bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross ancestry genetic study of psychiatric disorders from India
Authors: Holla Bharath , Mahadevan Jayant , Ganesh Suhas , Sud Reeteka , Janardhanan Meghana , Balachander Srinivas , Strom Nora , Mattheisen Manuel , Sullivan Patrick F , Huang Hailiang , Zandi Peter , Benegal Vivek , Reddy YC Janardhan , Jain Sanjeev ,   cVEDA collaborators,   ADBS-CBM consortium,   iPSYCH OCD consortium,   Consortium NORDiC OCD & Related Disorders, Purushottam Meera , Viswanath Biju
Published: April 2024

Genome-wide association studies across diverse populations may help validate and confirm genetic contributions to risk of disease. We estimated the extent of population stratification as well as the predictive accuracy of polygenic scores (PGS) derived from European samples to a data set from India. We analysed 2685 samples from two data sets, a population neurodevelopmental study (cVEDA) and a hospital-based sample of bipolar affective disorder (BD) and obsessive-compulsive disorder (OCD). Genotyping was conducted using Illumina’s Global Screening Array.

Population structure was examined with principal component analysis (PCA), uniform manifold approximation and projection (UMAP), support vector machine (SVM) ancestry predictions, and admixture analysis. PGS were calculated from the largest available European discovery GWAS summary statistics for BD, OCD, and externalizing traits using two Bayesian methods that incorporate local linkage disequilibrium structures (PGS-CS-auto) and functional genomic annotations (SBayesRC). Our analyses reveal global and continental PCA overlap with other South Asian populations. Admixture analysis revealed a north-south genetic axis within India (FST1.6%). The UMAP partially reconstructed the contours of the Indian subcontinent.

The Bayesian PGS analyses indicates moderate-to-high predictive power for BD. This was despite the cross-ancestry bias of the discovery GWAS dataset, with the currently available data. However, accuracy for OCD and externalizing traits was much lower. The predictive accuracy was perhaps influenced by the sample size of the discovery GWAS and phenotypic heterogeneity across the syndromes and traits studied. Our study results highlight the accuracy and generalizability of newer PGS models across ancestries. Further research, across diverse populations, would help understand causal mechanisms that contribute to psychiatric syndromes and traits.
Antibiotic-associated neutropenia is marked by depletion of intestinalLachnospiraceaein pediatric patients
Authors: Fernandez-Sanchez Josaura , Rodgers Rachel , Maknojia Arushana A. , Shaikh Nusrat , Yan Hannah , Mejia Marlyd E. , Hendricks Hope , Jenq Robert R. , Reddy Pavan , Banerjee Ritu , Schraw Jeremy M. , Baldridge Megan T. , King Katherine Y.
Published: April 2024

Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance ofLachnospiraceaefamily members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced byLachnospiraceae. Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance.

Key Points

Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.

We found no association between neutropenia and type of infection or class of antibiotic used.

Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence ofLachnospiraceaeand Lachnospiraceae metabolites such as citrulline.
Predictors of glycemic worsening in the next year in adults with screen-detected type 2 diabetes
Authors: Aguirre Rebecca Schneider , Hannon Tamara S , Considine Robert V , Patel Yash , Kirkman M Sue , Mather Kieren J
Published: April 2024

Background and Aims

Identifying simple markers of risk for worsening glucose can allow care providers to target therapeutic interventions according to risk of worsening glycemic control. We aimed to determine which routine clinical measures herald near-term glycemic worsening in early type 2 diabetes(T2D).

Methods

The Early Diabetes Intervention Program (EDIP) was a clinical trial in individuals with screen-detected T2D [HbA1C 6.3+0.63%(45+5mmol/mol)]. During the trial some participants experienced worsening fasting blood glucose (FBG). We investigated the time course of FBG, HbA1c, weight, and other clinical factors to determine which might herald glycemic worsening over the next year.

Results

Progressors (62/219, 28.5%) had higher FBG than non-progressors at baseline [118 vs 130mg/dL (6.6 vs 7.2 mmol/L), p=<0.001]. FBG was stable except in the year of progression, when progressors exhibited a large 1-year rise [mean change 14.2mg/dL(0.79 mmol/L)]. Current FBG and antecedent year change in FBG were associated with progression(p<0.01), although the magnitude of change was too small to be of clinical utility (0.19 mg/dL; 0.01 mmol/L). Current or antecedent year change in HbA1c, weight, TG or HDL were not associated with progression. In the year of glycemic worsening, rising glucose was strongly associated with a concurrent increase in weight (p<0.001).

Conclusions

Elevated FBG but not HbA1c identified individuals at risk for imminent glycemic worsening; the subsequent large rise in glucose was associated with a short-term increase in weight. Glucose and weight surveillance provide actionable information for those caring for patients with early diabetes.

Highlights

Recent change in fasting blood sugar is associated with near-term worsening of glycemia

Changes in weight, insulin, HbA1C were not informative for anticipating near-term worsening of glycemia

Increasing glucose was strongly associated with concurrent weight gain
CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC
Authors: Yuan Xueying , Hao Xiaoxin , Chan Hilda L. , Zhao Na , Pedroza Diego A. , Liu Fengshuo , Le Kang , Smith Alex J. , Calderon Sebastian J. , Lieu Nadia , Soth Michael J. , Jones Philip , Zhang Xiang H.-F. , Rosen Jeffrey M.
Published: April 2024

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

In neutrophil-enriched triple-negative breast cancer (TNBC) models, CREB binding protein (CBP)/P300 bromodomain (BRD) inhibition reduces tumor growth and systemic neutrophil accumulation while stimulating an antitumor immune response. This improves standard-of-care therapies, suggesting a potential therapeutic benefit of CBP/P300 BRD inhibitors for neutrophil-enriched TNBC.
Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma
Authors: Floros Konstantinos V. , Fairchild Carter K. , Li Jinxiu , Zhang Kun , Roberts Jane L. , Kurupi Richard , Hu Bin , Kraskauskiene Vita , Hosseini Nayyerehsadat , Shen Shanwei , Inge Melissa M. , Smith-Fry Kylie , Li Li , Sotiriou Afroditi , Dalton Krista M. , Jose Asha , Abdelfadiel Elsamani I. , Xing Yanli , Hill Ronald D. , Slaughter Jamie M. , Shende Mayuri , Lorenz Madelyn R , Hinojosa Mandy R. , Belvin Benjamin R. , Lai Zhao , Boikos Sosipatros A. , Stamatouli Angeliki M. , Lewis Janina P. , Manjili Masoud H. , Valerie Kristoffer , Li Renfeng , Banito Ana , Poklepovic Andrew , Koblinski Jennifer E. , Siggers Trevor , Dozmorov Mikhail G. , Jones Kevin B. , Radhakrishnan Senthil K. , Faber Anthony C.
Published: April 2024

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.
Massively parallel interrogation of human functional variants modulating cancer immunosurveillance
Authors: Liu Ying , Liu Yongshuo , Niu Xuran , Chen Ang , Li Yizhou , Yu Ying , Liu Zhiheng , Wei Wensheng
Published: April 2024

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized clinical cancer treatment, while abnormal PD-L1 or HLA-I expression in patients can significantly impact the therapeutic efficacy. Somatic mutations in cancer cells that modulate these critical immune regulators are closely associated with tumor progression and ICB response. However, a systematic interpretation of cancer immune-related mutations is still lacking. Here, we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible Serine/Threonine/Tyrosine residues across the human genome, which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression. Notably, we revealed functional mutations that co-regulate PD-L1 and HLA-I expression, represented by the clinically relevant mutation SETD2_Y1666, and verified that it can benefit from immunotherapyin vivo. Our findings generate an unprecedented resource of functional residues regulating cancer immunosurveillance, meanwhile, offer valuable guidance for clinical diagnosis, ICB therapy, and the development of innovative drugs in cancer treatment.
A two-component quasi-icosahedral protein nanocompartment with variable shell composition and irregular tiling
Authors: Dutcher Cassandra A. , Andreas Michael P. , Giessen Tobias W.
Published: April 2024

Protein shells or capsids are a widespread form of compartmentalization in nature. Viruses use protein capsids to protect and transport their genomes while many cellular organisms use protein shells for varied metabolic purposes. These protein-based compartments often exhibit icosahedral symmetry and consist of a small number of structural components with defined roles. Encapsulins are a prevalent protein-based compartmentalization strategy in prokaryotes. All encapsulins studied thus far consist of a single shell protein that adopts the viral HK97-fold. Here, we report the characterization of a Family 2B two-component encapsulin fromStreptomyces lydicus. We show the differential assembly behavior of the two shell components and demonstrate their ability to co-assemble into mixed shells with variable shell composition. We determined the structures of both shell proteins using cryo-electron microscopy. Using 3D-classification and crosslinking studies, we highlight the irregular tiling of mixed shells. Our work expands the known assembly modes of HK97-fold proteins and lays the foundation for future functional and engineering studies on two-component encapsulins.
Colorectal Cancer Stem Cell Subtypes Orchestrate Distinct Tumor Microenvironments
Authors: Hosohama Linzi , Tifrea Delia F. , Nee Kevin , Park Sung Yun , Wu Jie , Habowski Amber N. , Van Cassandra , Seldin Marcus M. , Edwards Robert A. , Waterman Marian L.
Published: April 2024

Several classification systems have been developed to define tumor subtypes in colorectal cancer (CRC). One system proposes that tumor heterogeneity derives in part from distinct cancer stem cell populations that co-exist as admixtures of varying proportions. However, the lack of single cell resolution has prohibited a definitive identification of these types of stem cells and therefore any understanding of how each influence tumor phenotypes. Here were report the isolation and characterization of two cancer stem cell subtypes from the SW480 CRC cell line. We find these cancer stem cells are oncogenic versions of the normal Crypt Base Columnar (CBC) and Regenerative Stem Cell (RSC) populations from intestinal crypts and that their gene signatures are consistent with the "Admixture" and other CRC classification systems. Using publicly available single cell RNA sequencing (scRNAseq) data from CRC patients, we determine that RSC and CBC cancer stem cells are commonly co-present in human CRC. To characterize influences on the tumor microenvironment, we develop subtype-specific xenograft models and we define their tumor microenvironments at high resolution via scRNAseq. RSCs create differentiated, inflammatory, slow growing tumors. CBCs create proliferative, undifferentiated, invasive tumors. With this enhanced resolution, we unify current CRC patient classification schema with TME phenotypes and organization
Ligand-Coupled Conformational Changes in a Cyclic Nucleotide-Gated Ion Channel Revealed by Time-Resolved Transition Metal Ion FRET
Authors: Eggan Pierce , Gordon Sharona E. , Zagotta William N.
Published: April 2024

Cyclic nucleotide-binding domain (CNBD) ion channels play crucial roles in cellular-signaling and excitability and are regulated by the direct binding of cyclic adenosine- or guanosine-monophosphate (cAMP, cGMP). However, the precise allosteric mechanism governing channel activation upon ligand binding, particularly the energetic changes within domains, remains poorly understood. The prokaryotic CNBD channel SthK offers a valuable model for investigating this allosteric mechanism. In this study, we investigated the conformational dynamics and energetics of the SthK C-terminal region using a combination of steady-state and time-resolved transition metal ion Förster resonance energy transfer (tmFRET) experiments. We engineered donor-acceptor pairs at specific sites within a SthK C-terminal fragment by incorporating a fluorescent noncanonical amino acid donor and metal ion acceptors. Measuring tmFRET with fluorescence lifetimes, we determined intramolecular distance distributions in the absence and presence of cAMP or cGMP. The probability distributions between conformational states without and with ligand were used to calculate the changes in free energy (ΔG) and differences in free energy change (ΔΔG) in the context of a simple four-state model. Our findings reveal that cAMP binding produces large structural changes, with a very favorable ΔΔG. In contrast to cAMP, cGMP behaved as a partial agonist and only weakly promoted the active state. Furthermore, we assessed the impact of protein oligomerization and ionic strength on the structure and energetics of the conformational states. This study demonstrates the effectiveness of time-resolved tmFRET in determining the conformational states and the ligand-dependent energetics of the SthK C-terminal region.

Significance Statement

Allosteric regulation is pivotal for the function of most proteins, especially ion channels like the cyclic nucleotide-binding domain (CNBD) channels. This study examines the allosteric mechanism of ligand binding in the C-terminal region of the prokaryotic CNBD ion channel SthK using steady-state and time-resolved tmFRET. We uncovered significant structural and energetic changes induced by ligand binding with the full-agonist cAMP and the weak partial agonist cGMP. Our approach also highlights the effectiveness of using fluorescence lifetimes to reveal conformational heterogeneity and free energy changes in proteins. These findings deepen our understanding of CNBD channel activation overall and lay the groundwork for a more comprehensive characterization of the effects of mutations and pharmacological agents in these channels.
Engineering PEG10 assembled endogenous virus-like particles with genetically encoded neoantigen peptides for cancer vaccination
Authors: Tang Ruijing , Guo Luobin , Wei Tingyu , Chen Tingting , Yang Huan , Ye Honghao , Lin Fangzhou , Zeng Yongyi , Yu Haijun , Cai Zhixiong , Liu Xiaolong
Published: April 2024

Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we firstly designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.
Results from Integrating Gender-Based Violence Services into HIV Care – a Case Study of Lighthouse Trust ART Clinic in Malawi
Authors: Kiruthu-Kamamia Christine , Kumwenda Tapiwa , Lungu Joseph , Sande Odala , Diele Joseph , MacLachlan Ellen , Thawani Agnes
Published: April 2024

Introduction

Gender-based violence (GBV) not only poses significant public health and human rights challenges but is also closely associated with HIV. GBV acts as a barrier to HIV prevention, testing, and treatment adherence, and fear of GBV inhibits disclosure of HIV status to sexual partners. In Malawi, where both GBV and HIV prevalence is high, integrating GBV services into HIV care is crucial. We describe the integration of GBV services into Lighthouse Trust’s ART clinics in Malawi, including screening, documentation, program implementation, and outcomes.

Methods

We conducted a retrospective analysis from January 2020 to September 2023. Data on cases identified, post-GBV services, and perpetrator demographics were collected from the GBV register. We used descriptive statistics to describe the program outcomes.

Results

We documented 7148 reported GBV cases from January 2020 to September 2023. Young women, particularly those aged 10-19, constituted a significant proportion of survivors. Psycho-social services were the most common type of service that was offered to GBV survivors (25%), followed by HIV testing (19%) and STI screening(18%). Perpetrators were mostly known to survivors or intimate partners of the survivor.

Conclusion

We successfully integrated GBV services into the Lighthouse Trust ART clinic, in close collaboration with the one-stop centers. Training healthcare providers enhanced support for GBV survivors, with a focus on increasing awareness, especially for minors. Recommended actions include improving access to services, confidentiality, and multi-sectoral collaboration to ensure comprehensive care aimed to create a safer, more dignified healthcare environment for all, particularly GBV survivors.

Key Messages

Key Findings Teaser Key Message

We successfully integrated GBV services into HIV care via adequate training, screening and identification procedures, and documentation.

Integrating GBV screening into ART care identified over 7000 cases with most cases of sexual violence in women aged 10 to 19 years.

There is still a need for public awareness of GBV and access to support services.

Key Messages and Implications to policy, program managers, donors etc

We provide a replicable model for healthcare providers and facility administrators, demonstrating the effectiveness of standardized screening, care, and referral processes in improving the support and outcomes for GBV survivors in low-resource settings.

Our findings can inform the development of more inclusive health policies and support services that address the needs of all GBV survivors.
Chikungunya Seroprevalence among Patients Presenting with Febrile illnesses in selected health facilities in Mt. Elgon region, Kenya
Authors: Kageha Sheila , Ngoi Joyce M. , Kubo Toru , Morita Kouichi , Mwau Matilu
Published: April 2024

Background

Chikungunya is an emerging epidemic-prone vector-borne disease of considerable significance globally. Infection with chikungunya virus induces an acute illness characterized by fever and painful arthralgia, which can evolve to chronic arthritis and rheumatism especially in elderly patients. Whereas febrile illness and arthralgia are common clinical presentations amongst residents of Mt. Elgon, the role of chikungunya virus as a causative agent is undocumented. This study was carried out to determine the prevalence of IgA, IgM and IgG antibodies against Chikungunya Virus (CHIKV) antigens in patients presenting with acute febrile illnesses in Mt. Elgon region, Kenya.

Methods

This was a cross-sectional seroprevalence study on febrile patients visiting Endebes, Andersen and Kitale County Referal Hospitals. Sociodemographic data was collected whenever possible. Serum samples were collected and screened using Indirect ELISA for 1gG+IgM+IgA antibodies. Sera that tested positive by ELISA were subjected to standard plaque reduction neutralization assays (PRNT) performed on monolayer cultures of Vero E6 cells for confirmation.

Results

By ELISA, a total of 317/1359 (23.33%) sera were positive for CHIKV antibodies. Of the 317 positive sera, 305 (96.21%) were of sufficient quantity and were subjected to PRNT. Ultimately, 127 (9.3%) samples tested positive for CHIKV neutralising antibodies by PRNT.

Conclusion

These findings suggest active circulation of CHIKV in Mt. Elgon, even though it has previously been considered a non-endemic region for the virus. There is need to closely monitor and continuously put in place surveillance strategies to prevent probable potential outbreaks in the future.
Impact of exposure frequency on disease burden of the common cold - a mathematical modeling perspective
Authors: Gerdes Sebastian , Rank Michael , Glauche Ingmar , Roeder Ingo
Published: April 2024

The common cold is a frequent disease in humans and can be caused by a multitude of different viruses. Despite its typically mild nature, the high prevalence of the common cold causes significant human suffering and economic costs. Oftentimes, strategies to reduce contacts are used in order to prevent infection. To better understand the dynamics of this ubiquitous ailment, we develop two novel mathematical models: the common cold ordinary differential equation (CC-ODE) model at the population level, and the common cold individual-based (CC-IB) model at the individual level. Our study aims to investigate whether the frequency of population / individual exposure to an exemplary common cold pathogen influences the average disease burden associated with this virus.

On the one hand, the CC-ODE model captures the dynamics of the common cold within a population, considering factors such as infectivity and contact rates, as well as development of specific immunity in the population. On the other hand, the CC-IB model provides a granular perspective by simulating individual-level interactions and infection dynamics, incorporating heterogeneity in contact rates.

By employing these models, we explore the impact of exposure frequencies upon the net disease burden of common cold infections in theoretical settings. In both modeling approaches, we show that under specific parameter configurations (i.e., characteristics of the virus and the population), increased exposure can result in a lower average disease burden. While increasing contact rates may be ethically justifiable for low-mortality common cold pathogens, we explicitly do not advocate for such measures in severe illnesses. The mathematical approaches we introduce are simple yet powerful and can be taken as a starting point for the investigation of specific common cold pathogens and scenarios.
Associations between IL-6 and trajectories of depressive symptoms across the life course: Evidence from ALSPAC and UK Biobank cohorts
Authors: Edmondson-Stait A. J. , Davyson E. , Shen X. , Adams M. J. , Khandaker G. M. , Miron V. E. , McIntosh A. M. , Lawrie S. M. , Kwong A. S. F. , Whalley H. C.
Published: April 2024

Peripheral inflammatory markers, including serum IL-6, are associated with depression, but less is known about how these markers associate with depression at different stages of the life-course. We examined associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10-28y;N=4,835) and UK Biobank (39- 86y;N=39,613) using multi-level growth curve modelling. Models were adjusted for sex, BMI and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire (SMFQ) in ALSPAC (max timepoints=11) and the Patient Health Questionnaire-2 (PHQ-2) in UK Biobank (max timepoints=8). Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 (ALSPAC, age 16y)). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts.
Bad company? The pericardium microbiome in people investigated for tuberculosis pericarditis in an HIV-prevalent setting
Authors: Nyawo Georgina , Naidoo Charissa , Wu Benjamin G. , Kwok Benjamin , Clemente Jose C. , Li Yonghua , Minnies Stephanie , Reeve Byron , Moodley Suventha , John Thadathilankal-Jess , Karamchand Sumanth , Singh Shivani , Pecararo Alfonso , Doubell Anton , Kyriakakis Charles , Warren Robin , Segal Leopoldo N. , Theron Grant
Published: April 2024

Background

The microbiome likely plays a role in tuberculosis (TB) pathogenesis. We evaluated the site-of-disease microbiome and predicted metagenome in people with presumptive tuberculous pericarditis, a major cause of mortality, and explored for the first time, the interaction between its association with C-reactive protein (CRP), a potential diagnostic biomarker and the site-of-disease microbiome in extrapulmonary TB.

Methods

People with effusions requiring diagnostic pericardiocentesis (n=139) provided background sampling controls and pericardial fluid (PF) for 16S rRNA gene sequencing analysed using QIIME2 and PICRUSt2. Blood was collected to measure CRP.

Results

PF from people with definite (dTB, n=91), probable (pTB, n=25), and non- (nTB, n=23) tuberculous pericarditis differed in β-diversity. dTBs were, vs. nTBs,Mycobacterium-, Lacticigenium-,andKocuria-enriched. Within dTBs, HIV-positives wereMycobacterium-, Bifidobacterium-,Methylobacterium-, andLeptothrix-enriched vs. HIV-negatives and HIV-positive dTBs on ART wereMycobacterium- andBifidobacterium-depleted vs. those not on ART. Compared to nTBs, dTBs exhibited short-chain fatty acid (SCFA) and mycobacterial metabolism microbial pathway enrichment. People with additional non-pericardial involvement had differentially PF taxa (e.g.,Mycobacterium-enrichment andStreptococcus-depletion associated with pulmonary infiltrates).Mycobacteriumreads were in 34% (31/91), 8% (2/25) and 17% (4/23) of dTBs, pTBs, and nTBs, respectively. β-diversity differed between patients with CRP above vs. below the median value (Pseudomonas-depleted). There was no correlation between enriched taxa in dTBs and CRP.

Conclusions

PF is compositionally distinct based on TB status, HIV (and ART) status and dTBs are enriched in SCFA-associated taxa. The clinical significance of these findings, including mycobacterial reads in nTBs and pTBs, requires evaluation.
Evidence of Gender Disparities in Citations and Altmetric Attention Score in Oncology
Authors: Campbell Rebecca A. , Helstrom Emma , Chew Lauren , Eapen Renu , Plimack Elizabeth , Correa Andres , Albersen Maarten , Kutikov Alexander , Abbosh Philip , Calaway Adam , Nizam Amanda , Gupta Shilpa , Psutka Sarah , Barata Pedro , Dizman Nazli , Sindhani Mohit , Weight Christopher , Haber Georges , Bukavina Laura
Published: April 2024

In this study, we assess gender disparities in both citation rates and Altmetric Attention Scores (AAS) within oncology, utilizing a dataset comprising over 600,000 articles from the past 15 years. The analysis focuses on the differential impact of gender on citation metrics and AAS, the latter of which expands the evaluation of research impact beyond traditional citation analysis to include digital engagement metrics such as social media mentions, news coverage, and policy discussions.

Methodologically, the study taps into the Altmetric database, using gender identification tools like the Gender Guesser API to classify articles by the gender composition of their first and last authors. Findings reveal a systemic over-citation of male-first and male-last author pairs (MM), with a mean citation difference (MCD) of +4.7. In stark contrast, female-first and female-last author pairs (WW) experience under-citation, with an MCD of -3.5.

A detailed examination of the Altmetric Attention Score shows that female-first authors receive a 7.19% lower AAS compared to male-first authors, indicating significant gender biases in the broader academic and public engagement. Delving deeper into the components of AAS, specifically news media coverage, reveals that female-first authors are covered 10.9% less in news media, 20.4% less patent references and 33.4% in Weibo mentions than their male counterparts. This disparity is significant and suggests a broader trend of underrepresentation and undervaluation of female-led research in more public-facing and influential media outlets.

These results underscore the persistent influence of gender on the recognition and valuation of scientific contributions within the field of oncology. They highlight the need for academia and publishing entities to implement more equitable practices to mitigate these disparities and ensure a balanced representation and recognition of scholarly work across genders.
A posterior approach to correct for focal plane offsets in lattice light sheet structured illumination microscopy
Authors: Shi Yu , Daugird Tim A. , Legant Wesley R.
Published: April 2024

Significance

Lattice light sheet structured illumination microscopy (latticeSIM) has proven highly effective in producing 3D images with super resolution rapidly and with minimal photobleaching. However, due to the use of two separate objectives, sample-induced aberrations can result in an offset between the planes of excitation and detection, causing artifacts in the reconstructed images.

Aim

We introduce a posterior approach to detect and correct for the axial offset between the excitation and detection focal planes in latticeSIM and provide a method to minimize artifacts in the reconstructed images.

Approach

We utilized the residual phase information within the overlap regions of the laterally shifted structured illumination microscopy (SIM) information components in frequency space to retrieve the axial offset between the excitation and the detection focal planes in latticeSIM.

Results

We validated our technique through simulations and experiments, encompassing a range of samples from fluorescent beads to subcellular structures of adherent cells. We also show utilizing transfer functions with the same axial offset as that which was present during the data acquisition results in reconstructed images with minimal artifacts and salvages otherwise unusable data.

Conclusion

We envision that our method will be a valuable addition to restore image quality in latticeSIM datasets even for those acquired under non-ideal experimental conditions.
Centromeric chromatin clearings demarcate the site of kinetochore formation
Authors: Kixmoeller Kathryn , Chang Yi-Wei , Black Ben E.
Published: April 2024

The centromere is the chromosomal locus that recruits the kinetochore, directing faithful propagation of the genome during cell division. The kinetochore has been interrogated by electron microscopy since the middle of the last century, but with methodologies that compromised fine structure. Using cryo-ET on human mitotic chromosomes, we reveal a distinctive architecture at the centromere: clustered 20-25 nm nucleosome-associated complexes within chromatin clearings that delineate them from surrounding chromatin. Centromere components CENP-C and CENP-N are each required for the integrity of the complexes, while CENP-C is also required to maintain the chromatin clearing. We further visualize the scaffold of the fibrous corona, a structure amplified at unattached kinetochores, revealing crescent-shaped parallel arrays of fibrils that extend >1 μm. Thus, we reveal how the organization of centromeric chromatin creates a clearing at the site of kinetochore formation as well as the nature of kinetochore amplification mediated by corona fibrils.
A Cell-Permeable Nanobody to Restore F508del Cystic Fibrosis Transmembrane Conductance Regulator Activity
Authors: Franz Luise , Rubil Tihomir , Balázs Anita , Overtus Marie , Kemnitz-Hassanin Kristin , Govaerts Cedric , Mall Marcus A. , Hackenberger Christian P.R.
Published: April 2024

Nanobodies have gained considerable attention as particularly promising biopharmaceuticals. However, nanobody-based modalities are currently limited to extracellular targets due to a lack of efficient delivery methods required to reach targets inside cells. In this study, we introduce cell-permeable nanobodies for targeting a disease-relevant intracellular protein, namely the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel with the most common cystic fibrosis (CF)-causing mutation F508del. We employ cell-penetrating peptides (CPPs) to deliver a CFTR-binding nanobody (NB1) that stabilizes misfolded F508del-CFTR and prevents its degradation to restore its function. Our data show that conjugation of a disulfide-linked CPP in combination with a cell-surface anchored CPP-additive enables intracellular delivery of NB1 into CF bronchial epithelial cells, which promotes maturation and trafficking of F508del-CFTR protein to the apical cell membrane. Furthermore, we demonstrate that the cell-permeable nanobody restores CFTR chloride channel function, which can be further enhanced by the clinically approved small molecule CFTR potentiator ivacaftor. This study highlights the use of cell-permeable nanobodies for modulation of protein function and illustrates their therapeutic potential as next-generation biopharmaceuticals for intracellular delivery and targeting.

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Serotype switching inPseudomonas aeruginosaST111 enhances adhesion and virulence
Authors: Anbo Mikkel , Lubna Mahbuba Akter , Moustafa Dina A. , Paiva Telmo O. , Serioli Laura , Zor Kinga , Sternberg Claus , Jeannot Katy , Dufrêne Yves F. , Goldberg Joanna B. , Jelsbak Lars
Published: April 2024

Evolution of the highly successful and multidrug resistant clone ST111 inPseudomonas aeruginosainvolves serotype switching from O-antigen O4 to O12. How expression of a different O-antigen serotype alters pathogen physiology to enable global dissemination of this high-risk clone-type is not understood. Here, we engineered isogenic laboratory and clinicalP. aeruginosastrains that express the different O-antigen gene clusters to assess the correlation of structural differences of O4 and O12 O-antigens to pathogen-relevant phenotypic traits. We show that serotype O12 is associated with enhanced adhesion, type IV pili dependent twitching motility, and tolerance to host defense molecules and serum. Moreover, we find that serotype O4 is less virulent compared to O12 in an acute murine pneumonia infection in terms of both colonization and survival rate. Finally, we find that these O-antigen effects may be explained by specific biophysical properties of the serotype repeat unit found in O4 and O12, and by differences in membrane stability between O4 and O12 expressing cells. The results demonstrate that differences in O-antigen sugar composition can directly affectP. aeruginosapathogenicity traits, and provide a better understanding of the potential selective advantages that underlie serotype switching and emergence of serotype O12 ST111.
Staphylococcus warneridampens SUMOylation and promotes intestinal inflammation
Authors: Loison Léa , Huré Marion , Lefranc Benjamin , Leprince Jérôme , Coëffier Moïse , Ribet David
Published: April 2024

Gut bacteria play key roles in intestinal physiology, via the secretion of diversified bacterial effectors. Many of these effectors remodel the host proteome, either by altering transcription or by regulating protein post-translational modifications. SUMOylation, a ubiquitin-like post-translational modification playing key roles in intestinal physiology, is a target of gut bacteria. Mutualistic gut bacteria can promote SUMOylation, via the production of short- or branched-chain fatty acids (SCFA/BCFA). In contrast, several pathogenic bacteria were shown to dampen SUMOylation in order to promote infection. Here, we challenge this dichotomic vision by showing thatStaphylococcus warneri, a non-pathogenic bacterium of the human gut microbiota, decreases SUMOylation in intestinal cells. We identified that Warnericin RK, a hemolytic toxin secreted byS. warneri, targets key components of the host SUMOylation machinery, leading to the loss of SUMO-conjugated proteins. We further demonstrate that the dampening of SUMOylation triggered by Warnericin RK promotes inflammation, and, more particularly, TNFα-dependent intestinal inflammatory responses.

Together, these results highlight the diversity of mechanisms used by non-pathogenic bacteria from the gut microbiota to manipulate host SUMOylation. They further highlight that changes in gut microbiota composition may impact intestinal inflammation, by changing the equilibrium between bacterial effectors promoting or dampening SUMOylation.
EnteropathogenicProvidencia alcalifaciens: A subgroup ofP. alcalifaciensthat causes diarrhea
Authors: Bulach Dieter , Carter Glen P. , Albert M. John
Published: April 2024

Even thoughProvidencia alcalifaciensis considered as a normal flora of the large intestine, there are reports of it causing diarrhea. In a previous study, a strain, 2939/90 obtained as a pure stool culture from a dead diarrheal patient was shown to cause invasion and actin condensation in mammalian cells, and diarrhea in a rabbit model. In a subsequent study, four TnphoAmutants of 2939/90 produced negligible invasion and actin condensation in mammalian cells. In the present study, the parent strain was sequenced by short-read and long-read sequencing, and the mutants by short read sequencing. In all four mutants, a TnphoAinsertion was detected in the type three secretion system (T3SS) locus present on the largest of four plasmids (p2939_90_1) and not in a seemingly independent, functional T3SS locus on the chromosome. A survey of 52 genomes ofP. alcalifaciensavailable in the public database identified the chromosomal T3SS locus in all strains, including bothP. alcalifaciensgenomic clades that we have classified as (group A) and (group B); a highly related gene layout and gene synteny flanking the locus suggested that these chromosomal loci are orthologous. There is a low sequence similarity between the chromosomal and plasmid-borne T3SS; a survey of plasmid T3SS showed its presence in only 21 of 52 genomes and mostly in group A genomes. Group A included several isolates from an outbreak of haemorrhagic diarrhea in dogs. Using prediction software (EffectiveDB), we detected several known and unknown effectors flanking the plasmid T3SS locus. The observation that TnphoAinsertion only in the plasmid T3SS locus affected the invasion phenotype suggested that this locus is critical for causation of diarrhea. This leads us to conclude that a subgroup ofP. alcalifaciensthat possesses this plasmid-borne T3SS locus (in the case of strain, 2939/90) can cause diarrheal disease. We name this subgroup as enteropathogenicP. alcalifaciens(EPA). EPA should be included in future studies of etiology of diarrhea. A unique sequence that may be present in the T3SS locus in the plasmid may be investigated as a marker in a simple molecular test for diagnosis of EPA.
Pervasive translation of the downstream ORF from bicistronic mRNAs by human cells: impact of the upstream ORF codon usage and splicing
Authors: Paget-Bailly Philippe , Helpiquet Alexandre , Decourcelle Mathilde , Bories Roxane , Bravo Ignacio G.
Published: April 2024

In this work, we present a straightforward model to study gene expression regulation from virus-like bicistronic mRNAs in human cells, composed by a shortshbleupstream ORF and a reporteregfpdownstream ORF. We have engineered thirteen synonymous versions of theshbleORF to explore a large parameter space in compositional and folding features, as well as differences in propensity to undergo splicing. Our experimental model focuses on the control and modulation ofshbletranslation elongation and their effects on downstream translation: i) regarding translation initiation, all constructs share identical 5’UTR, ribosomal binding site andshblestart codon context; and ii) regardingegfptranslation, all constructs share identicalshblestop codon context, spacer betweenshbleandegfpand the fullegfpsequence. Our results show first that the human translation machinery can translate the downstream ORF in bicistronic mRNAs, independently of the characteristics of the upstream ORF. Even if GFP protein levels are hundreds of times lower than SHBLE protein levels, our results challenge the textbook interpretation positing that the eukaryotic translation machinery does not handle the downstream ORF in bicistronic transcripts. Second, we show that synonymous recoding of the upstream ORF determines its own translation efficiency, can uncover cryptic splice signals, and largely conditions the probability of translation from the downstream ORF. Our results are consistent with a leaky scanning mechanism at play for downstream ORF translation from bicistronic mRNAs in human cells.
Long range segmentation of prokaryotic genomes by gene age and functionality
Authors: Wolf Yuri I. , Schurov Ilya V. , Makarova Kira S. , Katsnelson Mikhail I. , Koonin Eugene V.
Published: April 2024

Bacterial and archaeal genomes encompass numerous operons that typically consist of two to five genes. On larger scales, however, gene order is poorly conserved through the evolution of prokaryotes. Nevertheless, non-random localization of different classes of genes on prokaryotic chromosomes could reflect important functional and evolutionary constraints. We explored the patterns of genomic localization of evolutionarily conserved (ancient) and variable (young) genes across the diversity of bacteria and archaea. Nearly all bacterial and archaeal chromosomes were found to encompass large segments of 100-300 kilobases that were significantly enriched in either ancient or young genes. Similar clustering of genes with lethal knockout phenotype (essential genes) was observed as well. Mathematical modeling of genome evolution suggests that this long-range gene clustering in prokaryotic chromosomes reflects perpetual genome rearrangement driven by a combination of selective and neutral processes rather than evolutionary conservation.