bluuebunny/crossref_metadata_2025 huggingface dataset:
Post-transcriptional cross- and auto-regulation buffer expression of the human RNA helicasesDDX3XandDDX3Y
Authors: Rengarajan Shruthi , Derks Jason , Bellott Daniel W. , Slavov Nikolai , Page David C.
Published: July 2024

The Y-linked geneDDX3Yand its X-linked homologDDX3Xsurvived the evolution of the human sex chromosomes from ordinary autosomes.DDX3Xencodes a multi-functional RNA helicase, with mutations causing developmental disorders and cancers. We find that, among X-linked genes with surviving Y homologs,DDX3Xis extraordinarily dosage-sensitive. Studying cells of individuals with sex chromosome aneuploidy, we observe that when the number of Y chromosomes increases,DDX3Xtranscript levels fall; conversely, when the number of X chromosomes increases,DDX3Ytranscript levels fall. In 46,XY cells, CRISPRi knockdown of eitherDDX3XorDDX3Ycauses transcript levels of the homologous gene to rise. In 46,XX cells, chemical inhibition of DDX3X protein activity elicits an increase inDDX3Xtranscript levels. Thus, perturbation of eitherDDX3XorDDX3Yexpression is buffered – by negative cross-regulation ofDDX3XandDDX3Yin 46,XY cells, and by negative auto-regulation ofDDX3Xin 46,XX cells.DDX3X-DDX3Ycross-regulation is mediated through mRNA destabilization – as shown by metabolic labeling of newly transcribed RNA – and buffers total levels of DDX3X and DDX3Y protein in human cells. We infer that post-transcriptional auto-regulation of the ancestral (autosomal)DDX3gene transmuted into auto- and cross-regulation ofDDX3XandDDX3Yas these sex-linked genes evolved from ordinary alleles of their autosomal precursor.
Scoring consistency checks for the Clinician Administered PTSD Scale (CAPS-IV & CAPS-V)
Authors: Rabinowitz Jonathan , Rabinowitz Alon A. , Freedman Sara
Published: July 2024

Background

The CAPS is regarded as the “gold standard” in PTSD assessment. It is a structured interview that yields a categorical diagnosis of PTSD and also a measure of the severity of PTSD symptoms. Since a PTSD diagnosis in some settings could be connected to getting benefits, scoring inconsistencies may be more abundant with this rating scale as they not only reflect raters carelessness but intentional inaccurate reporting by the subject.

Objective

The objective of the current effort was to derive rating consistency flags for the CAPS-IV.

Methods

We deconstructed CAPS scoring instructions and anchors to identify potential scoring inconsistency flags. These inconsistency flags were reviewed and confirmed by expert raters. To test the ability of the flags to identify careless responses the flags were applied to Monte Carlo simulated data of 100,000 CAPS administrations.

Results

Twelve flags were derived (presented in Table 1). Two flags applied to most of the 17 symptom items (Flag 1: Frequency=0 & Intensity>0 and Flag 2: Frequency>0 & Intensity=0). The remaining 10 flags pertained to individual items. Five flags were rated as “High” flags, representing very probably or definitely incorrect rating, one as medium, reflecting probably incorrect rating. Flags were raised for 95% of the Monte Carlo simulated CAPS administrations, 78% of the administrations had 4 or more flags and 60% 5 or more.

Conclusions

Scoring consistency flags for the CAPS may be useful in the quest to improve reliability and validity of clinical trials. Modified flags are currently being developed to cover the CAPS-V. Further testing of flags using clinical trial data is planned to examine their potential impact on signal detection.
The Sexual Harassment of Medical Students – Victims, Experiences, Impact, and Barriers to Reporting
Authors: Menshawey Rahma , Menshawey Esraa
Published: July 2024

Background

Sexual harassment of medical students is a growing concern. Sexual harassment is an unethical and illegal conduct. Yet, medical students are at a unique disadvantage to be victimized to due organizational failures, fear of retaliation, and unique power dynamics. As more women, minorities, and vulnerable groups enter the medical field, the time is ripe for proactive measures to ensure their empowerment and protect in light of such heinous and harmful acts.

Main body of the abstract

Original research studies, which examined the sexual harassment of medical students were identified on the PubMed database using the key terms, “sexual harassment”, and “medical students”. A total of 36 studies were identified. The purpose of this review is to highlight the key findings in the original research literature on the sexual harassment of medical students, and to identify themes in hopes to inspire progressive solutions to embolden student safety.

Short conclusion

There is a growing global body of literature that has examined the sexual harassment experiences of medical students. Themes across the studies reveal a wide array of experiences. Medical students, especially females, are faced with harassment from professors, colleagues, and patients. The impact of harassment is far reaching, and includes depression, post-traumatic stress disorder, loss of concentration and academic interests, changing specialty of interest and relocation. There is a number of barriers to reporting these events, notably including a lack of institutional response, lack of time to go forward with a complaint, fear of retaliation and career impact. Proactive measures are needed to protect the students and embolden them and provide them with safe and accessible means to reporting these events, as well as ensuring adequate responses to reports on the institutional level, and continued emotional and career support are needed.
The Open Pediatric Cancer Project
Authors: Geng Zhuangzhuang , Wafula Eric , Corbett Ryan J. , Zhang Yuanchao , Jin Run , Gaonkar Krutika S. , Shukla Sangeeta , Rathi Komal S. , Hill Dave , Lahiri Aditya , Miller Daniel P. , Sickler Alex , Keith Kelsey , Blackden Christopher , Chroni Antonia , Brown Miguel A. , Kraya Adam A. , Koschmann Carl J. , Aldape Kenneth , Huang Xiaoyan , Rood Brian R. , Mason Jennifer L. , Trooskin Gerri R. , Abdullaev Zied , Wang Pei , Zhu Yuankun , Farrow Bailey K. , Farrel Alvin , Dybas Joseph M. , Zhong Chuwei , Van Kuren Nicholas , Zhang Bo , Santi Mariarita , Phul Saksham , Chinwalla Asif T , Resnick Adam C. , Diskin Sharon J. , Tasian Sarah , Stefankiewicz Stephanie , Maris John M. , Ennis Brian M. , Lueder Matthew R. , Naqvi Ammar S. , Coleman Noel , Ma Weiping , Taylor Deanne , Rokita Jo Lynne
Published: July 2024

Background

In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we extend the OpenPBTA to create the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multi-omic dataset from 6,112 pediatric cancer patients with 7,096 tumor events across more than 100 histologies. Combined with RNA-Seq from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA), OpenPedCan contains nearly 48,000 total biospecimens (24,002 tumor and 23,893 normal specimens).

Findings

We utilized Gabriella Miller Kids First (GMKF) workflows to harmonize WGS, WXS, RNA-seq, and Targeted Sequencing datasets to include somatic SNVs, InDels, CNVs, SVs, RNA expression, fusions, and splice variants. We integrated summarized CPTAC whole cell proteomics and phospho-proteomics data, miRNA-Seq data, and have developed a methylation array harmonization workflow to include m-values, beta-vales, and copy number calls. OpenPedCan contains reproducible, dockerized workflows in GitHub, CAVATICA, and Amazon Web Services (AWS) to deliver harmonized and processed data from over 60 scalable modules which can be leveraged both locally and on AWS. The processed data are released in a versioned manner and accessible through CAVATICA or AWS S3 download (from GitHub), and queryable through PedcBioPortal and the NCI’s pediatric Molecular Targets Platform. Notably, we have expanded PBTA molecular subtyping to include methylation information to align with the WHO 2021 Central Nervous System Tumor classifications, allowing us to create research-grade integrated diagnoses for these tumors.

Conclusions

OpenPedCan data and its reproducible analysis module framework are openly available and can be utilized and/or adapted by researchers to accelerate discovery, validation, and clinical translation.
Mapping the Global Distribution ofMus musculus: Implications for Evolutionary Genetics
Authors: Garretson Alexis C , Blanco-Berdugo Laura A , Dumont Beth L
Published: July 2024

House mice (Mus musculus) are a key biomedical research model and important vectors for disease transmission. In the wild, house mice are also an ecologically disruptive invasive species, and their activity is associated with significant economic and agricultural damage and cost. Despite the importance of house mice across these different contexts, the extent of their geographic distribution is not well understood. House mice are human commensals but are nonetheless sensitive to their prevailing environment, indicating that the range of human settlement cannot be used as a reliable proxy. Existing range maps forMus musculusare based on minimum convex hulls informed by potentially biased sampling and do not 1) fully integrate large, digitized data documenting species occurrences, 2) provide insight into the likely species distribution in under-sampled regions, and 3) delineate internal structures of the range, including barriers to dispersal or unsuitable internal habitat. Consequently, we know little about the bioclimatic tolerance and environmental envelope occupied by this species. To address these unknowns, we leverage publicly available mouse sampling and biodiversity data to provide an updated range map ofMus musculusand define the environmental limits of the house mouse distribution. Using genetic data from public archives, we also model the genetic diversity of house mice across our newly updated range. Using these data, we visualize global genetic diversity trends and confirm the ancestral origins ofMus musculusto the region of the Indian subcontinent occupied by modern-day Pakistan and northwestern India. Taken together, our efforts highlight areas where house mice are predicted to be at their environmental tolerance limit, including regions where future sampling efforts may uncover mice with unique adaptive traits.
Engineering programmable CAR-T cells with tunable controls as fail-safe mechanisms during cancer immunotherapy
Authors: Dogan Mikail , Kozhaya Lina , Placek Lindsey , Karhan Ece , Yigit Mesut , Mohammed Christina , Zhao Qi , Unutmaz Derya
Published: July 2024

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in treating various cancers, but significant risks of severe adverse effects remain. In this study, we present a synthetic biology toolbox for engineering CAR-T cells with tunable and controllable features to mitigate these risks. Using this toolbox, we programmed cytotoxic CAR-T cells to be turned on and off using synthetic genes with tetracycline response elements, referred to as iOnCAR and iOffCAR. We achieved temporal regulation of CAR expression using the synthetic Notch receptor system and “AND-gate” programs, which allow for additional control using doxycycline. We also engineered cooperation among T cells through CD4 help to CD8 T cells in targeting cancer cells via synthetic Notch receptors controlled by doxycycline treatment. Additionally, we developed a T cell fratricide system by triggering a genetic “Battle Royale” mechanism that enables CAR-T cells to eliminate each other. In this system, surviving T cells become activated, proliferate, and display high cytotoxicity to target cells. In conclusion, our synthetic biology toolbox provides targeted fail-safe solutions for improving the safety and potency of CAR-T cell therapies by integrating different genetic circuits with a commonly used antibiotic.
Atomistic Prediction of Structures, Conformational Ensembles and Binding Energetics for the SARS-CoV-2 Spike JN.1, KP.2 and KP.3 Variants Using AlphaFold2 and Molecular Dynamics Simulations: Mutational Profiling and Binding Free Energy Analysis Reveal Epistatic Hotspots of the ACE2 Affinity and Immune Escape
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Verkhivker Gennady
Published: July 2024

The most recent wave of SARS-CoV-2 Omicron variants descending from BA.2 and BA.2.86 exhibited improved viral growth and fitness due to convergent evolution of functional hotspots. These hotspots operate in tandem to optimize both receptor binding for effective infection and immune evasion efficiency, thereby maintaining overall viral fitness. The lack of molecular details on structure, dynamics and binding energetics of the latest FLiRT and FLuQE variants with the ACE2 receptor and antibodies provides a considerable challenge that is explored in this study. We combined AlphaFold2-based atomistic predictions of structures and conformational ensembles of the SARS-CoV-2 Spike complexes with the host receptor ACE2 for the most dominant Omicron variants JN.1, KP.1, KP.2 and KP.3 to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and computations of binding affinities, we identified binding energy hotspots and characterized molecular basis underlying epistatic couplings between convergent mutational hotspots. The results suggested that the existence of epistatic interactions between convergent mutational sites at L455, F456, Q493 positions that enable to protect and restore ACE2 binding affinity while conferring beneficial immune escape. To examine immune escape mechanisms, we performed structure-based mutational profiling of the spike protein binding with several classes of antibodies that displayed impaired neutralization against BA.2.86, JN.1, KP.2 and KP.3. The results confirmed the experimental data that JN.1, KP.2 and KP.3 harboring the L455S and F456L mutations can significantly impair the neutralizing activity of class-1 monoclonal antibodies, while the epistatic effects mediated by F456L can facilitate the subsequent convergence of Q493E changes to rescue ACE2 binding. Structural and energetic analysis provided a rationale to the experimental results showing that BD55-5840 and BD55-5514 antibodies that bind to different binding epitopes can retain neutralizing efficacy against all examined variants BA.2.86, JN.1, KP.2 and KP.3. The results support the notion that evolution of Omicron variants may favor emergence of lineages with beneficial combinations of mutations involving mediators of epistatic couplings that control balance of high ACE2 affinity and immune evasion.
Association of Alzheimer’s disease polygenic risk score with concussion severity and recovery metrics
Authors: Dybing Kaitlyn M. , McAllister Thomas W. , Wu Yu-Chien , McDonald Brenna C. , Broglio Steven P. , Mihalik Jason P. , Guskiewicz Kevin M. , Goldman Joshua T. , Jackson Jonathan C. , Risacher Shannon L. , Saykin Andrew J. , Nudelman Kelly N. H.
Published: July 2024

Identification of genetic alleles associated with both Alzheimer’s disease (AD) and concussion severity/recovery could help explain the association between concussion and elevated dementia risk. However, there has been little investigation into whether AD risk genes associate with concussion severity/recovery, and the limited findings are mixed. We used AD polygenic risk scores (PRS) andAPOEgenotypes to investigate any such associations in the NCAA-DoD Grand Alliance CARE Consortium (CARE) dataset. We assessed six outcomes in 931 total participants. The outcomes were two concussion recovery measures (number of days to asymptomatic status, number of days to return to play (RTP)) and four concussion severity measures (scores on SAC and BESS, SCAT symptom severity, and total number of symptoms). We calculated PRS using a published score [1] and performed multiple linear regression (MLR) to assess the relationship of PRS with the outcomes. We also used t-tests and chi-square tests to examine outcomes byAPOEgenotype, and MLR to analyze outcomes in European and African genetic ancestry subgroups. Higher PRS was associated with longer injury to RTP in the normal RTP (<24 days) subgroup (p= 0.024), and one standard deviation increase in PRS resulted in a 9.89 hour increase to the RTP interval. There were no other consistently significant effects, suggesting that high AD genetic risk is not strongly associated with more severe concussions or poor recovery in young adults. Future studies should attempt to replicate these findings in larger samples with longer follow-up using PRS calculated from diverse populations.
Perceptions of Water Security and Climate Change in Lima, Peru: Qualitative Study of Mothers and Healthcare Providers
Authors: Morales Danna Obregon , Ramos Karen , Jauregui Elena , Dueñas Milagros , Rumaldo Nancy , Gogia Shruti , Lecca Leonid , Shin Sonya S.
Published: July 2024

Background

Water insecurity, a global public health crisis, will be intensified by climate change. In coastal Peru, little is known about the health effects of water insecurity from a community perspective. Understanding first-hand experiences and perceptions of mothers and healthcare providers can inform strategies to mitigate the effects of water insecurity and climate change on health outcomes and health disparities.

Methods

This qualitative study took place in 2023 in Carabayllo, the Northernmost region of Lima, Peru comprised of urban and rural communities. We conducted six focus groups with 10 pregnant women and 23 mothers of children ages 0 to 10, as well as individual interviews with 22 healthcare providers. Data were analyzed through rapid qualitative analysis combining deductive and inductive methods.

Principal findings

Water insecurity was common among community members and was normalized as part of daily life. Access to water varied based on socioeconomic status and geography. Perceived health impacts were primarily related to hygiene and sanitation (e.g. diarrheal disease), water storage (dengue), and longer-term effects such as nutrition and child development. Respondents agreed that climate change would exacerbate water insecurity and endorsed strategies to take action.

Conclusions and significance

The lived experiences of water insecurity and its health impacts in Lima, Peru highlight the importance of mobilizing community stakeholders, health systems and local government to increase water security and support healthcare facilities and communities on water conservation and climate preparedness efforts.
Clinical Pilot of Bacterial Transcriptional Profiling as a Combined Genotypic and Phenotypic Antimicrobial Susceptibility Test
Authors: Young Eleanor L. , Roach David , Martinsen Melanie , McGrath Graham EG , Holbrook Nolan , Cho Ha Eun , Seyoum Eden , Pierce Virginia M. , Bhattacharyya Roby P.
Published: July 2024

Antimicrobial resistance is a growing health threat, but standard methods for determining antibiotic susceptibility are slow and can delay optimal treatment, which is especially consequential in severe infections such as bacteremia. Novel approaches for rapid susceptibility profiling have emerged that characterize either bacterial response to antibiotics (phenotype) or detect specific resistance genes (genotype). GoPhAST-R is a novel assay, performed directly on positive blood cultures, that integrates rapid transcriptional response profiling with detection of key resistance gene transcripts, thereby providing simultaneous data on both phenotype and genotype. Here, we performed the first clinical pilot of GoPhAST-R on 42 positive blood cultures: 26 growing Escherichia coli, 15 growing Klebsiella pneumoniae, and 1 with both. An aliquot of each positive blood culture was exposed to 9 different antibiotics, lysed, then underwent rapid transcriptional profiling on the NanoString® platform; results were analyzed using an in-house susceptibility classification algorithm. GoPhAST-R achieved 95% overall agreement with standard antimicrobial susceptibility testing methods, with the highest agreement for beta-lactams (98%) and the lowest for fluoroquinolones (88%). Epidemic resistance genes including the extended spectrum beta-lactamase blaCTX-M-15and the carbapenemase blaKPCwere also detected within the population. This study demonstrates the clinical feasibility of using transcriptional response profiling for rapid resistance determination, although further validation with larger and more diverse bacterial populations will be essential in future work. GoPhAST-R represents a promising new approach for rapid and comprehensive antibiotic susceptibility testing in clinical settings.
Cervical mucosal inflammation expands functional polymorphonuclear myeloid-derived suppressor cells
Authors: Pieren Daan K.J. , Benítez-Martínez Aleix , Descalzo Vicente , Arando Maider , Álvarez-López Patricia , Garcia-Perez Jorge N. , Massana Núria , Castellón Júlia , Hoyos-Mallecot Yannick , Alvárez-Sierra Daniel , Ramírez-Serra Clara , Rodriguez Nuria Laia , Mañalich-Barrachina Laura , Centeno-Mediavilla Cristina , Castellví Josep , Falcó Vicenç , Buzón María J. , Genescà Meritxell
Published: July 2024

The mucosal immune system plays a fundamental role in maintaining microbial balance. Microbial imbalance in the female genital tract increases the risk for adverse health outcomes in women and may increase susceptibility to genital tract infections. Among different relevant immune subsets, myeloid-derived suppressor cells (MDSCs) remain understudied in the context of female genital tract conditions. Here we show that frequency of polymorphonuclear (PMN-) MDSCs increased in the cervical mucosa of women withChlamydia trachomatis, bacterial vaginosis, or with a coinfection, but not in women with human papillomavirus. Mucosal PMN-MDSC frequencies correlated with mucosal IL-1β inC. trachomatispatients and ex vivoexposure of cervical tissue toC. trachomatiselevated both PMN-MDSC frequencies and IL-1β secretion. Likewise, exposure of cervical tissue to cervicovaginal lavage fluid fromC. trachomatisand bacterial vaginosis patients also enhanced PMN-MDSC frequencies. Lastly, cervical MDSCs expressed suppressive mediators and functionally suppressed cytotoxic T-cell responses. Our study identifies IL-1β-stimulated PMN-MDSCs as an immune suppressive mediator in female genital tract infections, potentially contributing to susceptibility to acquiring secondary infections at this site.
Medical Findings in Infants Prenatally Identified with Sex Chromosome Trisomy in Year One of Life
Authors: Tartaglia Nicole , Davis Shanlee , Howell Susan , Bothwell Samantha , Nocon Kayla , Kowal Karen , Ikomi Chijioke , Keene Andrew , Reynolds Victoria , Berglund Agnethe , Ross Judith
Published: July 2024

BACKGROUND AND OBJECTIVE

Sex chromosome trisomies (SCT), including XXY, XYY, and XXX syndromes, have been historically underdiagnosed. Noninvasive prenatal cell-free DNA screening has significantly increased identification of these conditions, leading to a need for pediatric care for a growing population of newborns with SCT. Our goal was to analyze and compare perinatal features, medical diagnoses, and physical features in infants with prenatal identification of SCT conditions through the first year of life.

METHODS

The eXtraordinarY Babies Study is an ongoing, prospective natural history study of prenatally identified children with SCT conducted by interdisciplinary teams in Colorado and Delaware. Participants were enrolled prior to 12 months of age and had pregnancy, birth, medical histories, and physical exams completed by board-certified pediatricians at 2, 6, and/or 12-month visits. Descriptive statistics were followed by comparisons between SCT groups using t-tests or ANOVA, Fisher exact, and correlations between medical features with alpha of 0.05. Relative risks were calculated compared to general population rates.

RESULTS

327 infants were included in the analysis (XXY=195, XXX=79, XYY=53). Major congenital anomalies were rare (1.7%). Relative risk compared to general population was elevated for breastfeeding difficulties (51.7%;RR 2.7), positional torticollis (28.2%;RR 7.2), eczema (48.0%;RR 3.5), food allergies (19.3%;RR 2.4), constipation requiring intervention (33.9%;RR 7.6), small cardiac septal defects (7.7%;RR 17.2), and structural renal abnormalities (4.4%;RR 9.7). Inpatient hospitalization was required for 12.4%, with 59.5% of hospitalizations attributable to respiratory infections.

DISCUSSION

These findings of medical conditions with a higher prevalence can inform anticipatory guidance and medical management for pediatricians caring for infants with SCT.

Article Summary

Medical findings in largest cohort of prenatally identified infants with XXY, Trisomy X, and XYY from birth to 12 months and implications for pediatric care.

What’s Known on This Subject

One in ∼500 individuals have an extra X or Y chromosome, or sex chromosome trisomy (SCT). Prenatal screening is now routinely identifying SCT, however there are few studies to guide perinatal and infant care for these individuals.

What This Study Adds

This prospective observational study presents medical features for 327 infants with prenatally identified SCT from birth through the first year of life. Results identify where proactive screenings and/or interventions may be warranted for infants with SCT.
Application of REDECA Framework to Improve Safety and Health of Agricultural Tractor Drivers
Authors: Ashrafi Negin , Alaei Kamiar , Placencia Greg , Pishgar Maryam
Published: July 2024

Introduction:Despite tremendous efforts, including research, teaching, and extension, toward improving the safety of agricultural tractor drivers, the number of incidents related to agricultural tractor drivers has not declined. This evidence points out an urgent need to explore artificial intelligence (AI) solutions to improve the safety of tractor drivers.Methods:This paper uses 171 Fatality Assessment and Control Evaluation (FACE) reports related to tractor drivers and a new framework called Risk Evolution, Detection, Evaluation, and Control of Accidents (REDECA) to identify existing AI solutions and specific areas where AI solutions are missed and can be developed to reduce incidents and recovery time. Fatality reports of tractor drivers were categorized into six main categories, including run over, pinned by, fall, others (fire and crashes), roll over, and overturn. Each category was then subcategorized based on similarities of incident causes in the reports.Results:The application of the REDECA framework revealed potential AI solutions that could improve the safety of tractor drivers. In all categories, the REDECA framework lacks AI solutions for three elements, including the probability of reducing recovery time in R3, detecting changes between R2 and R3, and intervention to send workers to R2. Except for the run over category, all other categories were missing AI solutions for interventions to prevent entry to the R3 element of the REDECA. In addition, the fall, roll over, and overturn categories lacked AI intervention that minimized damage and recovery in R3.Conclusions:The outcome of this study shows an urgent need to develop AI solutions to improve tractor driver safety.
The Effect of Medical Therapy on Reducing the Risk of Pacing Induced Cardiomyopathy
Authors: Agha Mahdi S , Schaich Christopher L , Rikhi Rishi , Hari Krupal , Bodziock George , Bhave Prashant
Published: July 2024

Background

High right ventricular (RV) pacing burden can result in pacing-induced cardiomyopathy (PICM).

Objectives

To investigate whether ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), and beta blockers (BB) reduce the risk of PICM in patients with high RV pacing burden.

Methods

This was a single center, retrospective study which included patients with normal ejection fraction (EF) and complete heart block who underwent pacemaker implantation between 1992 and 2013. The medical therapy group included patients who received ACEI/ARB, BB, or combination of these classes. The control group received neither ACEI/ARB nor BB. The primary endpoint was PICM, defined as upgrade to a biventricular device or reduction in EF to ≤40% without another etiology identified. Fine-Gray subdistribution hazard models accounting for death as a competing risk were used to determine the relationship between medical therapy (ACEI/ARB, BB, or combination) and cumulative incidence of PICM.

Results

The study included 642 patients (mean [SD] age 71 [14] years; 51% women). Over 10 years of follow-up, 76 (11.8%) patients received ACEI/ARB therapy only; 49 (7.6%) received BB therapy only; and 86 (13.4%) were exposed to both. PICM occurred in 10 of 211 patients in the medical therapy group (4.7%) and in 30 of 431 in the control group (7.0%). In adjusted analyses weighted for group-switching, the risk of PICM was significantly lower in the medical therapy group compared to the control group (HR 0.59, 95% CI 0.45 – 0.77). Patients exposed to combination therapy had the lowest risk (HR 0.46, 95% CI 0.31 – 0.69).

Conclusion

In patients with high RV pacing burden, BB therapy alone or in combination with ACEI/ARBs appears to reduce the risk of PICM within 10 years of pacemaker implantation.
Impact of PCSK9 Inhibitors on Lipoprotein(a): A Meta-analysis and Meta-regression of Randomized Controlled Trials
Authors: Rivera Frederick Berro , Cha Sung Whoy , Magalong John Vincent , Tang Vincent Anthony , Enriquez Mary Grace , Gulati Martha , Enkhmaa Byambaa , Pagidipati Neha , Shah Nishant P.
Published: July 2024

Background

Lipoprotein(a) [Lp(a)] has been independently associated with increased cardiovascular risk. We examined the effect of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on plasma Lp(a) levels across multiple clinical trials.

Methods

Studies were retrieved comparing the effect of PCSK9i vs. placebo on Lp(a) levels. The primary outcome was percent change in Lp(a) levels. Secondary outcomes included percent change in additional cholesterol markers. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on comparator, PCSK9i type, treatment duration, and presence of familial hypercholesterolemia (FH).

Results

47 studies with 67,057 patients were analyzed. PCSK9i reduced Lp(a) levels on average of -27% (95% CI: -29.8 to -24.1, p<0.001). Concurrent reduction in LDL-C, non-HDL-C, total cholesterol, triglycerides ApoB, ApoA-1, and increased HDL-C were also observed with PCSK9i use. Factors associated with the treatment effect included mean percent change in LDL-C (p=0.02, tau2=177.1, R2=0.00) and Apo-B (p<0.00, tau2=114.20, R2=1.42). Subgroup analyses revealed consistent treatment effect amongst comparators (vs. placebo: -27.69% (95% CI: - 30.85 to -24.54, p<0.00), vs. ezetimibe: -24.0% (95% CI: -29.95% to -18.01, p<0.00), type of PCSK9i, evolocumab: -29.35% (95% CI: -33.56 to -25.14, p<0.00) vs. alirocumab: -24.50% (95% CI: -27.96 to -21.04, p<0.00), and presence of FH: -25.63% (95% CI: -31.96% to -19.30, p<0.00 vs. no FH: -27.22% (95% CI: -30.34. to -24.09, p<0.00). Varying treatment effects were noted in the duration of treatment (12 weeks or shorter: -32.43% (95% CI: -36.63 to -28.23 vs. >12 weeks: -22.31% (95% CI: -25.13 to -19.49, p<0.00), p interaction <0.01.

Conclusion

PCSK9 inhibitors reduce Lp(a) levels by an average of 27%. Mean percent change in LDL-C and Apo-B were associated with treatment effect. PCSK9i also significantly reduced other atherogenic lipoproteins. Across multiple clinical trials, PCSK9i has a consistent effect of significantly lowering Lp(a) levels.
Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication
Authors: Yin Xin , Pu Yuan , Yuan Shuofeng , Pache Lars , Churas Christopher , Weston Stuart , Riva Laura , Simons Lacy M , Cisneros William , Clausen Thomas , de Jesus Paul , Kim Ha Na , Fuentes Daniel , Whitelock John , Esko Jeffrey , Lord Megan , Mena Ignacio , Garcia-Sastre Adolfo , Hultquist Judd , Frieman Matthew , Ideker Trey , Pratt Dexter , Martin-Sancho Laura , Chanda Sumit
Published: July 2024

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.
A porcine chronic hepatitis E virus (HEV) infection model exhibits HEV replication in male accessory reproductive glands and immune-mediated reproductive damage
Authors: Yadav Kush K. , Boley Patricia A , Laocharoensuk Thamonpan , Khatiwada Saroj , Lee Carolyn M , Bhandari Menuka , Hanson Juliette , Kenney Scott P.
Published: July 2024

Hepatitis E virus (HEV) is an expanding zoonotic viral disease threat. Although HEV causes acute viral hepatitis, it is increasingly being recognized as a systemic pathogen with detection and damage in extrahepatic tissues. The presence of HEV RNA in the semen of chronically infected human patients in the absence of viremia and fecal shedding and presence of HEV in the sperm head underscores the need to understand the interaction of HEV within the male reproduction system. Male accessory glands secrete biofluids necessary for sperm nourishment and to neutralize the acidity of the vagina. The role of male accessory glands in the dissemination and persistence of HEV infection have not been studied. Using an immunosuppressed pig model for chronic HEV infection, we demonstrate infectious HEV in mature sperm cells altering the sperm motility and morphology. HEV isolated from sperm cells remained infectious in human hepatoma cells. Spermatic fluid contained lower virus titers than the sperm cells from chronically infected pigs highlighting that the sperm cells themselves can associate with the virus. Evaluation of the male accessory glands demonstrated viral replication, infiltration of CD45 leukocytes, and apoptosis associated with HEV infection. A decrease in serum testosterone levels was evident in the HEV infected pigs. Even though a lower viral RNA titer was seen in serum and feces of chronically infected, immunosuppressed and ribavirin treated pigs, high viral RNA and infectious particles in sperm is a concern. Our findings necessitate further studies defining the mechanism of sperm cell invasion by HEV, length of HEV survival in sperm cells during chronic HEV infection, and risk of sexual transmission of HEV during both acute and chronic phases of infection.

Author Summary

Hepatitis E virus, a leading cause of acute viral hepatitis, causes both acute and chronic infection in humans. Recent advances within the HEV field have demonstrated extrahepatic diseases associated with HEV. More recent findings have revealed infectious HEV in the vagina, Sertoli cells, and ejaculate of humans, and sperm cells of pigs. We demonstrate that the male accessory sex glands may have a role in the persistence of HEV infection during chronic infections. We utilized an established immunosuppressed pig model and treated pigs with ribavirin to study the presence of virus in the sperm cells. We demonstrated high viral RNA loads and infectious particles associated with sperm cells. Our study further highlights the importance of the testis, as an immune privileged site, in the maintenance of chronic HEV infection. New studies to evaluate the mechanisms by which HEV associates with sperm cells, the length of HEV survival in sperm cell fractions, and consideration of the testes as a potential HEV reservoir are necessary.
Polysaccharide quantification using microbial enzyme cocktails
Authors: Pontrelli Sammy , Sauer Uwe
Published: July 2024

Polysaccharide quantification plays a vital role in understanding ecological and nutritional processes in microbes, plants, and animals. Traditional methods hydrolyze these large molecules into monomers, but these approaches are restricted to chemically hydrolysable polysaccharides. Enzymatic degradation is a promising alternative but typically requires the use of characterized recombinant enzymes or microbial isolates that secrete enzymes. In this study, we introduce a versatile method that employs undefined enzyme cocktails secreted by individual microbes or complex environmental microbial communities for the hydrolysis of polysaccharides. We focus on colloidal chitin and laminarin as representative polysaccharides of ecological relevance. Our results demonstrate that colloidal chitin can be effectively digested with an enzyme cocktail derived from a chitin-degradingPsychromonas sp.isolate. Utilizing a 3,5-dinitrosalicylic acid reducing sugar assay or liquid chromatography–mass spectrometry for mono- and oligomers detection, we successfully determined chitin concentrations as low as 62 mg/L and 15 mg/L, respectively. This allows for effective monitoring of microbial chitin degradation. To extend the applicability of our method, we also leveraged complex, undefined microbial communities as sources of enzyme cocktails capable of degrading laminarin. With this approach, we achieved a detection limit of 30 mg/L laminarin through the reducing sugar assay. Our findings highlight the potential of utilizing enzyme cocktails from both individual microbes and, notably, from undefined microbial communities for polysaccharide quantification. This advancement addresses limitations associated with traditional chemical hydrolysis methods.
The structural and biophysical basis of substrate binding to the hydrophobic groove in Ubiquilin Sti1 domains
Authors: Onwunma Joan , Binsabaan Saeed , Allen Shawn P. , Sankaran Banumathi , Wohlever Matthew L.
Published: July 2024

Ubiquilins are a family of cytosolic proteins that ferry ubiquitinated substrates to the proteasome for degradation. Recent work has demonstrated that Ubiquilins can also act as molecular chaperones, utilizing internal Sti1 domains to directly bind to hydrophobic sequences. Ubiquilins are associated with several neurodegenerative diseases with point mutations in UBQLN2 causing dominant, X-linked Amyotrophic Lateral Sclerosis (ALS). The molecular basis of Ubiquilin chaperone activity and how ALS mutations in the Sti1 domains affect Ubiquilin activity are poorly understood. This study presents the first crystal structure of the Sti1 domain from a fungal Ubiquilin homolog bound to a transmembrane domain (TMD). The structure reveals that two Sti1 domains form a head-to-head dimer, creating a hydrophobic cavity that accommodates two TMDs. Mapping the UBQLN2 sequence onto the structure shows that several ALS mutations are predicted to disrupt the hydrophobic groove. Using a newly developed competitive binding assay, we show that Ubiquilins preferentially bind to hydrophobic substrates with low helical propensity, motifs that are enriched in both substrates and in Ubiquilins. This study provides insights into the molecular and structural basis for Ubiquilin substrate binding, with broad implications for the role of the Sti1 domain in phase separation and ALS.
Developmental dynamics of the prefrontal cortical SST and PV interneuron networks: Insights from the monkey highlight human-specific features
Authors: Hosseini Fin Nafiseh S. , Yip Adrian , Teo Leon , Homman-Ludiye Jihane , Bourne James A.
Published: July 2024

The primate prefrontal cortex (PFC) is a quintessential hub of cognitive functions. Amidst its intricate neural architecture, the interplay of distinct neuronal subtypes, notably parvalbumin (PV) and somatostatin (SST) interneurons (INs), emerge as a cornerstone in sculpting cortical circuitry and governing cognitive processes. While considerable strides have been made in elucidating the developmental trajectory of these neurons in rodent models, our understanding of their postmigration developmental dynamics in primates still needs to be studied. Disruptions to this developmental trajectory can compromise IN function, impairing signal gating and circuit modulation within cortical networks. This study examined the expression patterns of PV and SST, ion transporter KCC2, and ion channel subtypes Kv3.1b, and Nav1.1 -associated with morphophysiological stages of development in the postnatal marmoset monkey in different frontal cortical regions (granular areas 8aD, 8aV, 9, 46; agranular areas 11, 47L). Our results demonstrate that the maturation of PV+ INs extends into adolescence, characterized by discrete epochs associated with specific expression dynamics of ion channel subtypes. Interestingly, we observed a postnatal decrease in SST interneurons, contrasting with studies in rodents. This endeavor broadens our comprehension of primate cortical development and furnishes invaluable insights into the etiology and pathophysiology of neurodevelopmental disorders characterized by perturbations in PV and SST IN function.

Summary Statement:

The prefrontal cortex (PFC) in primates is crucial for cognitive functions, with parvalbumin (PV) and somatostatin (SST) interneurons playing key roles. This study in marmoset monkeys explores their developmental dynamics, revealing prolonged maturation of PV interneurons and contrasting SST patterns from rodents, enhancing understanding of primate cortical development.
Star-polymers as potent broad-spectrum extracellular virucidal antivirals
Authors: Super Elana H. , Lai Si Min , Cytlak-Chaudhuri Urszula , Coppola Francesco , Saouaf Olivia , Song Ye Eun , Casey Kerriann M. , Batt Lauren J. , Macleod Shannan-Leigh , Bagley Robert H.T. , Walsh-Korb Zarah , Král Petr , Appel Eric A. , Travis Mark A. , Jones Samuel T.
Published: July 2024

Viruses pose a significant threat to both global health and the global economy. It is clear that novel antiviral strategies are urgently needed, with a broad-spectrum approach being most desired. We have discovered a broad-spectrum, non-toxic polymer virucide that can tackle the viral threat. This polymeric virucide is effective at nanomolar concentrations, against a broad-spectrum of viruses and, demonstrated using an intranasal respiratory syncytial virus (RSV) murine model, has excellent efficacy, low anti-coagulant properties and low toxicityin vivo. Molecular dynamic simulations show that this polymer achieves its virucidal antiviral effectviaself-assembly of viral-receptors leading to increased envelope forces and viral disassembly. The discovery of this cheap and readily produced polymer marks the start of a new type of receptor-crosslinking broad-spectrum antiviral that has significant potential to combat the global threat posed by viruses.
Comparative genomics reveals diversity and taxonomic relationships amongClostridioides difficilephages
Authors: Mondal Shakhinur Islam , Rolin Mohimenul Haque , Karim Daniyal , Jewel Nurnabi Azad , Khan Tahsin , Rahman Mustafizur , Akter Arzuba
Published: July 2024

Clostridioides difficileis associated with life-threatening antibiotic-associated diarrhea, colitis, and toxin-mediated infections. While antibiotics are the primary treatment againstC. difficileinfections, increasing resistance necessitates alternatives. Bacteriophages and bacteriophage-derived proteins such as endolysins hold promise as potential solutions. Understanding phage biology at the genomic level is crucial for their therapeutic use. We conducted a comparative genomic analysis of 44C. difficilephage genomes from public databases, examining both whole genome and proteome levels and grouping them by shared protein content. Relationships within each group were observed, and core and highly conserved genes were identified. Using genome and proteome phylogeny, average nucleotide identity, and core gene identification, we proposed an updated taxonomic classification. Nine distinct clusters were identified, without any singleton. Cluster members exhibited similar genome architecture, genome sizes, GC content, number of coding sequences, presence of core genes, and high nucleotide identity. Additionally, we propose 23 new genera, three families and the elevation of currently assigned genera to subfamilies. The lytic module proteins, endolysins, and holins were also characterized, revealing four distinct endolysin organizations with diverse domain architectures. Notably, the amidase_3 and LysM domains were highly conserved and subjected to purifying selection within the C. difficile phage genomes. This is the first comprehensive comparative study regardingC. difficilephage genomes. Our study provides valuable genomic insights that add to the current understanding of the phages. Our taxonomic analysis may improve the classification scheme ofC. difficilephages and aid in the future classification of newly isolatedC. difficilephage genomes.
Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure
Authors: Shao Meiyu , Botvinov Julia , Banerjee Deepro , Girirajan Santhosh , Lüscher Bernhard
Published: July 2024

Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons or brain region-specific chemogenetic activation of SST neurons in mice results in stress resilience. Here, we used RNA sequencing of mice with disinhibited SST neurons to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female mice with disinhibited SST neurons is characterized by resilience to chronic stress-induced transcriptome changes in the medial prefrontal cortex. Interestingly, the transcriptome of non-stressed stress-resilient male mice resembled the transcriptome of chronic stress-exposed stress-vulnerable mice. However, the behavior and the serum corticosterone levels of non-stressed stress-resilient mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of stress-resilient mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes indicating stress-induced enhancement of mRNA translation. Behaviorally, the mice with disinhibited SST neurons were not only resilient to chronic stress-induced anhedonia — they also showed an inversed anxiolytic-like response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in expression of putative stress resilience genes, through a sex-specific brain substrate.