bluuebunny/crossref_metadata_2025 huggingface dataset:
Increasing Engagement in Human Immunodeficiency Virus Prevention Among Cisgender Women in New York City With Sexual Health Self-Testing Kits: A MaxDiff Analysis
Authors: Goldberg Alison J. , Price Devon M. , Phi Amanda , Ma Maria , Edelstein Zoe R. , Golub Sarit A.
Published: November 2024

Background

Despite accounting for approximately 20% of new human immunodeficiency virus (HIV) diagnoses in the United States, cisgender women are consistently underrepresented and underengaged in HIV prevention services such as HIV testing and preexposure prophylaxis (PrEP). Black and Latina cisgender woman (BLCW) are disproportionately impacted by HIV, and face additional barriers to accessing prevention services due to racial/ethnic bias, sexism, and their intersection. Offering self-testing for sexually transmitted infections (STIs) and HIV is one potential strategy for increasing access to—and engagement in—preventative sexual health care among BLCW.

Methods

We conducted a study in consultation with the New York City Department of Health and Mental Hygiene (NYC DOHMH) and their collaborators in order to identify preferences for sexual health kits—including HIV and STI tests—among BLCW in New York City.

Results

We assessed the extent to which BLCW would be willing to accept and use HIV and STI self-testing. In addition, we identified the components of potential sexual health kits that would make them most attractive and would most increase the reach of a sexual health kit program in NYC. Finally, we examined differences in acceptability and preferences (by demographic factors, sexual behavior, and past service utilization) that may impact the development of future programs and interventions.

Conclusions

Self-testing for STIs and HIV represents a promising strategy for engaging BLCW in preventative sexual health services and increasing access to care.
The Optimized Use of a Contact-Free Continuous Monitoring System on Clinical Outcomes During COVID-19
Authors: Kim Alice , Dykes Patricia C. , Scully Darren , Wolski Paula , Franz Calvin , Lipsitz Stuart , Lowenthal Graham , Wien Matthew , Bates David W.
Published: November 2024

Objectives:

The purpose of this study was to examine the impact of a contact-free continuous monitoring system on clinical outcomes including unplanned intensive care unit (ICU) transfer (primary), length of stay (LOS), code blue, and mortality. A secondary aim was to evaluate the return on investment associated with implementing the contact-free continuous monitoring program during the COVID public health emergency.

Methods:

An interrupted time series evaluation was conducted to examine the association between the use of contact-free continuous monitoring and clinical outcomes. A cost-benefit analysis was planned to evaluate the return on investment.

Results:

Use of contact-free continuous monitoring was not significantly associated with unplanned ICU transfers, deaths, ICU LOS, and or rapid response team calls. However, there were significant increases in code blue events (P = 0.02) and mean hospital LOS (P = 0.01) in the postimplementation period when compared with the preimplementation period. Due to the lack of improvement, costs were calculated but a cost-benefit analysis was not conducted.

Conclusions:

Contact-free continuous monitoring bed use during the COVID-19 public health emergency was not associated with improvements in clinical outcomes, although there was substantial confounding. Future studies should include large randomized controlled trials to control for factors not under direct experimental control including unit staffing, staff turnover, and differences in the patient population related to surges in the COVID-19 pandemic.
Optimizing Myelomeningocele Repair: Assessing the Role of Synthetic Acellular Dermal Regeneration Templates in Complex Closures
Authors: Barrera Jose E. , Dunnigan Jennifer K. , Wang Ellen , Swiekatowski Kylie , Osamor III Charles , Nye Jessica R. , Manisundaram Arvind , Obinero Chioma G. , Sobol Danielle L. , Sandberg David I , Shah Manish N. , Fletcher Stephen A. , Greives Matthew R.
Published: November 2024

Background:

Myelomeningoceles threaten newborns with central nervous system infectious risk. While some myelomeningoceles can be repaired fetally, limited donor tissue in newborns makes covering a substantial defect challenging. This study evaluated the effectiveness of acellular dermal regeneration templates (ADRT) in safely healing refractory myelomeningoceles.

Methods:

Seven myelomeningocele repair cases using ADRT (Integra LifeSciences, Plainsboro, NJ) at an academic children’s hospital from April 2020 to June 2023 were reviewed. Patients had unsuccessful closure attempts through fetoscopic, postnatal, or revision surgeries by neurosurgery and plastic surgery, leading to complications that required ADRT to protect the dural repair and promote quicker granulation.

Results:

The case series included 3 male and 4 female patients, with a median delivery age of 37 weeks (IQR: 33–37). Three underwent fetoscopic repairs, and 4 had postnatal repairs within 48 hours of birth. Six patients required ADRT placement due to failed primary repair. One patient failed fetoscopic closure and required immediate ADRT placement following an emergent cesarean delivery. The median wound size covered was 12 cm2 (range, 4–20 cm2), and the median hospital stay was 84 days (IQR: 43–105). Three weeks post-ADRT placement, 4 patients showed healthy granulation tissue, and the external silicone layer was removed. Three patients needed additional ADRT for complete wound coverage and successful granulation. After granulation, all wounds eventually epithelialized by secondary intention, with no postoperative infection or wound dehiscence observed.

Conclusions:

ADRT can aid in wound healing and protect dural repair in myelomeningoceles, offering a viable option for complex or failed primary closures with limited donor tissue.
ICTV Virus Taxonomy Profile: Peribunyaviridae 2024
Authors: de Souza William M. , Calisher Charles H. , Carrera Jean Paul , Hughes Holly R. , Nunes Marcio R. T. , Russell Brandy , Tilson-Lunel Natasha L. , Venter Marietjie , Xia Han
Published: November 2024

Peribunyavirids produce enveloped virions with three negative-sense RNA segments comprising 10.7–12.5 kb in total. The family includes globally distributed viruses in multiple genera. While most peribunyavirids are maintained in geographically restricted vertebrate–arthropod transmission cycles, others are arthropod-specific or do not have a known vector. Arthropods can be persistently infected. Human and other vertebrate animal infections occur through blood feeding by an infected vector arthropod, resulting in diverse human and veterinary clinical outcomes in a strain-specific manner. Reassortment can occur between members of the same genus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Peribunyaviridae, which is available at ictv.global/report/peribunyaviridae.
Genotypic analysis of Shiga toxin-producing Escherichia coli clonal complex 17 in England and Wales, 2014–2022
Authors: Poh Ching-Ying J. , Rodwell Ella V. , Godbole Gauri , Jenkins Claire
Published: November 2024

Introduction. Shiga toxin-producing Escherichia coli (STEC) are zoonotic, gastrointestinal pathogens characterized by the presence of the Shiga toxin (stx) gene. Historically, STEC O157:H7 clonal complex (CC) 11 has been the most clinically significant serotype; however, recently there has been an increase in non-O157 STEC serotypes, including STEC O103:H2 belonging to CC17.

Gap statement. STEC O103:H2 is an STEC serotype frequently isolated in England, although little is known about the epidemiology, clinical significance, associated public health burden or evolutionary context of this strain.

Aim. Surveillance data and whole-genome sequencing data were analysed to determine the microbiological characteristics and public health burden of CC17, including the clinically significant serotype O103:H2, in England and Wales.

Methodology. Isolates of E. coli belonging to CC17 (n=425) submitted to the Gastrointestinal Bacteria Reference Unit from 2014 to 2022 were whole genome sequenced, integrated with enhanced surveillance questionnaire data and analysed retrospectively.

Results. Overall, diagnoses of CC17 infection increased every year since 2014. Most cases were female (58.5%), with the highest proportion of cases belonging to the 0–4 age group (n=83/424, 19.6%). Clinical presentation data identified diarrhoea (92.1%), abdominal pain (72.4%) and blood in stool (55.3%) as the most frequent symptoms, while 20.4% cases were admitted to hospital and 1.3% developed haemolytic uraemic syndrome. The five most common established serotypes were O103:H2 (64.5%), O123:H2 (11.1%), O151:H2 (6.6%), O71:H2 (3.3%) and O4:H2 (2.6%). The majority of CC17 isolates (78.6%) had the stx1a/eae virulence gene combination. Nine outbreak clusters of STEC infections that were mainly geographically dispersed and temporally related were identified and associated with foodborne transmission.

Conclusions. Nationwide implementation of PCR to detect non-O157 STEC and improvements to algorithms for the follow-up of PCR-positive faecal specimens is recommended. Enhanced surveillance is necessary to assess the incidence of CC17 infection and overall burden of this CC within the UK population.
Influence of DNA sequences on thermodynamic and structural stability of ZTA transcription factor - DNA complex: An all-atom molecular dynamics study
Authors: Duraisamy Boobalan , Pramanik Debabrata
Published: November 2024

The Epstein-Barr virus (EBV) is one of the cancer-causing gamma type viruses. Although more than 99% people are infected by this virus at some point, it remains in the body in a latent state, typically causing only minor symptoms. Our current understanding is that a known transcription factor (TF), the ZTA protein, binds with dsDNA (double stranded deoxyribonucleic acid) and plays crucial role in mediating the viral latent-to-lytic cycle through binding of specific ZTA responsive elements (ZREs). However, there is no clear understanding of the effect of DNA sequences on the structural stability and quantitative estimation of the binding affinity between the ZTA TF and DNA, along with their mechanistic details. In this study, we employ integrated classical all-atom molecular dynamics (MD) and enhanced sampling simulations to study the ZTA-dsDNA structural properties, thermodynamics, and mechanistic details for the ZTA protein and for two different dsDNA systems: core motif and core motif with flanking end sequences. For each system, we studied three different ZTA responsive elements (ZREs) sequences: ZRE 1, ZRE 2 and ZRE 3. We performed structural analyses, including RMSD and RMSF calculations, to assess conformational stability, along with detailed interaction profiles and hydrogen bond analysis. We conducted residue-level and nucleic acid-level analyses to assess the important protein residues and DNA bases forming interactions between the ZTA and dsDNA systems. We also explored the effect of adding flanking end sequences to the core motif on DNA groove lengths and interstrand hydrogen bonds. Our results indicate that the flanking sequences surrounding the core motif significantly influence the structural stability and binding affinity of the ZTA-dsDNA complex. Among ZRE 1, ZRE 2, and ZRE 3, particularly when paired with their naturally occurring flanking ends, ZRE 3 exhibits higher stability and binding affinity. These findings provide insights into the molecular mechanisms underlying EBV pathogenesis and may indicate potential targets for therapeutic intervention. A detailed of the binding mechanisms will allow for the design of better-targeted therapies against EBV-associated cancers. This study will serve as a holistic benchmark for future studies on these viral protein interactions.
A non-specialist worker delivered digital assessment of cognitive development (DEEP) in young children: a longitudinal validation study in rural India
Authors: Bhavnani Supriya , Ranjan Alok , Mukherjee Debarati , Divan Gauri , Prakash Amit , Yadav Astha , Lal Chaman , Gajria Diksha , Irfan Hiba , Sharma Kamal Kant , Todkar Smita Dattatraya , Patel Vikram , McCray Gareth
Published: November 2024

Background

Cognitive development in early childhood is critical for life-long well-being. Existing cognitive development surveillance tools require lengthy parental interviews and observations of children. Developmental Assessment on an E-Platform (DEEP) is a digital tool designed to address this gap by providing a gamified, direct assessment of cognition in young children which can be delivered by front-line providers in community settings.

Methods

This longitudinal study recruited children from the SPRING trial in rural Haryana, India. DEEP was administered at 39 (SD 1; N=1359), 60 (SD 5; N=1234) and 95 (SD 4; N=600) months and scores were derived using item response theory. Criterion validity was examined by correlating DEEP-score with age, Bayley’s Scales of Infant Development (BSID-III) cognitive domain score at age 3 and Raven’s Coloured Progressive Matrices (CPM) at age 8; predictive validity was examined by correlating DEEP-scores at preschool-age with academic performance at age 8 and convergent validity through correlations with height-for-age z-scores (HAZ) and early life adversities.

Findings

DEEP-score correlated strongly with age (r=0.83, 95% CI 0.82-0.84) and moderately with BSID-III (r=0.50, 0.39-0.60) and CPM (r=0.37; 0.30 – 0.44). DEEP-score at preschool-age predicted academic outcomes at school-age (0.32; 0.25 – 0.41) and correlated positively with HAZ and negatively with early life adversities.

Interpretation

DEEP provides a valid, scalable method for cognitive assessment. It’s integration into developmental surveillance programs could aid in monitoring and early detection of cognitive delays, enabling timely interventions.

Funding

SPRING, REACH and COINCIDE were funded through Wellcome Trust, Madura Microfinance Ltd and Wellcome Trust/DBT India Alliance respectively.
TomoPicker: Annotation-Efficient Particle Picking in cryo-electron Tomograms
Authors: Uddin Mostofa Rafid , Ahmed Ajmain Yasar , Tahmid Md Toki , Ul Alam Md Zarif , Freyberg Zachary , Xu Min
Published: November 2024

Particle picking in cryo-electron tomograms (cryo-ET) is crucial for in situ structure detection of macro-molecules and protein complexes. The traditional template-matching-based approaches for particle picking suffer from template-specific biases and have low throughput. Given these problems, learning-based solutions are necessary for particle picking. However, the paucity of annotated data for training poses substantial challenges for such learning-based approaches. Moreover, preparing extensively annotated cryo-ET tomograms for particle picking is extremely time-consuming and burdensome. Addressing these challenges, we present TomoPicker, an annotation-efficient particle-picking approach that can effectively pick particles when only a minuscule portion (∼ 0.3 − 0.5%) of the total particles in a cellular cryo-ET dataset is provided for training. TomoPicker regards particle picking as a voxel classification problem and solves it with two different positive-unlabeled learning approaches. We evaluated our method on a benchmark cryo-ET dataset of eukaryotic cells, where we observed about 30% improvement by TomoPicker against the most recent state-of-the-art annotation efficient learning-based picking approaches.
SingleFrag: A deep learning tool for MS/MS fragment and spectral prediction and metabolite annotation
Authors: Pérez-Ribera Maribel , Khan Muhammad Faizan , Giné Roger , Badia Josep M. , Junza Sandra , Yanes Oscar , Sales-Pardo Marta , Guimerà Roger
Published: November 2024

Metabolite and small molecule identification via MS/MS involves matching experimental spectra with prerecorded spectra of known compounds. This process is hindered by the current lack of comprehensive reference spectral libraries. To address this gap, we need accuratein silicofragmentation tools for predicting MS/MS spectra of compounds for which empirical spectra do not exist. Here, we present SingleFrag, a novel deep learning tool that predicts individual fragments separately, rather than attempting to predict the entire fragmentation spectrum at once. Our results demonstrate that SingleFrag surpasses state-of-the-artin silicofragmentation tools, providing a powerful method for annotating unknown MS/MS spectra of known compounds. As a proof of concept, we successfully annotate three previously unidentified compounds frequently found in human samples.
Chlorpyrifos induces lung metastases and modulation of cancer stem cell markers in triple negative breast cancer model
Authors: Lasagna Marianela , Mardirosian Mariana , Zappia Daniel , Enriquez Lucia , Miret Noelia , Dahir Lara , Zotta Elsa , Randi Andrea , Núñez Mariel , Cocca Claudia
Published: November 2024

Breast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in anin vivotriple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and BCSC markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in anin vivomodel induced in mice.
Inhibition of p38-MK2 pathway enhances the efficacy of microtubule inhibitors in breast cancer cells
Authors: Chen Yu-Chia , Takada Mamoru , Nagornyuk Aerica , Muhan Wu , Yamada Hideyuki , Nagashima Takeshi , Ohtsuka Masayuki , DeLuca Jennifer G. , Markus Steven , Takaku Motoki , Suzuki Aussie
Published: November 2024

Microtubule-targeting agents (MTAs) have been successfully translated from basic research into clinical therapies and have been widely used as first- and second-line chemotherapy drugs for various cancers. However, current MTAs exhibit positive responses only in subsets of patients and are often accompanied by side effects due to their impact on normal cells. This underscores an urgent need to develop novel therapeutic strategies that enhance MTA efficacy while minimizing toxicity to normal tissues. In this study, we demonstrate that inhibition of the p38-MK2 (MAP kinase-activated protein kinase 2) pathway sensitizes cancer cells to MTA treatment. We utilize CMPD1, a dual-target inhibitor, to concurrently suppress the p38-MK2 pathway and microtubule dynamicity. In addition to established role as an MK2 inhibitor, we find that CMPD1 rapidly induces microtubule depolymerization, preferentially at the microtubule plus-end, leading to the inhibition of tumor growth and cancer cell invasion in bothin vitroandin vivomodels. Notably, 10 nM CMPD1 is sufficient to induce irreversible mitotic defects in cancer cells, but not in non-transformed RPE1 cells, highlighting its high specificity to cancer cells. We further validate that a specific p38-MK2 inhibitor significantly potentiates the efficacy of sub-clinical concentrations of MTA. In summary, our findings suggest that the p38-MK2 pathway presents a promising therapeutic target in combination with MTAs in cancer treatment.
Disconnect betweenin vitroandin vivoefficacy of the MPS1 inhibitor NTRC 0066-0 against glioblastoma
Authors: de Gooijer Mark C. , Zhang Ping , Buil Levi C.M. , Çitirikkaya Ceren H. , Çolakoğlu Hilal , Maia Ana Rita R. , Bočkaj Irena , Espitia-Ballestas Margarita , Kuil Laura E. , Beijnen Jos H. , van Tellingen Olaf
Published: November 2024

Purpose

Glioblastoma (GBM) is the most common adult primary brain tumor for which new therapeutic strategies are desperately needed. Monopolar spindle 1 (MPS1) is a mitotic kinase that plays a pivotal role in the spindle assembly checkpoint (SAC). GBM appears to be dependent on SAC fidelity, as MPS1 is overexpressed in many GBM patients. Thus, inhibiting MPS1 seems a viable therapeutic strategy to enhance mitotic cell death by attenuating SAC fidelity. NTRC 0066-0 is an MPS1 inhibitor that combines low nanomolar potency with a relatively long on-target residence time.

Methods

We here investigate the potential of NTRC 0066-0 as monotherapy and in combination with chemo-radiation for treatment of GBM using variousin vitroand orthotopicin vivomodels.

Results

We show that NTRC 0066-0 efficiently induces GBM cell deathin vitro, following continuous exposure with IC50s in the low nanomolar range. In contrast to previous reports of studies with other MPS1 inhibitors, we did not observe synergyin vitrowith anti-microtubule drugs, such as docetaxel and vincristine. We demonstrate that NTRC 0066-0 has a high brain penetration, despite being a substrate of the efflux transporter P-glycoprotein. However, even when using recipientAbcb1a/b;Abcg2-/-mice with superior brain penetration and administering NTRC 0066-0 using a dose-dense regimen, we did not observe antitumor efficacy against an orthotopic GBM mouse model, neither as monotherapy nor in combination with standard-of-care temozolomide chemotherapy and radiotherapy.

Conclusion

These data indicate that GBM is probably not a suitable indication for developing MPS1 inhibitors.
Amino acid properties, substitution rates, and the nearly neutral theory
Authors: James Jennifer E. , Lascoux Martin
Published: November 2024

Do the properties of amino acids affect their rates of substitution? The nearly neutral theory predicts that greater selective constraint leads to slower rates of evolution; similarly, we expect amino acids that are more different from each other to have lower rates of exchange because such changes are most likely to affect protein structure and function. Here we test these predictions, using substitution rates estimated from empirical amino acid exchangeability matrices. To measure degree of amino acid difference, we focussed on two physicochemical properties, hydrophobicity and molecular weight, uncorrelated metrics that are known to have important implications for protein structure and function. We find that for both hydrophobicity and molecular weight, amino acid pairs with large differences had lower rates of substitution. We also found that amino acids that differed in both properties had the lowest rates of substitution, suggesting that both physicochemical properties are under selective constraint. Mutation properties, such as the number of mutations or the number of transitions as opposed to transversions separating amino acid pairs, were also important predictors of substitution rates. The relationship between amino acid substitution rates and differences in their physiochemical properties holds across several taxonomically restricted datasets. This finding suggests that purifying selection affects amino acid substitution rates in a similar manner across taxonomic groups with different effective population sizes.
Platelet-specific P2Y1receptor deficient mice have suppressed leukocyte recruitment in response to lipopolysaccharide
Authors: Pan Dingxin , Oralman Tolga , Evans Reah , Baker Oliver , Cocks Graham , Page Clive P. , Pitchford Simon C.
Published: November 2024

A role for the P2Y1receptor in inflammation has been established using a pharmacological approach over an acute 4 hour time span. However, nucleotide-structure P2Y1receptor antagonists have limited experimental use due to inadequate pharmacokinetics, and inability to decipher global versus cell specific effectsin vivo. The creation of a conditional knock out (platelet) P2Y1transgenic mouse model was designed to overcome these restrictions.

A homozygous P2Y1LoxPmouse colony was created using CRISPR/Cas9 technology, and crossed with a hemizygous P2Y1LoxPwith PF4-cre to provide offspring that are homozygous for P2Y1LoxPflanked allele, and hemizygous for the PF4cre (platelet P2Y1-/-) and offspring homozygous for P2Y1LoxPflanked allele, but non-carriers for PF4cre (control mice). Animals were intranasally administered LPS to induce pulmonary inflammation to assess the influence of phenotype on leukocyte recruitment.

24 hours post intranasal LPS administration; pulmonary neutrophil and platelet recruitment were significantly suppressed, despite the fact that neutrophils retained the ability to migrate to fMLPex vivo. Circulating platelet and leukocyte numbers were not different between control and platelet P2Y1-/-animals. Tail bleeding times revealed the platelet P2Y1-/-mice had a severe bleeding phenotype.

This is the first demonstration of a platelet specific P2Y1-/-mouse model to confirm the importance of platelet P2Y1receptors in the regulation of inflammatory responses with a 60-70% inhibition of leukocyte recruitment over an extended time period compared to previous pharmacological studies. platelet P2Y1-/-mice will help further elucidate the mechanisms by which P2Y1receptors regulate platelet activation during inflammation.

Key Points

Mice selectively deficient in the platelet P2Y1have suppressed leukocyte and platelet recruitment during inflammation.

We provide a methodology to determine mechanistic relevance that is otherwise limited by pharmacological approaches.
Septins regulate heart contractility through modulation of cardiomyocyte store-operated calcium entry
Authors: Tripoli Benjamin A. , Smyth Jeremy T.
Published: November 2024

Highly regulated cardiomyocyte Ca2+fluxes drive heart contractions. Recent findings from multiple organisms demonstrate that the specific Ca2+transport mechanism known as store-operated Ca2+entry (SOCE) is essential in cardiomyocytes for proper heart function, and SOCE dysregulation results in cardiomyopathy. Mechanisms that regulate SOCE in cardiomyocytes are poorly understood. Here we tested the role of cytoskeletal septin proteins in cardiomyocyte SOCE regulation. Septins are essential SOCE modulators in other cell types, but septin functions in cardiomyocytes are nearly completely unexplored. We show using targeted genetics and intravital imaging of heart contractility inDrosophilathat cardiomyocyte-specific depletion of septins 1, 2, and 4 results in heart dilation that phenocopies the effects of SOCE suppression. Heart dilation caused by septin 2 depletion was suppressed by SOCE upregulation, supporting the hypothesis that septin 2 is required in cardiomyocytes for sufficient SOCE function. A major function of SOCE is to support SERCA-dependent sarco/endoplasmic reticulum (S/ER) Ca2+stores, and augmenting S/ER store filling by SERCA overexpression also suppressed the septin 2 phenotype. We also ruled out several potential SOCE-independent septin functions, as septin 2 phenotypes were not due to septin function during development and septin 2 was not required for z-disk organization as defined by α-actinin labeling. These results demonstrate, for the first time, an essential role of septins in cardiomyocyte physiology and heart function that is due, at least in part, to septin regulation of SOCE function.
A common garden ofHalichondriasponges: taxonomic revision of Northeast Pacific Halichondriidae reveals many cryptic introduced species
Authors: Turner Thomas L. , Morrow Christine , Picton Bernard , Goodwin Claire , Thacker Robert W.
Published: November 2024

Sponges (phylum Porifera) possess biochemical, cellular, and physiological traits with valuable biotechnical applications. However, our ability to harness these natural innovations is limited by a classification system that does not fully reflect their evolutionary history. In this study, we uncover numerous cryptic species within the genusHalichondriathat are morphologically indistinguishable from the well-knownH. panicea. Many of these species have habitat preferences and geographic distributions that strongly suggest they have been dispersed by human activity. Most of these species are broadly sympatric with their closest relatives, and these overlapping distributions allow us to use patterns of DNA variation to infer reproductive isolation between clades in nature. With reproductively isolated species thus delineated, we can use DNA states as taxonomic characters to formally describe them. Though much remains to be learned about these newly discovered species, the natural “common gardens” of introduced sponges in California, New York, and other locations provide opportunities to test hypotheses about their diversification in future work.
Shapes of Plasma Membrane Vesicles and PC-Cholesterol Vesicles Reveal Their Effective Spontaneous Curvature
Authors: Kaur Harshmeet , Pandey Tanmay , Bhatia Tripta
Published: November 2024

Giant membrane vesicles (GUVs) and giant plasma membrane vesicles (GPMVs) are useful models for studying cellular membrane properties. Our research analyzed the reduced volume of vesicles made from phospholipid and 10% cholesterol to investigate transbilayer sugar asymmetries. We found that GPMVs have an average reduced volume of (0.88±0.06) with buffer asymmetry of 323 mM, lower than the (0.92±0.08) observed for DOPC: cholesterol vesicles with sucrose/glucose asymmetry of 390 mM. GUVs with different sugars inside and outside were more deflated, demonstrating a greater volume reduction than those with the same sugar inside and out. We applied the area-difference elasticity (ADE) model to map GPMVs and used the spontaneous curvature (SC) model to analyze DOPC: cholesterol GUVs, extracting spontaneous curvature based on their reduced volume.

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Highly efficientXISTreactivation in female hPSC by transient dual inhibition of TP53 and DNA methylation during Cas9 mediated genome editing
Authors: Motosugi Nami , Hasegawa Keita , Kurosaki Natsumi , Kawaguchi Erika , Izumi Kenji , Iida Yumi , Higashiseto Misaki , Yokoyama Keiko , Sasaki Ayumi , Nakabayashi Kazuhiko , Fukuda Atsushi
Published: November 2024

Erosion of X-chromosome inactivation (XCI) complicates disease and developmental modeling in female human pluripotent stem cells (hPSCs). Previous studies demonstrated that Cas9-mediated editing of theXISTpromotervianon-homologous end joining (NHEJ) or homology-directed repair (HDR) with a selection cassette upstream ofXISTcan trigger DNA demethylation andXISTreactivation, restoring XCI. Here, we show that NHEJ-mediated XCI reacquisition is more stable during differentiation than HDR. We further developed a novel, efficientXISTreactivation method by combining TP53 inhibition with DNA methylation maintenance suppression during Cas9-mediated NHEJ, offering a robust approach to achieving stable XCI in female hPSCs for diverse applications.
Accurate Detection of Tandem Repeats from Error-Prone Sequences with EquiRep
Authors: Song Zhezheng , Zahin Tasfia , Li Xiang , Shao Mingfu
Published: November 2024

A tandem repeat is a sequence of nucleotides that occurs as multiple contiguous and near-identical copies positioned next to each other. These repeats play critical roles in genetic diversity, gene regulation, and are strongly linked to various neurological and developmental disorders. While several methods exist for detecting tandem repeats, they often exhibit low accuracy when the repeat unit length increases or the number of copies is low. Furthermore, methods capable of handling highly mutated sequences remain scarce, highlighting a significant opportunity for improvement. We introduce EquiRep, a tool for accurate detection of tandem repeats from erroneous sequences. EquiRep estimates the likelihood of positions originating from the same position in the unit by self-alignment followed by a novel approach that refines the estimation. The built equivalent classes and the consecutive position information will be then used to build a weighted graph, and the cycle in this graph with maximum bottleneck weight while covering most nucleotide positions will be identified to reconstruct the repeat unit. We test EquiRep on simulated and real HOR and RCA datasets where it consistently outperforms or is comparable to state-of-the-art methods. EquiRep is robust to sequencing errors, and is able to make better predictions for long units and low frequencies which underscores its broad usability for studying tandem repeats.
Nascent transcript O-MAP reveals the molecular architecture of a single-locus subnuclear compartment built by RBM20 and theTTNRNA
Authors: Kania Evan E. , Fenix Aidan , Marciniak Daphnée M. , Lin Qiaoyi , Bianchi Sara , Hristov Borislav , Li Shuai , Camplisson Conor K. , Fields Rose , Beliveau Brian J. , Schweppe Devin K. , Noble William S. , Ong Shao-En , Bertero Alessandro , Murry Charles E. , Shechner David M.
Published: November 2024

Eukaryotic nuclei adopt a highly compartmentalized architecture that influences nearly all genomic processes. Understanding how this architecture impacts gene expression has been hindered by a lack of tools for elucidating the molecular interactions at individual genomic loci. Here, we adapt oligonucleotide-mediated proximity-interactome mapping (O-MAP) to biochemically characterize discrete, micron-scale nuclear neighborhoods. By targeting O-MAP to introns within theTTNpre-mRNA, we systematically map the chromatin loci, RNAs, and proteins within a muscle-specific RNA factory organized around theTTNlocus. This reveals an unanticipated compartmental architecture that organizescis- andtrans-interacting chromosomal domains, including a hub of transcriptionally silenced chromatin. The factory also recruits dozens of unique RNA-binding and chromatin-scaffolding factors, including QKI and SAFB, along with their target transcripts. Loss of the cardiac-specific splicing factor RBM20—a master regulator ofTTNsplicing that is mutated in dilated cardiomyopathy—remodels nearly every facet of this architecture. This establishes O-MAP as a pioneering method for probing single-locus, microcompartment-level interactions that are opaque to conventional tools. Our findings suggest new mechanisms by which coding genes can "moonlight" in nuclear-architectural roles.
Hantaan virus-derived peptides that stabilize HLA-E could abrogate inhibition of CD56dimNKG2A+NK cells
Authors: Xue Manling , Tang Kang , Zhang Yusi , Xu Xiaoyue , Zhang Chunmei , Zuo Jiajia , Wang Fenglan , Zhang Xiyue , Zheng Xuyang , Zhuang Ran , Zhang Yun , Jin Boquan , Ma Ying
Published: November 2024

NK cells could participate in the pathogenesis process of virus infectious diseases through the inhibitory receptor CD94/NKG2A interacting with HLA-E/virus-derived peptide complex. However, the effects and mechanisms of NKG2A-HLA-E axis-mediated NK cell responses in hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus (HTNV) infection remain unclear. Single-cell RNA sequencing and flow cytometry were employed to analyze the phenotype and function of different NK cell subsets in HFRS patients. The K562/HLA-E cells binding assay was used for peptide affinity detection. The binding capacity of HLA-E/peptide-CD94/NKG2A was detected using ligand-receptor binding assay and tetramer staining. The cytotoxicity assay of NK cells against peptide-pulsed K562/HLA-E cells was conducted for functional evaluation. In this study, CD56dimCD16+NKG2A+NK cells were the main subset in HFRS patients, showing activation and proliferation phenotypes with NKG2C−CD57−and the ability to secrete cytokines and cytotoxic mediators. Notably, none of the four identified HTNV epitopes presented by HLA-E could be recognized by CD94/NKG2A on CD56dimNKG2A+NK cells. Furthermore, the subset of CD56dimNKG2A+NK cells showed the enhanced cytolytic capacity against HTNV peptide pulsed K562/HLA-E cells ex vivo. Taken together, the findings demonstrate that HTNV-derived peptides presented by HLA-E could “abrogate” the inhibition of CD56dimNKG2A+NK cells, contributing to the antiviral immune response in HFRS patients.

Author Summary

Hantaan virus (HTNV) is one of the main pathogens causing hemorrhagic fever with renal syndrome (HFRS) characterized by fever, hemorrhage, renal injury, and thrombocytopenia. Recently, the studies have shown that the interaction of human leukocyte antigen E (HLA-E) and natural-killer group 2, member A (NKG2A) inhibitory receptors could regulate the functions of NK cells, participating the pathogenesis process of virus infectious diseases. However, the role of NK cell response induced by HTNV infection in the pathogenesis of HFRS has not been completely determined. Here, the findings demonstrate that the elevated percentage of CD56dimNKG2A+NK cell subset in peripheral blood of HFRS patients might exert antiviral effects through the unrecognize between CD94/NKG2A and HLA-E/HTNV peptide complex, which may abrogate the inhibition of NKG2A-expressing NK cells. This study may provide the mechanisms of NKG2A-HLA-E axis on regulating NK cell responses in HTNV infections.
Bioclimatic modelling of the spread of the West Nile virus in Europe, with a special focus on Ukraine
Authors: Mezhzherin S.V. , Tytar V.M. , Kozynenko I.I.
Published: November 2024

West Nile virus (WNV) is a re-emerging zoonotic pathogen transmitted by mosquitoes and causes fever and encephalitis in humans, equines, and birds.While all WNV lineages can cause human illness, the lineage WNV2 has gained particular attention in Europe due to its rapid spread and potential for causing severe disease, with large outbreaks happening in summer months.While WNV is not as prevalent in Ukraine as in some other regions of Europe, outbreaks do occur periodically. This is becoming an alarming trend. In this study we focused on the ability of bioclimatic predictors to envisage WNV outbreaks in Europe, making a special emphasis on Ukraine. For this purpose we employ a machine learning methodology for drawing predictions and the SHAP framework from XAI (i.e., eXplainable artificial intelligence) to rank and uncover the most influential WNV drivers.In terms of bioclimatic predictors, the most important for SDM constructions at the European scale was the mean daily air temperature of the coldest quarter and temperature seasonality for Ukraine. Our model suggests that under an impending health threat are areas in the west (excluding the Carpathian highlands) and south of Ukraine.
Integrative metagenomics and metabolomics reveal age-associated gut microbiota and metabolite alterations in experimental COVID-19
Authors: Rodrigues Patrícia Brito , de Rezende Rodovalho Vinícius , Sencio Valentin , Benech Nicolas , Creskey Marybeth , Silva Angulo Fabiola , Delval Lou , Robil Cyril , Gosset Philippe , Machelart Arnaud , Haas Joel , Descat Amandine , Goosens Jean François , Beury Delphine , Maurier Florence , Hot David , Wolowczuk Isabelle , Sokol Harry , Zhang Xu , Ramirez Vinolo Marco Aurélio , Trottein François
Published: November 2024

Aging is a key contributor of morbidity and mortality during acute viral pneumonia. The potential role of age-associated dysbiosis on disease outcomes is still elusive. In the current study, we used high-resolution shotgun metagenomics and targeted metabolomics to characterize SARS-CoV-2-associated changes in the gut microbiota from young (2-month-old) and aged (22-month-old) hamsters, a valuable model of COVID-19. We show that age-related dysfunctions in the gut microbiota are linked to disease severity and long-term sequelae in older hamsters. Our data also reveal age-specific changes in the composition and metabolic activity of the gut microbiota during both the acute phase (day 7 post-infection, D7) and the recovery phase (D22) of infection. Aged hamsters exhibited the most notable shifts in gut microbiota composition and plasma metabolic profiles. Through an integrative analysis of metagenomics, metabolomics, and clinical data, we identified significant associations between bacterial taxa, metabolites and disease markers in the aged group. On D7 (high viral load and lung epithelial damage) and D22 (body weight loss and fibrosis), numerous amino acids, amino acid-related molecules, and indole derivatives were found to correlate with disease markers. In particular, a persistent decrease in phenylalanine, tryptophan, glutamic acid, and indoleacetic acid in aged animals positively correlated with poor recovery of body weight and/or lung fibrosis by D22. In younger hamsters, several bacterial taxa (Eubacterium,Oscillospiraceae,Lawsonibacter) and plasma metabolites (carnosine and cis-aconitic acid) were associated with mild disease outcomes. These findings support the need for age-specific microbiome-targeting strategies to more effectively manage acute viral pneumonia and long-term disease outcomes.
Nanoparticle-Supported, Rapid, Digital Quantification of Neutralizing Antibodies Against SARS-CoV-2 Variants
Authors: Mirjalili Seyedsina , Ikbal Md Ashif , Hou Ching-Wen , Mohammadi Maziyar Kalateh , Choi Yeji , Kelbauskas Laimonas , VanBlargan Laura A. , Hogue Brenda G. , Murugan Vel , Diamond Michael S. , Wang Chao
Published: November 2024

The measurement of neutralizing immune responses to viral infection is essential, given the heterogeneity of human immunity and the emergence of new virus strains. However, neutralizing antibody (nAb) assays often require high-level biosafety containment, sophisticated instrumentation, and long detection times. Here, as a proof-of-principle, we designed a nanoparticle-supported, rapid, electronic detection (NasRED) assay to assess the neutralizing potency of monoclonal antibodies (mAbs) against SARS-CoV-2. The gold nanoparticles (AuNPs) coated with human angiotensin-converting enzyme 2 (ACE2) protein as nAb potency reporters were mixed with the mAbs to be tested, as well as streptavidin-conjugated multivalent spike (S) protein or their receptor binding domains (RBD). High-affinity and ACE2-competitive nAbs alter the S (or RBD)-to-ACE2 binding level and modulate AuNP cluster formation and precipitation. The amount of free-floating AuNP reporters is quantified by a semiconductor-based readout system that measures the AuNPs’ optical extinction, producing nAb signals that can differentiate SARS-CoV-2 variants (Wuhan-Hu-1, Gamma, and Omicron). The modular design nature, short assay time (less than 30 minutes), and portable and inexpensive readout system make this NasRED-nAb assay applicable to measuring vaccine potency, immune responses to infection, and the efficacy of antibody-based therapies.
Reproducible processing of TCGA regulatory networks
Authors: Fanfani Viola , Shutta Katherine H. , Mandros Panagiotis , Fischer Jonas , Saha Enakshi , Micheletti Soel , Chen Chen , Ben Guebila Marouen , Lopes-Ramos Camila M. , Quackenbush John
Published: November 2024

Background

Technological advances in sequencing and computation have allowed deep exploration of the molecular basis of diseases. Biological networks have proven to be a useful framework for interrogating omics data and modeling regulatory gene and protein interactions. Large collaborative projects, such as The Cancer Genome Atlas (TCGA), have provided a rich resource for building and validating new computational methods resulting in a plethora of open-source software for downloading, pre-processing, and analyzing those data. However, for an end-to-end analysis of regulatory networks a coherent and reusable workflow is essential to integrate all relevant packages into a robust pipeline.

Findings

We developed tcga-data-nf, a Nextflow workflow that allows users to reproducibly infer regulatory networks from the thousands of samples in TCGA using a single command. The workflow can be divided into three main steps: multi-omics data, such as RNA-seq and methylation, are downloaded, preprocessed, and lastly used to infer regulatory network models with the netZoo software tools. The workflow is powered by the NetworkDataCompanion R package, a standalone collection of functions for managing, mapping, and filtering TCGA data. Here we show how the pipeline can be used to study the differences between colon cancer subtypes that could be explained by epigenetic mechanisms. Lastly, we provide pre-generated networks for the 10 most common cancer types that can be readily accessed.

Conclusions

tcga-data-nf is a complete yet flexible and extensible framework that enables the reproducible inference and analysis of cancer regulatory networks, bridging a gap in the current universe of software tools.
PLM-interact: extending protein language models to predict protein-protein interactions
Authors: Liu Dan , Young Francesca , Lamb Kieran D. , Claudio Quiros Adalberto , Pancheva Alexandrina , Miller Crispin , Macdonald Craig , Robertson David L , Yuan Ke
Published: November 2024

Computational prediction of protein structure from amino acid sequences alone has been achieved with unprecedented accuracy, yet the prediction of protein-protein interactions (PPIs) remains an outstanding challenge. Here we assess the ability of protein language models (PLMs), routinely applied to protein folding, to be retrained for PPI prediction. Existing PPI prediction models that exploit PLMs use a pre-trained PLM feature set, ignoring that the proteins are physically interacting. Our novel method, PLM-interact, goes beyond a single protein, jointly encoding protein pairs to learn their relationships, analogous to the next-sentence prediction task from natural language processing. This approach provides a significant improvement in performance: Trained on human-human PPIs, PLM-interact predicts mouse, fly, worm,E. coliand yeast PPIs, with 16-28% improvements in AUPR compared with state-of-the-art PPI models. Additionally, it can detect changes that disrupt or cause PPIs and be applied to virus-host PPI prediction. Our work demonstrates that large language models can be extended to learn the intricate relationships among biomolecules from their sequences alone.
Data Resource Profile: Genomic Data in Multiple British Birth Cohorts (1946-2001)—Health, Social, and Environmental Data from Birth to Old Age
Authors: Shireby Gemma , Morris Tim T , Wong Andrew , Chaturvedi Nish , Ploubidis George B , Fitzsimmons Emla , Goodman Alissa , Sanchez-Galvez Adelaida , Davies Neil M , Wright Liam , Bann David
Published: November 2024

Birth cohort studies have a rich history of contributing to science across disciplinary fields, notably health and social sciences. Here, we introduce a curated resource comprising genomic data from five British birth cohort studies—longitudinal studies with extensive data collected prospectively across life, each deliberately sampled to be nationally representative (born 1946–2001). These contain health and social data from birth to older age, enabling longitudinal and cross-cohort genetically informed research. The Millennium Cohort Study additionally includes data on parents and offspring, enabling within-family analyses. Across five cohorts born in 1946, 1958, 1970, 1989–90, and 2000–2002, 27,432 participants have harmonized, imputed, and quality-controlled genetic data from genotyping arrays covering 6.7 million common SNPs. The Millennium Cohort Study contains over 6,000 mother-offspring pairs and over 3,000 mother-father-offspring trios. Pseudonymized data are freely available to the global research community upon approval of a data access request (https://cls.ucl.ac.uk/data-access-training).