bluuebunny/crossref_metadata_2025 huggingface dataset:
Socio-economic status and outcomes after transcatheter aortic valve implantation: a systematic review and meta-analysis
Authors: Verhemel Sarah , Protty Majd , Ruparelia Neil , Hailan Ahmed , Chase Alexander , Khawaja Saud , Hadjiloizou Nearchos , Malik Iqbal , Mikhail Ghada , Khamis Ramzi , Hartley Adam
Published: January 2025

Background

Transcatheter aortic valve implantation (TAVI) procedures to treat severe aortic stenosis are rising, in line with aging populations and advancements in healthcare access. Economic development correlates with AS mortality rates. Socio-economic status (SES), defined by social and economic factors such as median household income, significantly influences cardiovascular outcomes. This study analyses the impact of SES on TAVI outcomes.

Methods

Following PRISMA guidelines, a comprehensive search was conducted across PubMed, Medline, Embase, Cochrane,ClinicalTrials.govand Google Scholar, including literature up to August 1, 2024. The search employed keywords related to SES and TAVI. Of 393 identified studies, 127 were selected for full-text review, with ten addressing SES effects post-TAVI. Most studies had a retrospective design.

Results

The patient cohort comprised 319,557 individuals, (144,583 from low SES backgrounds and 174,974 from high SES backgrounds). The analysis revealed a higher burden of comorbidities in low SES patients. Post-TAVI, lower SES related to increased 30-day mortality, major adverse cardiovascular events and the need for pacemaker implantation, although it did not affect in-hospital mortality or 30-day readmission rates.

Conclusion

These findings underscore the substantial socio-economic disparities in TAVI outcomes and highlight the need for specific interventions to improve care for patients from less advantaged backgrounds.

Key Learning Points

A.

What is already known

Lower SES negatively impacts cardiovascular outcomes due to disparities in healthcare access and comorbidities.

TAVI is the standard treatment for severe aortic stenosis, especially in elderly patients.

SES influences outcomes in cardiovascular procedures, but its impact on TAVI was unclear.

B.

What this study adds

Low SES increases 30-day mortality, MACE, and pacemaker implantation rates after TAVI.

SES does not affect in-hospital mortality or 30-day readmissions.

Highlights the need for standardized SES metrics in TAVI research.
Multicancer analyses of short tandem repeat variations reveal shared gene regulatory mechanisms
Authors: Xia Feifei , Verbiest Max , Lundström Oxana , Sonay Tugce Bilgin , Baudis Michael , Anisimova Maria
Published: January 2025

Background

Short tandem repeats (STRs) have been reported to influence gene expression across various human tissues. While STR variations are enriched in colorectal (CRC), stomach (STAD) and endometrial (UCEC) cancers, particularly in microsatellite instable (MSI) tumors, their functional effects and regulatory mechanisms on gene expression remain poorly understood across these cancer types.

Results

Here, we leverage whole-exome sequencing and gene expression data to identify STRs for which repeat lengths are associated with the expression of nearby genes (eSTRs) in CRC, STAD and UCEC tumors. Our analyses reveal that tumor STR profiles effectively capture both MSI phenotype and population structure. While most eSTRs are cancer-specific, shared eSTRs across multiple cancers exhibit consistent effects on gene expression. Notably, coding-region eSTRs identified in all three cancer types show positive correlations with nearby gene expression. We further validate the functional effects of eSTRs by demonstrating associations between somatic eSTR mutations and gene expression changes during the transition from normal to tumor tissues, suggesting their potential roles in tumorigenesis. Combined with DNA methylation data, we perform the first quantitative analysis of the interplay between STR variations and DNA methylation in tumors. We identify eSTRs where repeat lengths are associated with methylation levels of nearby CpG sites (meSTRs) and show that over 70% of eSTRs are significantly linked to local DNA methylation. Importantly, the effects of meSTRs on DNA methylation remain consistent across cancer types.

Conclusions

Overall, our findings enhance the understanding of how functional STR variations influence gene expression and DNA methylation. Our study highlights shared regulatory mechanisms of STRs across multiple cancers, offering a foundation for future research into their broader implications in tumor biology.
Wnt signaling drives stromal inflammation in inflammatory arthritis
Authors: Mueller Alisa A. , Zou Angela E. , Marsh Lucy-Jayne , Kemble Samuel , Nayar Saba , Watts Gerald F.M. , Murphy Cassandra L. , Taylor Emily , Major Triin , Gardner David , Buckley Christopher D. , Wei Kevin , Raychaudhuri Soumya , Korsunsky Ilya , Filer Andrew , Croft Adam P. , Brenner Michael B.
Published: January 2025

The concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation. Yet, therapeutic agents specifically targeting fibroblasts are not available. Here, we find that Wnt receptors and modulators are predominantly expressed in stromal populations in the synovium. Importantly, non-canonical Wnt activation induces robust inflammatory gene expression including an abundance of cytokines and chemokines in synovial fibroblastsin vitro. Strikingly, the addition of Wnt ligands or inhibition of Wnt secretion exacerbates or reduces arthritis severity, respectively,in vivoin a murine model of inflammatory arthritis. These observations are relevant in human disease, as Wnt activation signatures are enhanced in fibroblasts derived from inflamed RA synovial tissue as well as fibroblasts across other inflammatory diseases. Together, these findings implicate Wnt signaling as a major driver of fibroblast-mediated inflammation and joint pathology. They further suggest that targeting the Wnt pathway is a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments and who often express fibroblast-predominant synovial phenotypes.
Ramp sequence may explain synonymous variant association with Alzheimer’s disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA)
Authors: Miller Justin B. , Brandon J. Anthony , McKinnon Lauren M. , Sabra Hady W. , Lucido Chloe C. , Gonzalez Murcia Josue D. , Nations Kayla A. , Payne Samuel H. , Ebbert Mark T.W. , Kauwe John S.K. , Ridge Perry G.
Published: January 2025

BACKGROUND

Synonymous variantNC_000007.14:g.100373690T>C(rs2405442:T>C) in the Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) gene was previously associated with decreased risk for Alzheimer’s disease (AD) in genome-wide association studies, but its biological impact is largely unknown.

OBJECTIVE

We hypothesized thatrs2405442:T>Cdecreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5’ end ofPILRA.

METHODS

We assessedrs2405442:T>Cpredicted effects onPILRAthrough quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells.

RESULTS

Both mRNA (P=1.9184 × 10−13) and protein (P=0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on destroying a ramp sequence.

CONCLUSIONS

We show thatrs2405442:T>Calone directly impactsPILRAmRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.

Research in Context

Systematic review:Genetic variants identified through genome-wide association studies often lack biological support for their association with Alzheimer’s disease. Although synonymous variantrs2405442:T>CinPILRAwas previously reported as protective against Alzheimer’s disease, its effects have generally been attributed to linkage with missense variant,rs1859788:A>G.

Interpretation:We show thatrs2405442:T>Calone decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the beginning ofPILRA. We also show that a ramp sequence is present inPILRAand likely regulates mRNA and protein levels, thus offering a plausible biological mechanism explainingrs2405442:T>Cassociation with Alzheimer’s disease independent ofrs1859788:A>G.

Future directions:We provide the first protocol to evaluate how disease-associated variants impact ramp sequences, which could explain why some genetic variants are reported by genome-wide association studies. Future studies might examine if the ramp sequence could be therapeutically targeted to regulatePILRAexpression without changing the protein product.
Maximizing Nature-based Solutions using Artificial Intelligence to align global biodiversity, climate, and water targets
Authors: Alejo Camilo , Luers Amy , Ventimiglia Andréa , Matthews H. Damon
Published: January 2025

Nature-based Solutions (NbS) can represent holistic pathways to reach sustainable biodiversity, climate, and water outcomes through conservation and restoration. Yet, existing prioritization frameworks rarely identify holistic NbS that maximize these outcomes. Here, we present an AI-driven framework that prioritizes NbS locations, maximizing biodiversity protection with ecological intactness, carbon storage, and water surface stability. We implement this framework through scenarios combining specific biodiversity and co-benefits outcomes to achieve Canada’s 30×30 conservation and restoration targets. Our results reveal inevitable environmental trade-offs and critical implications for equitable NbS and extractive activities. To achieve conservation targets, protecting threatened biodiversity and irrecoverable carbon storage in forests would effectively address trade-offs and enhance Protected Areas outcomes. However, minimizing trade-offs to achieve restoration targets will require targeted interventions in existing forested and agricultural lands. These findings demonstrate that frameworks integrating AI and biodiversity-co-benefit scenarios reveal strategic land use planning, policies, and investments for holistic NbS.
Off-target genomic effects in MRP8-Cre driver mice complicate its use in weight gain and metabolic studies
Authors: Soltani Fatemeh , Duval Cedric , Ariëns Robert A. S. , Kaartinen Mari T.
Published: January 2025

Background

Thromboinflammation of adipose tissue involves accumulation of pro-fibrinogenic factors to adipose tissue in obesity, which promotes immune cell infiltration, affects weight gain and can lead to metabolic dysfunction. The role of neutrophil genes in inflammation are frequently investigated using MRP8-Cre mice to generate neutrophil-specific knockouts. Recent study demonstrated that MRP8-Cre mice have off-target deletions inSerpine1andAp1s1genes.Serpine1, encoding plasminogen activator inhibitor-1, is a key anti-fibrinolytic factor linked to thromboinflammation and metabolic dysfunctions in obesity. In this study, we provide evidence suggesting a critical limitation in using MRP8-Cre model to study adipose tissue, weight-related dysfunctions and/or metabolic disorders.

Methods

MRP8-Cre andF13a1-/-MRP8mice were placed on either control diet or high-fat diet for 16 weeks, with body weight monitored weekly. The expression ofSerpine 1, Ap1s1andAdgre1(macrophage marker) genes in inguinal and epididymal adipose tissues were analyzed using qRT-PCR and compared to the wild-type mice.

Results

MRP8-Cre shows noSerpine1orAp1s1expression in inguinal and epididymal adipose tissues. MRP8-Cre mouse is resistant to weight gain on obesogenic diet and does not show macrophage marker in adipose tissue compared to control obesity model. The resistance to weight gain translates to a neutrophil knockout model,F13a1-/-MRP8that was not expected to show resistance to weight gain as its global knockout does not exhibit this phenotype.

Conclusion

Our work suggests that MRP8-Cre model may not be suitable to investigate metabolic outcomes of neutrophil genes, or pathologies that have underlying etiology in thomboinflammation.
Clonality, specificity, and HLA restriction of human T cell receptors againstPlasmodium falciparumCSP
Authors: van Dijk Hannah , Wahl Ilka , Kraker Sara , Robben Paul M. , Dutta Sheetij , Wardemann Hedda
Published: January 2025

Plasmodium falciparummalaria remains a significant global health challenge. Current vaccines elicit antibody responses against circumsporozoite protein (PfCSP) that prevent the infection of hepatocytes but offer only moderate protection. Cellular immunity has emerged as a critical component of pre-erythrocytic protection that might be leveraged to develop improved PfCSP vaccines. Here, we characterized the clonality, molecular features, epitope specificity, and HLA-restrictions of the human PfCSP-specific CD4+and CD8+T cell response to vaccination with an adjuvanted PfCSP vaccine, FMP013/ALFQ. Using TCR expression cloning, we identified novel conserved CD4+T cell epitopes in the PfCSP N terminus and show that the C-terminal CS.T3 epitope was targeted by CD4+and rare CD8+T cells, which recognized this epitope co-receptor-independently presented on a class II HLA. Our findings provide insights into the utility of these epitopes as targets for strain-transcending immunity compared to the immunodominant but highly polymorphic epitopes in the PfCSP C terminus, offering guidance for the design of improved malaria vaccines.
Single-molecule analysis of PARP1-G-quadruplex interaction
Authors: Gaur Paras , Bain Fletcher E. , Meah Riaz , Spies Maria
Published: January 2025

The human genome contains numerous repetitive nucleotide sequences that display a propensity to fold into non-canonical DNA structures including G-quadruplexes (G4s). G4s have both positive and negative impacts on various aspects of nucleic acid metabolism including DNA replication, DNA repair and RNA transcription. Poly (ADP-ribose) polymerase (PARP1), an important anticancer drug target, has been recently shown to bind a subset of G4s, and to undergo auto-PARylation. The mechanism of this interaction, however, is poorly understood. Utilizing Mass Photometry (MP) and single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate that PARP1 dynamically interacts with G4s with a 1:1 stoichiometry. Interaction of a single PARP1 molecule with nicked DNA or DNA containing G4 and a primer-template junction is sufficient to activate robust auto-PARylation resulting in the addition of poly (ADP-ribose) chains with molecular weight of several hundred kDa. Pharmacological PARP inhibitors EB-47, Olaparib and Veliparib differently affect PARP1 retention on G4-containing DNA compared to nicked DNA.
Polygenic transcriptome risk scores enhance predictive accuracy in atopic dermatitis
Authors: Antonatos Charalabos , Budu-Aggrey Ashley , Pontikas Alexandros , Akritidis Adam , Pasmatzi Efstathia , Tsiogka Aikaterini , Gregoriou Stamatis , Grafanaki Katerina , Paternoster Lavinia , Vasilopoulos Yiannis
Published: January 2025

Background

Incorporation of gene expression when estimating polygenic risk scores (PRS) in atopic dermatitis (AD) may provide additional insights in disease pathogenesis and enhance predictive accuracy.

Objective

In this study, we developed polygenic transcriptome risk scores (PTRSs) derived from AD-enriched tissues and evaluated their performance against traditional PRS models and a baseline risk model incorporating eosinophil and lymphocyte counts in the prediction of AD.

Methods

We conducted transcriptome-wide association studies (TWAS) using the PrediXcan framework to construct tissue-specific PTRSs. Risk score performance was assessed in 256888 Europeans (10,816 cases) and validated in an independent cohort of 64152 Europeans (2669 cases) from the UK Biobank.

Results

We observed a modest correlation between PRS and PTRS, exerting independent effects on AD risk. While PRS demonstrated superior predictive performance compared to single-tissue PTRSs, combining both models significantly enhanced prediction accuracy, yielding a c-statistic of 0.646 (95% confidence intervals: 0.634–0.656). Notably, tissue-specific PTRSs revealed stronger associations with baseline risk factors, where Eppstein-Bar virus (EBV)-transformed lymphocytes and unexposed skin PTRSs tissues reported positive associations with lymphocyte counts.

Conclusion

Our findings highlight the value of integrating transcriptome-based risk models to incorporating additional omics layer to refine risk prediction and enhance our understanding of genetic architecture of complex traits.
Maternal thyroid hormone imbalance and risk of autism spectrum disorder
Authors: Elbedour Leena , Weinberg May , Meiri Gal , Michaelovski Analya , Menashe Idan
Published: January 2025

Maternal thyroid hormones play crucial roles in fetal neurodevelopment, with hypothyroidism and hyperthyroidism consistently being reported as potential risk factors for autism spectrum disorder (ASD) in offspring. Nevertheless, the mechanism underlying this association remains vague. In this retrospective cohort study of 51,296 singleton births in a single hospital, we examined the impact of different maternal thyroid conditions on the risk of ASD in the offspring. Chronic and gestational hyper-and hypothyroidism were determined based on ICD-9 criteria and maternal thyroid hormone levels, respectively. ASD diagnosis was determined based on DSM-5 criteria. Kaplan-Meier plots and Cox regression models were used to assess ASD risk in the offspring of women with and without thyroid conditions. A total of 4,306 (8.4%) of the mothers showed abnormal thyroid function. ASD cumulative incidence was similar in the offspring of women with normal and abnormal thyroid function (log-rank p=0.28). However, further classification of the study groups revealed an increased ASD risk in the offspring of women with both chronic and gestational thyroid dysfunction (aHR= 2.68, 95%CI=1.52-4.72). In addition, trimester-specific analysis revealed a dose effect in that the longer the period of thyroid imbalance, the higher the ASD risk, namely, for one, two or three trimesters of hypo- or hyperthyroidism, aHR= 1.69 (95%CI=1.19-2.83), aHR=2.39 (95%CI=1.24-5.78), aHR=3.25 (95%CI=1.07-7.21), respectively. Thus, the findings suggest that uncontrolled gestational thyroid dysfunction is associated with an elevated risk of ASD in offspring, underscoring the importance of routine thyroid function screening and treatment throughout pregnancy in mitigating ASD risk in offspring.
Pregnenolone Reduces Provoked Craving and Cocaine Use in Men and Women with Cocaine Use Disorder: A Pilot Trial
Authors: Sakmar Elcin , Wemm Stephanie , Fogelman Nia , Hermes Gretchen , Sinha Rajita , Milivojevic Verica
Published: January 2025

Aim

Chronic cocaine use is associated with decreases in neuroactive steroid levels. These adaptations may contribute to continued cocaine use and high relapse risk in individuals with cocaine use disorder (CUD). Thus, this pilot study assessed chronic treatment with 2 supraphysiologic doses of the neuroactive steroid precursor pregnenolone (PREG, 300 mg/day; 500 mg/day) to boost endogenous neuroactive steroid levels and assess its impact on provoked craving and cocaine use outcomes in an 8-week trial in men and women with CUD.

Methods

Fifty-five treatment-seeking individuals with CUD were randomly assigned to receive either placebo (PLA; n=18; 12M/6F), 300mg PREG/day (n=20; 15M/5F) or 500mg PREG/day (n=17; 12M/5F) for 8 weeks, along with outpatient weekly relapse prevention treatment. Plasma was collected at weeks 2, 5 and 7 to assess circulating pregnenolone levels. A subset of subjects participated in a 3-day experimental component of guided imagery exposure to stress, cocaine cue and neutral conditions in about week 2 of the trial to assess craving response. Cocaine use outcomes was also assessed over the 8-week treatment period. Intent-to-treat analyses were conducted using linear mixed effects models.

Results

There were no differences between treatment groups on demographic variables and baseline cocaine use. Plasma pregnenolone levels were higher in the 300mg and 500mg PREG groups compared to PLA (p’s< 0.032). Participant trial completion rates were 100% for PLA, 90% for 300mg and 94% for 500mg PREG groups. Placebo group had increased craving in response to stress (p< .001) and cocaine cue (p< .001) provocation, whereas the PREG groups showed no increased in provoked cocaine craving. For cocaine use outcomes during the 8-week trial, a significant main effect of treatment group (p= .005) on the weekly amounts of cocaine use showed e significantly lower amounts used in the 300mg PREG compared to the 500mg PREG group (p= 0.01) and to PLA (p= .047). There was also a trend for a treatment group main effect for days of cocaine used (p<.12)

Conclusions

These pilot findings suggest that supraphysiologic neuroactive steroid PREG doses reduces cocaine craving and may also improve cocaine use outcomes in treatment seeking individuals with CUD. Findings support further assessment and development of PREG in the treatment of CUD.
Long-term tillage regime structures bacterial carbon assimilation
Authors: Schaedel Marie , Koechli Chantal , Buckley Daniel
Published: January 2025

Microbial growth dynamics are deterministic of the fate of carbon in soil, responsible for the transformation of new carbon inputs and their stabilization on soil surfaces. Bacterial life history strategies are predictive of C substrate assimilation and growth response. High disturbance management practices such as tillage alter microbial community structure but have a poorly described impact on life histories that are central to C metabolism. We conducted a DNA stable isotope probing experiment using soil from a long-term field experiment with a 42-year legacy of no-till or annual moldboard plowing. We predicted that divergent legacies of disturbance would result in bacterial communities with distinct life histories, altering C assimilation dynamics. We incubated soil from each tillage regime with13C-xylose and13C-cellulose, two substrates that are components of plant litter and which differ in bioavailability. We identified 730 bacterial taxa that incorporated the labeled substrates and tracked their abundance in bulk microcosm soil over a 30 day period. Carbon addition rapidly altered bacterial community structure and function, with tilled soils demonstrating lower mineralization rates of each substrate. Xylose-assimilating taxa exhibited significantly lagged growth in tilled soils relative to no-till. We also found a higher number and diversity of late (day 30) cellulose incorporators in no-till soil, suggesting that minimal disturbance resulted in a longer residence time of13C-cellulose in members of the bacterial community. We show that soil management practices shape the path of carbon through bacterial communities by altering dynamic growth responses and secondary incorporation of carbon.

Highlights

DNA SIP identified divergent carbon dynamics resulting from tillage legacies

Xylose assimilation in plow-till soils was late and decoupled from mineralization

Cellulose-C was assimilated later in no-till soils relative to plow-till

Growth responses of incorporator taxa differ by tillage and explain mineralization
Virus and Cell Specific HMGB1 Secretion and Subepithelial Infiltrate Formation in Adenovirus Keratitis
Authors: Saha Amrita , Islam Mohammad Mirazul , Kumar Rahul , Ismail Ashrafali Mohamed , Garcia Emanuel , Gullapali Rama R , Chodosh James , Rajaiya Jaya
Published: January 2025

A highly contagious infection caused by human adenovirus species D (HAdV-D), epidemic keratoconjunctivitis (EKC) results in corneal subepithelial infiltration (SEI) by leukocytes, the hallmark of the infection. To date, the pathogenesis of corneal SEI formation in EKC is unresolved. HMGB1 (high-mobility group box 1 protein) is an alarmin expressed in response to infection and a marker of sepsis. Earlier studies using a different adenovirus species, HAdV-C, showed retention of HMGB1 in the infected cell nucleus by adenovirus protein VII, enabling immune evasion. Here, using HAdV-D we show cell-specific HMGB1 secretion by infected cells, and provide an HAdV-D specific mechanism for SEI formation in EKC. HMGB1 was secreted only upon infection of human corneal epithelial cells, not from other cell types, and only upon infection by HAdV-D types associated with EKC. Acetylated HMGB1 translocation from the nucleus to the cytoplasm, then to the extracellular milieu, was tightly controlled by CRM1 and LAMP1, respectively. Primary stromal cells when stimulated by rHMGB1 expressed proinflammatory chemokines. In a novel 3D culture system in tune with the architecture of the cornea, HMGB1 released by infected corneal epithelial cells induced leukocytic infiltrates either directly and/or indirectly via stimulated stromal cells, which together explains SEI formation in EKC.
Evaluating the Link Between Efflux Pump Expression and Motility Phenotypes inPseudomonas aeruginosaTreated with Virulence Inhibitors
Authors: Lembke Hannah K. , Nauta Kelsie. M. , Hunter Ryan C. , Carlson Erin E.
Published: January 2025

Antibiotic resistance continues to rise as a global health threat. Novel anti-virulence strategies diminish the drive for evolutionary pressure, but still hinder a pathogen’s ability to infect a host. Treatment of the highly virulentPseudomonas aeruginosastrain PA14 with virulence inhibitors (R-2 and R-6) elicited widely varying transcriptional profiles. Of interest, expression of a family of resistance-nodulation-division (RND) efflux pumps implicated in the intrinsic drug resistance ofP. aeruginosa, was significantly altered by R-2 and R-6 treatment. While structurally similar, these inhibitors caused differential expression of various RND efflux pumps within the Mex family—R-2 treatment stimulated expression ofmexEF-oprNwhile R-6 treatment led to increasedmexAB-oprMexpression. Further expansion into a small library of virulence inhibitors revealed chemical motifs that trigger increases in RND efflux pump expression. Additionally, activation of these efflux pumps suggests low accumulation of virulence inhibitors in WT PA14. Treatment of an efflux pump-deficient strain with R-2 or R-6 resulted in inhibition of several virulence factors, for example R-2 was found to abolish swimming motility. Collectively, treatment with either R-2 or R-6 gives rise to a convoluted transcriptomic response, confounded by the impact of efflux pump expression on the system. However, understanding the moieties that lead to high expression of the efflux pumps enables further rational design of novel virulence inhibitors that do not cause RND efflux pump activation.

Antibiotic resistance continues to rise across the world. The continued failure of antibiotics to treat infectious disease clearly demonstrates the need for new therapeutics. Small molecule inhibitors of virulence, or the ability of a bacteria to establish and maintain an infection, have showed promise in this area. By reducing virulence, the host immune system can clear the infection on its own and there is less selective pressure on the bacteria, reducing the emergence of resistance.

Our work demonstrates a clear link between virulence inhibitors and efflux pump expression. Efflux pumps are critical for bacteria to extrude toxic compounds from their interior. Interestingly, the changes in efflux pump expression can be quite large even with similar molecular structures. Additionally, the repression of efflux expression caused by our virulence inhibitors results in synergy with current antibiotics. This work will allow the future design of virulence inhibitors that do not activate efflux pump expression and therefore, enable high intracellular concentrations.
Isolation of phages infecting the zoonotic pathogenStreptococcus suisreveals novel structural and genomic characteristics
Authors: Osei Emmanuel Kuffour , O’Hea Reuben , Cambillau Christian , Athalye Ankita , Hille Frank , Franz Charles M.A.P. , O’Doherty Áine , Wilson Margaret , Murray Gemma G. R , Weinert Lucy A. , Manzanilla Edgar Garcia , Mahony Jennifer , Kenny John G
Published: January 2025

Bacteriophage research has experienced a renaissance in recent years, owing to their therapeutic potential and versatility in biotechnology, particularly in combating antibiotic resistant-bacteria along the farm-to-fork continuum. However, certain pathogens remain underexplored as targets for phage therapy, including the zoonotic pathogenStreptococcus suiswhich causes infections in pigs and humans. Despite global efforts, the genome of only one infectiveS. suisphage has been described. Here, we report the isolation of two phages that infectS. suis: Bonnie and Clyde. The phages infect 58% of 100S. suisstrains tested, including representatives of seven different serotypes and thirteen known sequence types from diverse geographical origins. Clyde suppressed bacterial growthin vitrowithin two multi-strain mixes designed to simulate a polyclonalS. suisinfection. Both phages demonstrated stability across various temperatures and pH levels, highlighting their potential to withstand storage conditions and maintain viability in delivery formulations. Genome comparisons revealed that neither phage shares significant nucleotide identity with any cultivated phages in the NCBI database and thereby represent novel species belonging to two distinct novel genera. This study is the first to investigate the adhesion devices ofS. suisinfecting phages. Structure prediction and analysis of adhesion devices with AlphaFold2 revealed two distinct lineages ofS. suisphages:Streptococcus thermophilus-like (Bonnie) andS. suis-like (Clyde). The structural similarities between the adhesion devices of Bonnie andS. thermophilusphages, despite the lack of nucleotide similarity and differing ecological niches, suggest a common ancestor or convergent evolution, highlighting evolutionary links between pathogenic and non-pathogenic streptococcal species. These findings provide valuable insights into the genetic and phenotypic characteristics of phages that can infectS. suis, providing new data for the therapeutic application of phages in a One Health context.
Pluripotency factors enhance the firing efficiency of late DNA replication origins in mouse embryonic stem cells
Authors: Rodriguez-Carballo Eddie , Dionellis Vasilis S. , Ntallis Sotirios G. , Bernasconi Lilia , Keskin Ezgi , Halazonetis Thanos D.
Published: January 2025

DNA replication initiates at genomic loci known as origins, which fire according to a spatiotemporal program, still not yet well-defined in mammals. Here, we investigated whether pluripotent mouse embryonic stem cells (mESCs), which proliferate rapidly and have very short G1 phases, have a different spatiotemporal origin firing program than differentiated cells. Using EdU-seq combined with various cell cycle synchronization methods, we identified DNA replication initiation zones (IZs) in mESCs, mesenchymal stem cells and mouse embryo fibroblasts (MEFs). Similar profiles of IZs were present in the early-replicating genomic domains in all cell types. Uniquely in mESCs, we observed, within 1-2 hours of entry into S phase, origin firing at IZs that mapped to the mid and late-replicating genomic domains. This change in the replication timing program, which did not lead to shortening of the length of S phase, was driven by pluripotency transcription factors, notably OCT4, as documented by examining mESCs in which OCT4 expression was transiently suppressed. We propose that pluripotency factors in mESCs bind to IZs at mid and late-replicating genomic domains to enhance chromatin accessibility, which in turn leads to changes in the replication timing program. These results provide an example of how transcription factors control DNA replication in a cell type-specific manner.
Regionalized regulation of actomyosin organization influences cardiomyocyte cell shape changes during chamber curvature formation
Authors: Leerberg Dena M. , Avillion Gabriel B. , Priya Rashmi , Stainier Didier Y.R. , Yelon Deborah
Published: January 2025

Cardiac chambers emerge from a heart tube that balloons and bends to create expanded ventricular and atrial structures, each containing a convex outer curvature (OC) and a recessed inner curvature (IC). A comprehensive understanding of the cellular and molecular mechanisms underlying the formation of these characteristic curvatures remains lacking. Here, we demonstrate in zebrafish that the initially similar populations of OC and IC ventricular cardiomyocytes diverge in the organization of their actomyosin cytoskeleton and subsequently acquire distinct OC and IC cell shapes. Altering actomyosin dynamics hinders cell shape changes in the OC, and mosaic analyses indicate that actomyosin regulates cardiomyocyte shape in a cell-autonomous manner. Additionally, both blood flow and the transcription factor Tbx5a influence the basal enrichment of actomyosin and squamous cell morphologies in the OC. Together, our findings demonstrate that intrinsic and extrinsic factors intersect to control actomyosin organization in OC cardiomyocytes, which in turn promotes the cell shape changes that drive curvature morphogenesis.
Identification of Dehydrogenase, Hydratase, and Aldolase Required for C17 Propionyl Residue Removal in Steroid Degradation byComamonas testosteroniTA441: Structural and Functional Insights into the (ChsE1-ChsE2)2and (ChsH1-ChsH2MaoC)2-(Ltp2-ChsH2DUF35)2Complexes
Authors: Horinouchi Masae
Published: January 2025

Bacterial steroid degradation is gaining attention for its diverse roles, such asMycobacterium tuberculosis’s reliance on the degradation of the C17 side chain of cholesterol for survival in host environments. ORF40 to ORF44 ofComamonas testosteroniTA441, previously characterized for its A-, B-, C-, and D-ring cleavage pathways, were hypothesized to correspond to theigroperon ofM. tuberculosis, encoding the dehydrogenase ChsE1E2, hydratase ChsH1H2maoC, and aldolase Ltp2 ChsH2DUF35, responsible for propionyl residue removal in C17 side-chain degradation. However, low amino acid identity between the corresponding enzymes precluded functional assignment without experimental evidence.

In this study, we generated gene-disrupted mutants of ORF40–44 and demonstrated that ORF41/44, ORF40/42, and ORF43 encode the dehydrogenase, hydratase, and aldolase, respectively. ORF40 encodes a bifunctional protein comprising MaoC and DUF35 domains. The MaoC domain of ORF40 and the ORF42-encoded protein form the hydratase, while the DUF35 domain is essential for aldolase activity. A mutant expressing ORF40MaoCand ORF40DUF35separately exhibited both hydratase and aldolase activities, suggesting these activities do not require a strictly formed complex of hydratase and aldolase. However, efficient propionyl residue removal appears to depend on the proper formation of each enzymatic complex, including ChsE1E2, ChsH1H2MaoC, and Ltp2ChsH2DUF35; although (ChsE1-ChsE2)2does not form a stable complex with (ChsH1-ChsH2MaoC)2-(Ltp2-ChsH2DUF35)2, some degree of interaction was suggested. AlphaFold-predicted 3D structures of the TA441 enzymes and their complexes revealed striking similarities to those ofM. tuberculosis, despite low amino acid identities. These findings shed light on the structural and functional conservation of bacterial steroid-degrading enzymes.

IMPORTANCE

Research on bacterial steroid degradation began over 50 years ago, primarily to produce substrates for steroid drugs. Recently, the role of steroid-degrading bacteria in human health has garnered increasing attention.Comamonas testosteroniTA441 is a prominent model organism for studying aerobic steroid degradation, with its overall pathways for A-, B-, C-, and D-ring cleavage already elucidated. In this study, we identified the mechanism for removing the propionyl residue at C17, a crucial step in degrading steroids with a C17 side chain, such as cholic acid, cholesterol, and other biologically significant compounds in animals and plants. The functions and structures of the identified enzymes show remarkable similarity to those inMycobacterium tuberculosis. These findings suggest that insights gained from TA441 could provide valuable clues for understandingM. tuberculosissteroid metabolism and the broader ecological and health-related implications of bacterial steroid degradation.
Measurement and interpretation of the Harare HIV combination prevention cascade in priority populations: A population survey of adolescent girls and young women and young men in Zimbabwe
Authors: Moorhouse Louisa , Imai-Eaton Jeffrey W. , Dadirai Tawanda , Maswera Rufurwokuda , Museka Tafadzwa , Mandizvidza Phyllis , Dzamatira Freedom , Tsenesa Blessing , Hallett Timothy B , Nyamukapa Constance , Gregson Simon
Published: January 2025

Introduction

HIV-negative adolescent girls and young women (AGYW), and male partners, have disproportionately high HIV incidence in many African countries. We used a new HIV Prevention Cascade (HPC) approach to quantify levels of, and barriers to, prevention method use to guide interventions to increase effective uptake of primary HIV prevention.

Methods

Data from the Manicaland HPC pilot study (2018-19; N=9803) in Zimbabwe were used to measure levels of sexual risk behaviour and construct HPCs for male condom, PrEP (females), VMMC (males) and combination prevention use by HIV-negative sexually-active AGYW (15-24-years) and male partners (15-29-years).

Results

19% of AGYW (N=1140) and 37% of young men (N=955) who had started sex reported one or more HIV risk behaviour and met the definition of the priority populations for HIV prevention. Of these, 63% of females and 87% of males were motivated to use an HIV prevention method, 28% and 63% had access to a method, and 16% and 53% used a method. Male condoms were the most commonly used prevention method, accounting for 97% of use in females and 55% in males. Barriers to motivation, access and capacity to use were reported for all priority populations and methods. Some barriers were common across HPCs (e.g. lack of risk perception, social unacceptability, and lack of acceptable provision); others were specific to particular prevention methods or priority populations (e.g. lack of availability).

Conclusion

HIV risk behaviours were commonly reported, but use of prevention methods is low in young people in Manicaland. Population survey measurements of HPCs revealed large gaps in all steps in the cascade (lack of motivation, lack of access and lack of capacity to use prevention) but also provided information on the reasons for these gaps that can aid in designing interventions that reduce new infections.
A Microphysiological Model of Progressive Human Hepatic Insulin Resistance
Authors: Hellen Dominick J. , Ungerleider Jessica , Tevonian Erin , Sphabmixay Pierre , Roy Priyatanu , Lewis Caroline , Jeppesen Jacob , Demozay Damien , Griffith Linda G.
Published: January 2025

Background & Aims

Hepatic insulin resistance is a fundamental phenomenon observed in both Type 2 diabetes (T2D) and metabolic (dysfunction) associated fatty liver disease (MAFLD). The relative contributions of nutrients, hyperinsulinemia, hormones, inflammation, and other cues are difficult to parsein vivoas they are convoluted by interplay between the local and systemic events. Here, we used a well-established human liver microphysiological system (MPS) to establish a physiologically-relevant insulin-responsive metabolic baseline and probe how primary human hepatocytes respond to controlled perturbations in insulin, glucose, and free fatty acids (FFAs).

Methods

Replicate liver MPS were maintained in media with either 200 pM (normal) or 800 pM (T2D) insulin for up to 3 weeks. Conditions of standard glucose (5.5 mM), hyperglycemia (11 mM glucose), normal (20µM) and elevated FFA (100 µM), alone and in combination were used at each insulin concentration, either continuously or reversing back to standard media after 2 weeks of simulated T2D conditions. Hepatic glucose production, activation of signaling pathways, insulin clearance, transcriptome analysis, and intracellular lipid and bile acid accumulation were assessed.

Results

Hyperinsulinemia alone induces insulin resistance after one week of exposure, while hyperglycemia and increased FFAs significantly exacerbate this phenotype. Hyperinsulinemia, along with elevated glucose and FFAs, transcriptionally predisposes hepatocytes to insulin resistance through altered metabolic and immune signaling pathways. The phenotypes observed in hyperinsulinemia and nutrient overload are partially reversible upon return to normophysiologic conditions.

Conclusions

Our enhancedin vitromodel, replicating multiple aspects of the insulin-resistant condition, offers improved insights into disease mechanisms with relevance to human physiology.

Lay Summary

The many nutritional, hormonal, and systemic inflammatory factors that contribute to the loss of sensitivity to insulin in Type 2 Diabetes and other metabolic disorders are difficult to parse in human patients, and animal models fail to capture all the human dimensions of the relevant biology. We, therefore, developed a microphysiological systems model, involving a microfluidic platform that cultures a simulated human liver for weeks at a time, under controlled nutrient and hormone concentrations, to analyze how the effects of nutrition (glucose and free fatty acids) together with increased insulin cause pathological features seen in human liverin vivo. We found that continually high levels of insulin predispose the liver to some of these features, along with reversal when the nutritional and insulin levels were restored to healthy values.
Genome Analysis of Bacillus paralicheniformis AA1 isolated from a conventional milpa farming system in the northwestern region of Sonora, Mexico
Authors: Verdugo-Fuentes Abel Alberto , Chavez-Almanza Andres , Villa-Rodriguez Eber , Rojas-Padilla Jonathan , Cantu-Soto Ernesto , Diaz-Quiroz Carlos
Published: January 2025

This study provides an in-depth genome analysis of Bacillus paralicheniformis AA1, a bacterial strain isolated from a traditional milpa farming system in Sonora, Mexico. The genomic investigation revealed a high level of completeness, demonstrated by the presence of a diverse and functionally significant repertoire of genes associated with fundamental biological processes, including nutrient assimilation, stress response, and cellular regulation. Notably, the genome also contains genes responsible for the biosynthesis of secondary metabolites, highlighting its potential for biotechnological applications. Taxonomic classification was rigorously conducted using integrated genome-wide approaches, which definitively confirmed the identification of isolate AA1 as belonging to the species Bacillus paralicheniformis. Comparative genomic analysis further established a high degree of genetic similarity between AA1 and other B. paralicheniformis strains with well-characterized biotechnological capabilities. This similarity strongly suggests that AA1 harbors genetic elements responsible for the synthesis of antimicrobial compounds, enzymes with industrial relevance, and metabolites that promote plant growth. The findings underscore the potential of Bacillus paralicheniformis AA1 as a valuable resource for biotechnology and sustainable agriculture. By enhancing our understanding of microbial diversity within traditional agroecosystems, this study contributes to the broader knowledge base required for the development of innovative agricultural practices. Future research should focus on functional validation of key genes to fully unlock AA1 potential as a bioresource for antimicrobial production, enzyme synthesis, and crop enhancement, paving the way for its application in environmentally sustainable farming systems.
Impact of background field localization on vacuum polarization effects
Authors: Marmier Carl , Seegert Nico , Karbstein Felix
Published: January 2025

We aim at insights about how localization of the background field impacts nonlinear quantum vacuum signatures probed by photons in purely magnetic, electric and crossed fields. The starting point of our study are the one-loop results for the Heisenberg-Euler effective Lagrangian and the photon polarization tensor in quantum electrodynamics (QED) evaluated in a uniform constant electromagnetic field. As is well known and often employed, especially in the weak-field limit, within certain restrictions these results also allow for the reliable analysis of vacuum polarization effects in slowly varying background fields. Here, our main interest is in manifestly nonperturbative effects. To this end, we make use of the fact that for the particular case of background field inhomogeneities of Lorentzian shape with 0≤d≤3 inhomogeneous directions analytical insights are possible. We study the scaling of conventional nonlinear QED signatures, such as probe-photon polarization flip and probe-photon induced electron-positron pair production, with relevant parameters. Special attention is put on the d dependence of the considered effects.

Published by the American Physical Society
2025
Neural network decoder for near-term surface-code experiments
Authors: Varbanov Boris M. , Serra-Peralta Marc , Byfield David , Terhal Barbara M.
Published: January 2025

Neural network decoders can achieve a lower logical error rate compared to conventional decoders, like minimum-weight perfect matching, when decoding the surface code. Furthermore, these decoders require no prior information about the physical error rates, making them highly adaptable. In this study, we investigate the performance of such a decoder using both simulated and experimental data obtained from a transmon-qubit processor, focusing on small-distance surface codes. We first show that the neural network typically outperforms the matching decoder due to better handling of errors leading to multiple correlated syndrome defects, such as Y errors. When applied to the experimental data of Google Quantum AI [R. Acharya , ], the neural network decoder achieves logical error rates approximately 25% lower than minimum-weight perfect matching, approaching the performance of a maximum-likelihood decoder. To demonstrate the flexibility of this decoder, we incorporate the soft information available in the analog readout of transmon qubits and evaluate the performance of this decoder in simulation using a symmetric Gaussian-noise model. Considering the soft information leads to an approximately 10% lower logical error rate, depending on the probability of a measurement error. The good logical performance, flexibility, and computational efficiency make neural network decoders well-suited for near-term demonstrations of quantum memories.

Published by the American Physical Society
2025
Smart resetting: An energy-efficient strategy for stochastic search processes
Authors: Tal-Friedman Ofir , Keidar Tommer D. , Reuveni Shlomi , Roichman Yael
Published: January 2025

Stochastic resetting, a method for accelerating target search in random processes, often incurs temporal and energetic costs. For a diffusing particle, a lower bound exists for the energetic cost of reaching the target, which is attained at low resetting rates and equals the direct linear transportation cost against fluid drag. Here, we study smart resetting, a strategy that aims to beat this lower bound. By strategically resetting the particle only when this benefits its progress toward the target, smart resetting leverages information to minimize energy consumption. We analytically calculate the energetic cost per mean first passage time and show that smart resetting consistently reduces the energetic cost compared to regular resetting. Surprisingly, smart resting achieves the minimum energy cost previously established for regular resetting, irrespective of the resetting rate. Yet, it fails to reduce this cost further. We extend our findings in two ways: first, by examining nonlinear energetic cost functions, and second, by considering smart resetting of drift-diffusion processes.

Published by the American Physical Society
2025