteasome system. Media supplementation with pantothenate decreased PanB levels in acoaXand Pup-proteasome-dependent manner.In vitro, CoaX accelerated depupylation of Pup∼PanB, while addition of pantothenate inhibited this reaction. Collectively, we propose CoaX contributes to proteasomal degradation of PanB by modulating depupylation of Pup∼PanB in response to pantothenate levels.

One Sentence Summary

A pseudo-pantothenate kinase regulates proteasomal degradation of a pantothenate synthesis enzyme inM. tuberculosis.
A comprehensive two-hybrid analysis to explore theL. pneumophilaeffector-effector interactome
Authors: O’Connor Mount Harley , Urbanus Malene L. , Sheykhkarimli Dayag , Coté Atina G. , Laval Florent , Coppin Georges , Kishore Nishka , Li Roujia , Spirohn-Fitzgerald Kerstin , Petersen Morgan O. , Knapp Jennifer J. , Kim Dae-Kyum , Twizere Jean-Claude , Calderwood Michael A. , Vidal Marc , Roth Frederick P. , Ensminger Alexander W.
Published: March 2024

Legionella pneumophilauses over 300 translocated effector proteins to rewire host cells during infection and create a replicative niche for intracellular growth. To date, several studies have identifiedL. pneumophilaeffectors that indirectly and directly regulate the activity of other effectors, providing an additional layer of regulatory complexity. Amongst these are “metaeffectors” – a special class of effectors that regulate the activity of other effectors once inside the host. A defining feature of metaeffectors is direct, physical interaction with a target effector. Metaeffector identification to date has depended on phenotypes in heterologous systems and experimental serendipity. Using a multiplexed, recombinant-barcode-based yeast two-hybrid technology we screened for protein-protein interactions amongst allL. pneumophilaeffectors and several components of the Dot/Icm type IV secretion system (>167,000 protein combinations). Of the 52 protein interactions identified by this approach, 44 are novel protein interactions, including ten novel effector-effector interactions (doubling the number of known effector-effector interactions).
Sex-Specific Cardiovascular Adaptations to Simulated Microgravity in Sprague-Dawley Rats
Authors: Elsangeedy Ebrahim , Yamaleyeva Dina N. , Edenhoffer Nicholas P. , Deak Allyson , Soloshenko Anna , Ray Jonathan , Sun Xuming , Shaltout Omar H. , Diaz Nildris Cruz , Westwood Brian , Kim-Shapiro Daniel , Diz Debra I. , Soker Shay , Pulgar Victor M. , Ronca April , Willey Jeffrey S. , Yamaleyeva Liliya M.
Published: April 2024

Men and women have different cardiovascular responses to spaceflight; however few studies have focused on direct comparisons between sexes. Therefore, we investigated cardiovascular system differences, including arterial stiffness between socially and sexually mature 20-week-old male and female Sprague Dawley (SD) rats exposed to hindlimb unloading (HLU) - an analogue for spaceflight-induced microgravity. Two weeks of HLU had no effect on body weight in either male or female rats. The index of arterial stiffness determined by ultrasound, pulse wave velocity (PWV), was greater in the aortic arch and carotid artery of females after HLU versus control females. HLU had no effect on arterial PWV in males. α smooth muscle actin, myosin, collagen, elastin, and collagen-to-elastin ratio were not different in rats of either sex in response to HLU. HLU exposure did not alter individual collagen fiber characteristics in studied groups. The levels of G protein-coupled estrogen receptor (GPER) were lower in the aorta of SD females exposed to HLU compared with female controls but not in males. These changes were associated with lower PPAR γ and increased oxidative stress markers (8-hydroxy-2’-deoxyguanosine and p47phox) in the females. Diastolic cardiac function was altered in females after HLU versus control females. GPER agonist, G1 prevented the increase in pulse wave velocity and 8-hydroxy-2’-deoxyguanosine, without altering PPAR γ or p47phox. Our data revealed that lower GPER in the HLU females contributes to the development of arterial stiffness, and that the SD rat is a suitable model to study the cardiovascular response of females to HLU.
Prophages express a type IV pilus component to provide anti-phage defence
Authors: Sztanko Kristina M. , Javorčík P. Nathael , Fitzpatrick Alexa D. , Lenskaia Tatiana , Maxwell Karen L. , Davidson Alan R.
Published: March 2024

Phage genomes integrated within bacterial genomes, known as prophages, frequently encode proteins that provide defence against further phage infection. These proteins often function at the cell surface and prevent phages from attaching to their host receptor. Here, we describe the discovery of prophage-encoded proteins that resemble FimU, a component of thePseudomonas aeruginosatype IV pilus. These phage FimU proteins are incorporated into the pilus without altering its function, yet they mediate robust protection against infection by phages that bind to the tip of the pilus, where FimU is likely located. The phage FimU proteins and the phage tail proteins that interact with FimU are highly diverse, suggesting that evolution in this system is driven by phage versus phage competition. To our knowledge, this is the first example of anti-phage defence mediated by replacement of a bacterial cell surface component with a phage-encoded protein.
p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer
Authors: Luo Jie , Chen Zhixiang , Qiao Yuanyuan , Tien Jean Ching-Yi , Young Eleanor , Mannan Rahul , Mahapatra Somnath , He Tongchen , Eyunni Sanjana , Zhang Yuping , Zheng Yang , Su Fengyun , Cao Xuhong , Wang Rui , Cheng Yunhui , Seri Rithvik , George James , Shahine Miriam , Miner Stephanie J. , Vaishampayan Ulka , Wang Mi , Wang Shaomeng , Parolia Abhijit , Chinnaiyan Arul M.
Published: March 2024

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which is exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition or the inhibition of its catalytic domain.In vivoexperiments using an orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.
An old inversion polymorphism involving giant mobile elements in an invasive fungal pathogen
Authors: Hartmann Fanny E. , Rodriguez de la Vega Ricardo C. , Demené Arthur , Badet Thomas , Vernadet Jean-Philippe , Rougemont Quentin , Labat Amandine , Snirc Alodie , Stauber Lea , Croll Daniel , Prospero Simone , Dutech Cyril , Giraud Tatiana
Published: March 2024

Recombination suppression can evolve in sex or mating-type chromosomes, or in autosomal supergenes, with different haplotypes being maintained by balancing selection. In the invasive chestnut blight fungusCryphonectria parasitica, a genomic region was suggested to lack recombination and to be partially linked to the mating-type (MAT) locus based on segregation analyses. Using hundreds of availableC. parasiticagenomes and generating new high-quality genome assemblies, we show that a ca. 1.2 Mb genomic region proximal to the mating-type locus lacks recombination, with the segregation of two highly differentiated haplotypes in balanced proportions in invasive populations. High-quality genome assemblies further revealed an inversion in one of the haplotypes in the invaded range. The two haplotypes were estimated to have diverged 1.5 million years ago, and each harboured specific genes, some of which likely belonging toStarshipelements, that are large mobile elements, mobilized by tyrosine recombinases, able to move accessory genes, and involved in adaptation in multiple fungi. The MAT-proximal region carried genes upregulated under virus infection or vegetative incompatibility reaction. In the native range, the MAT-proximal region also appeared to have a different evolutionary history than the rest of the genome. In all continents, the MAT-Proximal region was enriched in non-synonymous substitutions, in gene presence/absence polymorphism, in tyrosine recombinases and in transposable elements. This study thus sheds light on a case of a large non-recombining region partially linked to a mating compatibility locus, with likely balancing selection maintaining differentiated haplotypes, possibly involved in adaptation in a devastating tree pathogen.
Loss of Paneth cells dysregulates gut ILC subsets and enhances weight gain response to high fat diet in a mouse model
Authors: Joldrichsen Marisa R. , Kim Eunsoo , Steiner Haley E. , Jeong Yea Ji , Premanandan Christopher , Hsueh Willa , Ziouzenkova Ouliana , Cormet-Boyaka Estelle , Boyaka Prosper N.
Published: April 2024

Obesity has been associated with dysbiosis, but innate mechanisms linking intestinal epithelial cell subsets and obesity remain poorly understood. Using mice lacking Paneth cells (Sox9ΔIECmice), small intestinal epithelial cells specialized in the production of antimicrobial products and cytokines, we show that dysbiosis alone does not induce obesity or metabolic disorders. Loss of Paneth cells reduced ILC3 and increased ILC2 numbers in the intestinal lamina propria. High-fat diet (HFD) induced higher weight gain and more severe metabolic disorders in Sox9ΔIECmice. Further, HFD enhances the number of ILC1 in the intestinal lamina propria of Sox9ΔIECmice and increases intestinal permeability and the accumulation of immune cells (inflammatory macrophages and T cells, and B cells) in abdominal fat tissues of obese Sox9ΔIEC. Transplantation of fecal materials from Sox9ΔIECmice in germ-free mice before HFD further confirmed the regulatory role of Paneth cells for gut ILC subsets and the development of obesity.
The Evolution of Microbiome-Mediated Traits
Authors: Week Bob , Morris Andrew H. , Bohannan Brendan J. M.
Published: March 2024

The role of host-associated microbiomes in shaping host fitness is becoming increasingly recognized, and may have important evolutionary consequences. The degree to which microbiomes contribute to host evolution depends on how they are inherited. To understand the conditions under which host evolution is mediated by microbiome inheritance, we introduce a simple mathematical model. Our model tracks the evolution of a quantitative host trait that is mediated by host genotype and host microbiome. Unlike host genotype, the host microbiome may have several routes of transmission, including social contact and environmental acquisition. Our model takes a breeding-value approach to formally generalize classical quantitative genetic theory to account for these various modes of microbiome inheritance. A key prediction of our model is that, as long as microbiomes are transmitted between host generations, their mode of transmission has no effect on host trait dynamics. To understand the conditions required for this result, we analyze microbiome-explicit simulations that break important model assumptions. We then discuss avenues to generalize our model and connections with related concepts. Taken together, this work provides novel insights into the dynamics of non-Mendelian populations, and makes first steps towards establishing a theory of microbiome-mediated trait evolution.
Detection of known and novel virus sequences in the black solider fly and expression of host antiviral pathways
Authors: Walt Hunter K. , Jordan Heather R. , Meyer Florencia , Hoffmann Federico G.
Published: March 2024

Mass rearing of animals in close quarters can be highly conducive to microbe transmission, including pathogens. This has been shown multiple times in the case of important industrial insects such as crickets, silkworms, and honeybees. One industrial insect of increasing importance is the black soldier fly (Diptera:Hermetia illucens), as it can convert organic waste into high quality protein and fatty acids. Along with this, they take up far less space than traditional protein sources, as millions of black soldier flies can be reared in a relatively small facility. Because of this, there is a growing interest in the pathogens that could impact black soldier fly rearing efforts. So far, only three black soldier fly-associated viruses have been identified. We used metatranscriptomic sequencing to survey black soldier fly guts, frass, and diet for viruses. We detected sequences from two novel viruses. One, which we nameHermetia illucenssigma-like virus 1, is phylogenetically related to viruses of the genus Sigmavirus, which have been highly studied inDrosophila. The other novel virus, which we nameHermetia illucenstoti-like virus 2, is the second toti-like virus to be described in the black soldier fly. We also detected two black soldier fly-associated viruses previously identified by our group: BSF nairo-like virus, and BSF uncharacterized bunya-like virus. Consistent with our previous study, these two viruses are found primarily in frass samples and occur together more often than expected at random. When analyzing host transcription, we found significant differences in gene expression for eight candidate antiviral genes in black soldier fly when comparing samples with and without viral sequences. Our results suggest that black soldier fly-virus interactions are ongoing, and they could be of interest to black soldier fly producers.
Co-Essentiality Analysis Identifies PRR12 as a Regulator of Cohesin and Genome Integrity
Authors: Nguyen Alexandra L. , Smith Eric , Cheeseman Iain M.
Published: March 2024

The cohesin complex is critical for genome regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a regulator of cohesin and genome integrity. We show that PRR12 interacts with cohesin and PRR12 loss results in a reduction of nuclear-localized cohesin and an accumulation of DNA lesions. We find that different cell lines across human and mouse exhibit significant variation in their sensitivity to PRR12 loss. Unlike the modest phenotypes observed in human cell lines, PRR12 depletion in mouse cells results in substantial genome instability. Despite a modest requirement in human cell lines, mutations in PRR12 lead to severe developmental defects in human patients, suggesting context-specific roles in cohesin regulation. By harnessing comparative studies across species and cell lines, our work reveals critical insights into how cohesin is regulated across diverse cellular contexts.
A next generation of hierarchical Bayesian analyses of hybrid zones enables direct quantification of variation in introgression in R
Authors: Gompert Zachariah , DeRaad Devon A. , Alex Buerkle C.
Published: March 2024

Hybrid zones, where genetically distinct groups of organisms meet and interbreed, offer valuable insights into the nature of species and speciation. Here, we present a new R package bgchm, for population genomic analyses of hybrid zones. This R package extends and updates the existing bgc software and combines Bayesian analyses of hierarchical genomic clines with Bayesian methods for estimating hybrid indexes, interpopulation ancestry proportions, and geographic clines. Compared to existing software, bgchm offers enhanced efficiency through Hamiltonian Monte Carlo sampling and the ability to work with genotype likelihoods combined with a hierarchical Bayesian approach, enabling accurate inference for diverse types of genetic datasets. The package also facilitates the quantification of introgression patterns across genomes, which is crucial for understanding reproductive isolation and speciation genetics. We first describe the models underlying bgchm and then provide an overview of the R package and illustrate its use through the analysis of simulated and empirical data sets. We show that bgchm generates accurate estimates of model parameters under a variety of conditions, especially when the genetic loci analyzed are highly ancestry informative. This includes relatively robust estimates of genome-wide variability in clines, which has not been the focus of previous models and methods. We also illustrate how both selection and genetic drift contribute to variability in introgression among loci and how additional information can be used to help distinguish these contributions. We conclude by describing the promises and limitations of bgchm, comparing bgchm to other software for genomic cline analyses, and identifying areas for fruitful future development.
Multispecies interactions and the community context of the evolution of virulence
Authors: Evensen Claire , White Andy , Boots Mike
Published: March 2024

In nature, host-parasite/pathogen relationships are embedded in a network of ecological interactions that have the potential to shape the evolutionary trajectories of shared pathogens. Understanding this community context of infectious disease evolution is important for wildlife, agricultural, and human systems alike – illustrated, for example, by the increasing risk of zoonotic disease emergence. We introduce an eco-evolutionary model that examines ecological feedbacks across a range of host-host interactions. Specifically, we analyze a model of the evolution of virulence of a pathogen infecting hosts who themselves exhibit competitive, mutualistic, or exploitative relationships. We find that pathogen specialism is necessary for inter-host interactions to impact parasite evolution. An important general result is that increasing competition between hosts leads to higher shared pathogen virulence, while increasing mutualism leads to lower virulence. Across a range of scenarios, the nature of pathogen specialization is critical to the outcome – for instance, if hosts only differ in initial susceptibility to infection, there is no impact of host-host interactions on virulence evolution. In contrast, specialization in terms of onward transmission, host tolerance, or intra-host pathogen growth rate critically impact the evolution of virulence. For example, stronger specialism in transmission selects for lower virulence, while stronger specialism in tolerance and growth rate selects for higher virulence. Our work provides testable hypotheses for multi-host disease systems, predicts how changing interaction networks may impact the evolution of virulence, and broadly demonstrates the importance of looking beyond pairwise relationships to understand evolution in realistic natural contexts.