bluuebunny/crossref_metadata_2025 huggingface dataset:
Reassessing the link between adiposity and head and neck cancer: a Mendelian randomization study
Authors: Morales-Berstein Fernanda , Khouja Jasmine , Gormley Mark , Ebrahimi Elmira , Virani Shama , McKay James , Brennan Paul , Richardson Tom G , Relton Caroline L , Davey Smith George , Borges M Carolina , Dudding Tom , Richmond Rebecca C
Published: November 2024

Background

Adiposity has been associated with an increased risk of head and neck cancer (HNC). Although body mass index (BMI) has been inversely associated with HNC risk among smokers, this is likely due to confounding. Previous Mendelian randomization (MR) studies could not fully discount causality between adiposity and HNC due to limited statistical power. Hence, we aimed to revisit this using the largest genome-wide association study (GWAS) of HNC available, which has more granular data on HNC subsites.

Methods

We assessed the genetically predicted effects of BMI (N=806,834), waist-to-hip ratio (WHR; N=697,734) and waist circumference (N=462,166) on the risk of HNC (N=12,264 cases and 19,259 controls) and its subsites (oral, laryngeal, hypopharyngeal and oropharyngeal cancers) using a two-sample MR framework. We used the inverse variance weighted (IVW) MR approach and multiple sensitivity analyses including the weighted median, weighted mode, MR-Egger, MR-PRESSO, and CAUSE approaches. We also used multivariable MR (MVMR) to explore the direct effects of the adiposity measures on HNC, while accounting for smoking behaviour, a well-known HNC risk factor.

Results

In univariable MR, higher genetically predicted BMI increased the risk of overall HNC (IVW OR=1.17 per 1 standard deviation [1-SD] higher BMI, 95% CI 1.02–1.34, p=0.03), with no heterogeneity across subsites (Q p=0.78). However, the effect was not consistent in sensitivity analyses. The IVW effect was attenuated when smoking was included in the MVMR model (OR accounting for comprehensive smoking index=0.96 per 1-SD higher BMI, 95% CI 0.80–1.15, p=0.64) and CAUSE indicated the IVW results could be biased by correlated pleiotropy. Furthermore, we did not find a link between genetically predicted WHR (IVW OR=1.05 per 1-SD higher WHR, 95% CI 0.89–1.24, p=0.53) or waist circumference and HNC risk (IVW OR=1.01 per 1-SD higher waist circumference, 95% CI 0.85–1.21, p=0.87).

Conclusions

Our findings suggest that adiposity does not play a role in HNC risk.
Evaluating the Efficacy of Miglustat and Ambroxol Combination Therapy in a Phase 1b/2 Virtual Drug Trial for Type 1 Tay-Sachs Disease Using aiHumanoid Simulations
Authors: Danter WR
Published: November 2024

Abstract (Draft1)

Type 1 Tay-Sachs Disease (TSD) is a rare and severe neurodegenerative disorder caused by HEXA Loss of Function (LOF) gene mutations, leading to the accumulation of lysosomal GM2 gangliosides and progressive neurological decline, with high lethality before age 10. Current treatments are primarily palliative, focusing on symptom management. This study investigates the therapeutic potential of Miglustat and Ambroxol, individually and combined, in slowing neurodegeneration and cognitive decline in Type 1 TSD, leveraging aiHumanoid virtual simulations. Miglustat, a substrate reduction therapy, and Ambroxol, a pharmacological chaperone, offer complementary mechanisms that may enhance lysosomal function and reduce ganglioside accumulation. In a virtual Phase 1b/2 trial, simulated cohorts of children received these treatments across four dose levels (10%, 20%, 33.3%, and 50% of maximum tolerated dose [MTD]), with outcomes assessed at intervals from birth to 10 years. Key metrics included cognitive and motor function, quality of life, and lysosomal enzyme activity. Results indicated that combination therapy significantly reduced neurodegenerative symptoms and improved cognitive and motor outcomes, particularly at intermediate dose levels. Findings suggest that Miglustat and Ambroxol may provide a beneficial intervention strategy, warranting further clinical evaluation. These results also provide important potential insights into dose optimization and therapeutic synergies, offering a basis for real-world trials in Type 1 Tay-Sachs Disease. The use of aiHumanoid simulations demonstrates a novel approach for drug testing in rare diseases, enabling detailed assessment of efficacy and safety profiles across developmental stages. The trial’s findings are based on virtual simulations rather than traditional clinical trials.
The Role of Birth Companionship in Women’s Experiences of Mistreatment during Childbirth and Postpartum Depression
Authors: Hameed Waqas , Khan Bushra , Avan Bilal Iqbal
Published: November 2024

Introduction

Birth companionship during facility-based childbirth has been recommended by the World Health Organization to improve maternal and newborn outcomes. However, limited evidence exists on how companionship affects women’s experiences of mistreatment during childbirth and their mental health.

Objectives

To assess the characteristics of birth companionship during intrapartum care and examine its associations with women’s experiences of mistreatment and postpartum anxiety and depression.

Methods

We analysed cross-sectional data on 314 women who gave birth in six public health facilities in rural Sindh, Pakistan. Women were interviewed 42 days postpartum about their childbirth experiences and postpartum anxiety and depression. Multivariable regression models were used to examine associations between birth companionship, mistreatment, and postpartum anxiety/depression. Path analysis explored whether mistreatment mediated the relationship between companionship and postpartum anxiety and depression.

Results

Most women (83.1%) had a full-time companion in the labor room, with in-laws (44.6%) being the most common, followed by family members (26.1%) and friends (15.0%). Higher levels of companion support were associated with lower levels of mistreatment, particularly regarding non-confidential care, lack of supportive care, and ineffective communication. Women receiving low companion support were 2.86 times more likely to experience postpartum anxiety and depression compared to those receiving high support. Informational support emerged as the strongest protective factor against both mistreatment and postpartum anxiety/depression. Path analysis revealed that the effect of companion support on postpartum mental health was mediated by experiences of mistreatment during childbirth.

Conclusion

Birth companionship, especially informational support, plays a crucial role in reducing mistreatment during childbirth and improving maternal mental health outcomes. These findings underscore the need for supportive policies and health system interventions that actively encourage the engagement of companions from a woman’s personal network during labor and childbirth. Future research should explore strategies to optimize the role of birth companions in promoting respectful maternity care and maternal well-being.
Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2
Authors: Esmaeili Shadisadat , Owens Katherine , Standing Joseph F. , Lowe David M. , Zhang Shengyuan , Watson James A. , Schilling William H. K. , Wagoner Jessica , Polyak Stephen J. , Schiffer Joshua T.
Published: November 2024

Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 7-8 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ∼0.5 log10in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.
Transcriptome-wide analyses delineate the genetic architecture of expression variation in atopic dermatitis
Authors: Antonatos Charalabos , Mitsoudi Dimitra , Pontikas Alexandros , Akritidis Adam , Xiropotamos Panagiotis , Georgakilas Georgios K. , Georgiou Sophia , Tsiogka Aikaterini , Gregoriou Stamatis , Grafanaki Katerina , Vasilopoulos Yiannis
Published: November 2024

Genome-wide association studies (GWASs) for atopic dermatitis (AD) have uncovered 81 risk loci in European participants, however translating these findings into functional and therapeutic insights remains challenging. We conducted a transcriptome-wide association study (TWAS) in AD leveragingcis-eQTL data from 3 central AD tissues and the latest GWAS of AD in Europeans. We implemented the OTTERS pipeline that combines polygenic risk score (PRS) techniques accommodating diverse assumptions in the architecture of gene regulation. We also used differential expression datasets and co-expression networks to characterize the transcriptomic landscape of AD. We identified 176 gene-tissue associations covering 126 unique genes (53 novel). Most TWAS risk genes were identified by adaptive PRS frameworks, with non-significant differences compared to clumping and thresholding approaches. The novel TWAS risk genes were enriched in allergic reactions (e.g.,AQP7,AFF4), skin barrier integrity (e.g.,ACER3) and inflammatory pathways (e.g.,TAPBPL). By integrating co-expression networks of lesional AD skin, we identified 16 hub genes previously identified as TWAS risk genes (6 novel) that orchestrate inflammatory responses (e.g.,HSPA4) and keratinization (e.g.,LCE3E,LCE3D), serving as potential drug targets through drug-gene interactions. Collectively, our findings provide additional risk genes for AD with potential implications in therapeutic approaches.
Mobilizing community-driven public health response: increasing access to diagnostic testing for underserved and uninsured individuals in Connecticut through lab-in-a-van partnerships
Authors: Choate Brittany , Sardana Ruhani , Mathews Acsah , Weirsman Stephanie , Fajardo Katherine , Ali Yasmine , Liu Chen , Hui Pei , Schofield Kevin , Wyllie Anne L. , Levi Angelique W.
Published: November 2024

Background

Partnering with community leaders, we sought to address ongoing diagnostic testing needs in underserved neighborhoods and evaluate whether a saliva-based mobile testing program could help overcome barriers to testing for uninsured and low-income individuals. This is critical as many lack a primary care provider, cannot access reliable health information, or have limited financial resources.

Methods

Free saliva-based, SARS-CoV-2 diagnostic testing was offered at 123 local community events in Connecticut, between June 2023 to July 2024. The SalivaDirect extraction-free RT-qPCR protocol was run on a CLIA licensed van operated by Yale Pathology Labs under FDA Emergency Use Authorization. Testing locations were identified and advertised in partnership with the community. Patient perspectives on approachability, convenience, and usefulness of mobile testing were recorded via REDcap.

Results

Approximately 100 local contacts informed the mobile testing model. Overall, 1,428 individuals participated, with 838 completing a testing experience survey. Of these, 54% identified as Black, Indigenous, People of Color; 59% reported annual household income less than $25,000; 31% were uninsured. Test results were reported in an average 3.1 hours, 48 positive samples were identified. Test takers agreed it was easy to access the van (74%) and felt comfortable (75%); 29% received their first COVID-19 test at the van; 48% were unaware of alternate testing; 44% reported difficulty accessing health care; and 49% identified transportation as a challenge.

Conclusions

This study demonstrated the positive impact mobile testing could have for overcoming barriers to accessing healthcare, and its potential to serve as a framework for managing and responding to future public health needs.
Coordinated protein modules define DNA damage responses to carboplatin at single cell resolution in human ovarian carcinoma models
Authors: Bedia Jacob S. , Huang Ying-Wen , Gonzalez Antonio Delgado , Gonzalez Veronica D. , Funingana Ionut-Gabriel , Rahil Zainab , Mike Alyssa , Lowber Alexis , Vias Maria , Ashworth Alan , Brenton James D. , Fantl Wendy J.
Published: November 2024

Tubo-ovarian high-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy and frequently responds to platinum-based chemotherapy because of common genetic and somatic impairment of DNA damage repair (DDR) pathways. The mechanisms of clinical platinum resistance are diverse and poorly molecularly defined. Consequently, there are no biomarkers or medicines that improve patient outcomes. Herein we use single cell mass cytometry (CyTOF) to systematically evaluate the phosphorylation and abundance of proteins known to participate in the DNA damage response (DDR). Single cell analyses of highly characterized HGSC cell lines that phenocopy human patients show that cells with comparable levels of intranuclear platinum, a proxy for carboplatin uptake, undergo different cell fates. Unsupervised analyses revealed a continuum of DDR responses. Decompositional methods were used to identify eight distinct protein modules of carboplatin resistance and sensitivity at single cell resolution. CyTOF profiling of primary and secondary platinum-resistance patient models shows that a complex DDR sensitivity module is strongly associated with response, suggesting it as a potential tool to clinically characterize complex drug resistance phenotypes.
Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging
Authors: Zhang Zihan , Ma Bin , Li Buyao , Li Zhiwei , Gao Min , Zhao Hailong , Peng Rui , Hu Jiang , Wang Yu , You Wei , Gui Xun , Wang Rui , Hu Xiaoqing , Chen Beidi , Zhang Yuanjie , Hao Yanyun , Zhou Demin , Yang Yun , Deng Mi , Miao Lei
Published: November 2024

mRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipid’s packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPAR’s relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders.

One Sentence Summary

We’ve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.
Sustained non-photochemical quenching and regulation of PSII repair cycle during combined low temperature and high light stress in lettuce
Authors: Lempiäinen Tapio , Muth-Pawlak Dorota , Vainonen Julia P. , Rintamäki Eevi , Tikkanen Mikko , Aro Eva-Mari
Published: November 2024

In nature, light and other environmental conditions are constantly changing, requiring plants to have several overlapping regulatory mechanisms to keep light reactions and metabolism in balance. Here, we show that high light (HL) induces a much stronger down-regulation of light reactions when lettuce plants are exposed to 1500 µmol photons m−2s−1for 4 h at 13°C (low temperature, LT) compared to 23°C (growth temperature, GT). GT/HL treatment induced non-photochemical quenching (NPQ), which relaxed during 1 h recovery in darkness. In contrast, LT/HL treatment induced an exceptionally high NPQ that only partially relaxed during 1 h in darkness at GT. Such a high sustained NPQ (sNPQ) cannot be explained by canonical NPQ mechanism(s). Instead, sNPQ was associated with partial disassembly of PSII-LHCII complexes and a transient increase in phosphorylation of the minor antenna proteins LHCB4.1/LHCB4.2. This coincided with increased expression of the light-harvesting-like proteins SEP2 and ELIP1.2, the PSII assembly proteins HCF173 and LPA3, and accumulation of the pre-D1 protein. These results lead us to propose that LHCB4.1/LHCB4.2 phosphorylation- dependent disassembly of PSII-LHCII supercomplexes allows SEP2 to bind to CP47 and hypothetically quenches the inner PSII core antenna, while free CP43 released during PSII repair is proposed to be protected by LPA3.
Impact of Acute Endurance Exercise on Alternative Splicing in Skeletal Muscle
Authors: Ahn Alexander , Kim Jeongjin J. , Slusher Aaron L. , Ying Jeffrey Y. , Zhang Eric Y. , Ludlow Andrew T.
Published: November 2024

Purpose

Alternative RNA splicing (AS) is a highly conserved post-transcriptional mechanism, generating mRNA variants to diversify the proteome. Acute endurance exercise appears to transiently perturb AS in skeletal muscle, but transcriptome-wide responses are not well-defined. We aimed to better understand differential AS (DAS) in skeletal muscle by comparing short-read RNA sequencing (SRS) and long-read RNA sequencing (LRS) data.

Methods

Publicly accessible SRS of clinical exercise studies were extracted from the Gene Expression Omnibus. Oxford Nanopore LRS was performed on mouse gastrocnemius before and following treadmill exercise. Differential gene expression (DGE), DAS, and isoform switching were analyzed. Western blots were performed to validate expression changes of candidate genes.

Results

Both SRS and LRS illustrated significant DGE in skeletal muscle post-exercise, whereby 57 and 15 RNA-binding proteins (RBPs) were up-/down-regulated, respectively. rMATS analysis of SRS data revealed that exon-skipping and intron-retaining splicing events were the most common. Swan analysis of LRS data revealed 38 RBPs with significant isoform switching: one of these RBPs,Hnrnpa3, underwent a significant intron-retained to protein-coding switch. HnRNP-A3 protein levels validated nearly two-fold increases at 1 hour (p=.0043) and 24 hours (p=.0103) post-exercise.

Conclusions

This study illustrates that acute endurance exercise can elicit changes in AS-related responses and RBP expression in skeletal muscle. SRS is certainly a powerful tool for analyzing DGE but lacks AS detection. As such, “hidden” genes with no transcriptional changes but significant DAS and protein expression changes pose a major gap in knowledge. Our work highlights how LRS can uncover previously unknown transcript diversity and mechanisms influencing endurance exercise adaptations and responses.
Dermatopontin-expressing fibroblasts mediate an essential skin macrophage niche
Authors: Vollmers Apple Cortez , Wu Sunny Z. , Altieri Anthony , McCartney Erika E. , Bender Hannah , Lee Wyne P. , Zhang Juan , Hu Crystal , Uttarwar Salil , Vander Heiden Jason A. , Davidson Christopher , Chung Yein , Ortiz Willie , Long Michael , Asuncion Raymond , Yang Yeqing Angela , Jiang Jean X. , Modrusan Zora , Krishnamurty Akshay T. , Fu Wenxian , Müller Sören , Buechler Matthew B. , Turley Shannon J.
Published: November 2024

Fibroblasts are present in all tissues and are crucial for maintaining tissue homeostasis. We previously identified fibroblasts marked byDermatopontin(Dpt) but their role in supporting macrophage homeostasis remains unclear. Here, we generated novel mesenchymal lineage-restricted genetic tools to targetDptexpressing fibroblasts and elucidate their role in supporting skin macrophages. Transcriptional profiling, flow cytometry, and in situ hybridization uncovered two broad populations of F4/80-expressing skin macrophages, denoted by high expression of CD206 and CD64 (CD206hiCD64+), or CD11c. Targeted depletion ofDpt+ fibroblasts resulted in a profound loss of both macrophage populations. Conditional deletion of colony-stimulating factor-1 (Csf1)inDpt+ fibroblasts revealed that CD206hiCD64+, and not CD11c+, macrophages are acutely dependent on fibroblast-derivedCsf1, consistent with their higher expression of theCsf1receptor. FollowingCsf1deletion inDpt+ fibroblasts, loss of CD206hiCD64+ macrophages were observed across the dermis, dermal white adipose tissue (dWAT), and adventitia, accompanied by a modest upregulation of fibroblast-related and extracellular matrix (ECM) genes and structural changes to the skin. Alterations to the skin network upon loss of fibroblast-derivedCsf1and CD206hiCD64+ macrophages led to a significant delay in wound healing. We also demonstrate the CSF1-CSF1R signaling pathway is functionally relevant in human systemic sclerosis, or scleroderma, as elevated levels of CSF1 produced by fibroblasts and an increased abundance of macrophages both correlate with disease severity. Our findings demonstrate the role ofDpt+ fibroblasts in regulating aCsf1-dependent macrophage niche in skin and orchestrating responses in injury and disease.
Proteome allocation of the microbiome reveals how diet and metabolic dysbiosis impact disease
Authors: Tibocha-Bonilla Juan D. , Santibanez-Palominos Rodrigo , Weng Yuhan , Kumar Manish , Zengler Karsten
Published: November 2024

The gut microbiome plays a critical role in human health, spurring extensive research into host-microbe interactions using multi-omic technologies. Although these tools offer valuable insights, they often fall short in capturing the complexity of microbial interactions and assigning causality to disease onset, progression, and treatment. Proteome allocation is intertwined with microbial interactions, yet there is little mechanistic knowledge. Here, we deploy models of metabolism and gene expression (ME-models) that predict proteome allocation. Despite their potential, their deployment has been limited by the laborious reconstruction process. To address this, we reconstructed 495 ME-models for human gut microbes using an automated pipeline. By integrating ME-models with multi-omics data from patients with inflammatory bowel disease (IBD), we identified taxa responsible for variations in amino acids, short-chain fatty acids, and pH in the gut of IBD patients. Thus, this approach provides a mechanistic understanding and paves the way for new intervention strategies.
Interpretable AI in Tissue Engineering: XGBoost and SHAP for PLGA Scaffold Biocompatibility
Authors: Rafat Md Tanzim
Published: November 2024

The refinement of scaffold materials is essential in tissue engineering to promote cellular growth and tissue regeneration. This study applied Extreme Gradient Boosting (XGBoost) and SHapley Additive exPlanations (SHAP) to predict and interpret the biocompatibility of poly(lactic-co-glycolic acid) (PLGA)-based scaffolds. A dataset of 10,010 synthetic samples was analyzed, examining key scaffold features such as Young’s Modulus, Ultimate Tensile Strength, Strain at Failure, Compressive Modulus, Pore Size, Porosity, and Degradation Time. The XGBoost model demonstrated high predictive accuracy with a Root Mean Square Error (RMSE) of 2.59. SHAP analysis identified Young’s Modulus, Strain at Failure, and Ultimate Tensile Strength as the most influential factors affecting biocompatibility. These findings highlight the critical role of mechanical properties in scaffold performance, particularly in cell adhesion and tissue integration. This research offers a data-driven framework for optimizing scaffold designs and integrating machine learning predictions with biological insights for improved tissue engineering applications.
Reconciling competing models on the roles of condensates and soluble complexes in transcription factor function
Authors: Bremer Anne , Lang Walter H. , Kempen Ryan P. , Sweta Kumari , Taylor Aaron B. , Borgia Madeleine B. , Ansari Aseem Z. , Mittag Tanja
Published: November 2024

Phase separation explains the exquisite spatial and temporal regulation of many biological processes, but the role of transcription factor–mediated condensates in gene regulation is contentious, requiring head-to-head comparison of competing models. Here, we focused on the prototypical yeast transcription factor Gcn4 and assessed two models for gene transcription activation, i.e., mediated via soluble complexes or transcriptional condensates. Both models rely on the ability of transcription factors and coactivators to engage in multivalent interactions. Unexpectedly, we found that propensity to form homotypic Gcn4 condensates does not correlate well with transcriptional activity. Contrary to prevailing models, binding to DNA suppresses Gcn4 phase separation. Notably, the ability of Gcn4 to form soluble complexes with coactivator subunit Med15 closely mirrored the propensity to recruit Med15 into condensates, indicating that these properties are intertwined and cautioning against interpretation of mutational data without head-to-head comparisons. However, Gcn4 variants with the highest affinity for Med15 do not function as well as expected and instead have activities that reflect their abilities to phase separate with Med15. These variants therefore indeed form cellular condensates, and those attenuate activity. Our results show that transcription factors can function as soluble complexes as well as condensates, reconciling two seemingly opposing models, and have implications for other phase-separating systems.

Highlights

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Homotypic phase separation propensities of Gcn4 variants do not predictin vivoactivities well.

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DNA binding leads to solubilization of GCN4 condensates, which is reversed by Med15 association.

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The abilities to co-phase separate and form soluble complexes with Med15 are highly intertwined.

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Variants with high affinities for Med15 form condensates that attenuate function.
Diverse priming outcomes under conditions of very rare precursor B cells
Authors: Madden Patrick J. , Marina-Zárate Ester , Rodrigues Kristen A. , Steichen Jon M. , Shil Monolina , Ni Kaiyuan , Michaels Katarzyna Kaczmarek , Maiorino Laura , Upadhyay Amit A. , Saha Swati , Pradhan Arpan , Kalyuzhiny Oleksandr , Liguori Alessia , Lopez Paul G. , Phung Ivy , Phelps Nicole , Georgeson Erik , Alavi Nushin , Kubitz Michael , Lu Danny , Eskandarzadeh Saman , Metz Amanda , Rodriguez Oscar L. , Shields Kaitlyn , Schultze Steven , Smith Melissa L. , Healy Brandon S. , Lim Deuk , Lewis Vanessa R. , Ben-Akiva Elana , Pinney William , Gregory Justin , Xiao Shuhao , Carnathan Diane G. , Kasturi Sudhir Pai , Watson Corey T. , Bosinger Steven E. , Silvestri Guido , Schief William R. , Irvine Darrell J , Crotty Shane
Published: November 2024

Rare B cells can have special pathogen-recognition features giving them the potential to make outsized contributions to protective immunity. However, rare naive B cells infrequently participate in immune responses. We investigated how germline-targeting vaccine antigen delivery and adjuvant selection affect priming of exceptionally rare BG18-like HIV broadly neutralizing antibody-precursor B cells (~1 in 50 million) in non-human primates. Only escalating dose (ED) priming immunization using the saponin adjuvant SMNP elicited detectable BG18-like cells in germinal centers (GCs). All groups had strong GC responses, but only ED+SMNP and bolus+SMNP induced BG18-like memory B cells in >50% of animals. One group had vaccine-specific GC responses equivalent to ED+SMNP, but BG18-like memory B cells were rarely detected. Following homologous boosting, BG18-like memory B cells were more frequent in a bolus priming group, but had lower somatic hypermutation and affinities. This outcome was inversely associated with post-prime antibody titers, suggesting antibody feedback can significantly influence rare precursor B cell responses.
TheSalmonellapathogenicity island 1-encoded small RNA InvR mediates post-transcriptional feedback control of the activator HilA inSalmonella
Authors: Hou Yutong , Kim Kyungsub , Cakar Fatih , Golubeva Yekaterina A. , Slauch James M. , Vanderpool Carin K.
Published: November 2024

SalmonellaPathogenicity Island 1 (SPI1) encodes a type three secretion system (T3SS) essential forSalmonellainvasion of intestinal epithelial cells. Many environmental and regulatory signals control SPI1 gene expression, but in most cases, the molecular mechanisms remain unclear. Many of these regulatory signals control SPI1 at a post-transcriptional level and we have identified a number of small RNAs (sRNAs) that control the SPI1 regulatory circuit. The transcriptional regulator HilA activates expression of the genes encoding the SPI1 T3SS structural and primary effector proteins. Transcription ofhilAis controlled by the AraC-like proteins HilD, HilC, and RtsA. ThehilAmRNA 5’ untranslated region (UTR) is ~350-nuclotides in length and binds the RNA chaperone Hfq, suggesting it is a likely target for sRNA-mediated regulation. We used the rGRIL-seq (reverse global sRNA target identification by ligation and sequencing) method to identify sRNAs that bind to thehilA5’ UTR. The rGRIL-seq data, along with genetic analyses, demonstrate that the SPI1-encoded sRNA InvR base pairs at a site overlapping thehilAribosome binding site. HilD and HilC activate bothinvRandhilA. InvR in turn negatively regulates the translation of thehilAmRNA. Thus, the SPI1-encoded sRNA InvR acts as a negative feedback regulator of SPI1 expression. Our results suggest that InvR acts to fine-tune SPI1 expression and prevent overactivation ofhilAexpression, highlighting the complexity of sRNA regulatory inputs controlling SPI1 andSalmonellavirulence.

IMPORTANCE

SalmonellaTyphimurium infections pose a significant public health concern, leading to illnesses that range from mild gastroenteritis to severe systemic infection. Infection is initiated and requires a complex apparatus that the bacterium uses to invade the intestinal epithelium. Understanding howSalmonellaregulates this system is essential for addressing these infections effectively. Here we show that the small RNA (sRNA) InvR imposes negative feedback regulation on expression of the invasion system. This work underscores the role of sRNAs inSalmonella’scomplex regulatory network, offering new insights into how these molecules contribute to bacterial adaptation and pathogenesis.
Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway
Authors: Yu Shang , Ding Jin-hui , Wang Weize , Wang Jia-le , Zuo Peng , Yang Ao , Dai Zonglin , Yin Yuxin , Sun Jin-peng , Liang Ling
Published: November 2024

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cellular metabolism and growth by coordinating nutrient resources, including cholesterol, and its aberrant activation is linked to various age-related diseases. LYCHOS is a cholesterol sensor on the lysosome and bound to the GATOR1 complex, a GTPase-activating protein for the Rag GTPase, at high cholesterol concentrations, thereby activating the protein kinase mTORC1. However, how LYCHOS senses cholesterol and transduces signal to GATOR1 remain largely unknown. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. The PLD shares a conserved Na+/H+antiporter (NhaA) fold, which much resembles plant auxin transporter PINs. Cholesterol locates between PLD and GLD and cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which mediates the interaction between LYCHOS and GATOR1. Strikingly, structure-guided mutations of Gly702 in GLD of LYCHOS increase its affinity for cholesterol, leading to sustained mTORC1 activation in cells. This indicates that LYCHOS’s moderate affinity for cholesterol is crucial as a cholesterol sensor. Our results not only showed a solute carrier mechanistically coordinates a GPCR domain, elucidating the structural mechanism of cholesterol sensing by the mTORC1 pathway on the lysosome; but also provides a structural basis for developing inhibitors that selectively target to mTORC1 pathway to treat age-related diseases by blocking LYCHOS in its expanded state.
Involvement of Hepatitis B Core–Related Antigen in Viral Genome Integration in Patients With Prior Hepatitis B Virus Infection
Authors: Saito Tomoya , Suzuki Rigel , Rahman Akhinur , Mori Kento , Rajib Samiul Alam , Kobayashi Nobuhiro , Ichikawa Takaya , Orimo Tatsuya , Kakisaka Tatsuhiko , Liang Lihan , Nao Naganori , Suzuki Saori , Tamura Tomokazu , Satou Yorifumi , Taketomi Akinobu , Fukuhara Takasuke
Published: November 2024

Background

The incidence of non-B non-C hepatocellular carcinoma (NBNC-HCC), which is negative for hepatitis B surface antigen and hepatitis C virus antibodies, is on the rise. Relatively high numbers of NBNC-HCC patients are hepatitis B core antibody (HBcAb) positive, suggesting that previous HBV infection may play a role in NBNC-HCC development, though the exact mechanisms are unclear. This study aimed to investigate whether HBV genomes are integrated into the host genome of HBcAb-positive NBNC-HCC cases and how these integrations may contribute to cancer development and progression.

Methods

HBV detection PCR using HBV-specific primers on DNA extracted from HBcAb-positive NBNC-HCC tissue samples was performed. Positive samples were further examined for HBV integration sites using viral DNA–capture sequencing. Additionally, hepatitis B core-related antigen (HBcrAg) serum levels were measured to assess whether they could be predictive for HBV detection PCR results.

Results

Among 90 HBcAb-positive NBNC-HCC samples, HBV genome amplification was detected in 18 samples, and elevated HBcrAg levels were associated with the HBV detection PCR results. Seventeen of these samples exhibited HBV integration. The HBV genome was integrated near theTERTgene in 7 samples, resulting in significantly increasedTERTmRNA levels; in theKMT2Bgene (2 samples); and downstream ofLOC441666(2 samples).

Conclusion

The integration sites we identified in our samples have been previously reported in HBV-related HCC, suggesting that HBV integration may also contribute to hepatocarcinogenesis in HBcAb-positive NBNC-HCC. Furthermore, HBcrAg could serve as a potential, noninvasive marker for detecting HBV integration in these cases.
A high-quality phased genome assembly of stinging nettle,Urtica dioicassp.dioica
Authors: Hirabayashi Kaede , Dumigan Christopher R. , Ku•ka Matúš , Percy Diana M. , Guerriero Gea , Cronk Quentin , Deyholos Michael K. , Todesco Marco
Published: November 2024

Stinging nettles (Urtica dioica) have a long history of association with human civilization, having been used as a source of textile fibres, food and medicine. Here, we present a chromosome-level, phased genome assembly for a diploid female clone ofUrtica dioicafrom Romania. Using a combination of PacBio HiFi, Oxford Nanopore and Illumina sequencing, and Hi-C long-range interaction data (using a novel Hi-C protocol presented here), we assembled two haplotypes of 574.9 Mbp (contig N50 = 10.9 Mbp, scaffold N50 = 44.0 Mbp) and 521.2 Mbp (contig N50 = 13.5 Mbp, scaffold N50 = 48.0 Mbp), with assembly BUSCO scores of 92.6% and 92.3%. We annotated 20,333 and 20,140 genes for each haplotype, covering over 90% of the complete BUSCO genes and including two copies of a gene putatively encoding the neurotoxic peptide urthionin, which could contribute to nettle’s characteristic sting. Despite its relatively small size, the nettle genome displays very high levels of repetitiveness, with transposable elements comprising more than 60% of the genome, as well as considerable structural variation. This genome assembly represents an important resource for the nettle community and will enable the investigation of the genetic basis of the many interesting characteristics of this species.
Cultural Stigma, Psychological Distress and Help-Seeking: Moderating role of Self-esteem and Self-stigma
Authors: Sawma Toni , Hallit Souheil , Jaber Jad , Younis Chloe , El Khoury Malhame Myriam
Published: November 2024

Background/Objective: Mental illness is a common and often stigmatized condition. Stigma around mental illness refers to the negative attitudes and beliefs society holds about individuals with mental health conditions, and can sometimes prevent those individuals from seeking adequate therapy. This study aims to explore the intricate relation between stigma, psychological distress, self-confidence and help-seeking behavior among young adults with diagnosed mental illnesses. Method: A cross-sectional online survey was shared via digital platforms between February 2023 and August 2024. A total of 245 participants from various educational backgrounds and located in different Lebanese regions participated in the study and filled demographics data as well as assessments for stigma (Stigma Scale), self-esteem (Rosenberg Self-Esteem scale), help seeking (Attitudes Towards Seeking Professional Psychological Help -short form (ATSPPH-SF)), distress (Kessler Psychological Distress scale (K6)) and self-stigma (Self-Stigma Questionnaire (SSQ)). Results: Results from our multivariable analysis revealed a significant association between high levels of stigma and low self-esteem scores, high levels of stigma and high psychological distress, as well as negative attitudes towards seeking professional help. We mostly found that fear of individuals with mental illnesses, prejudice and lack of enough knowledge and awareness were driving reasons for current stigma around mental health in Lebanon. Conclusion: Stigma remains a pervasive condition leading to more mental health suffering, decreased self-esteem and lower tendencies to seek help. These inaccurate beliefs and stereotypes lead to fear, avoidance and overall discomfort, vis-à-vis people with mental distress perceived as unpredictable, impulsive and dangerous. It is important for public policy makers within collectivist culture to better address these misconceptions and promote help-seeking attitudes.
FARFOOD: A database of potential interactions between food compounds and drugs
Authors: Nevado-Bulnes Ana María , Benitez Dixan Agustin , Cumplido-Laso Guadalupe , Carvajal-González Jose María , Mulero-Navarro Sonia , Román Angel-Carlos
Published: November 2024

Nutrition is a fundamental aspect in human life development, both from a socio-economic and medical perspective. In recent years, new personalized approaches have been added to the biochemical study of nutrients. These approaches consider both the effect of foods on the body and the role of genes in metabolizing or digesting different nutrients. Although drug-food interactions have been known for decades, there is a lack of studies that address these processes in a comprehensive way, using structural and computational biochemistry techniques. In this paper we develop a method to predict potential interactions between foods and drugs based on the structural similarity between food compounds and medications. Our results have produced a database and an app to consult potential interactions between drugs and foods that we have called FARFOOD. Additionally, we validated two of these potential interactions with widely used drugs (lisinopril and bupropion) through structural docking between the ligand protein and the food compounds that are structurally similar to the drug. Moreover, patient surveys are used in the lisinopril and bupropion cases in addition to allopurinol to assess the possible effects of the potentially interacting foods on the symptoms of the conditions for which the medication is prescribed. In summary, this manuscript presents an interesting computational resource for predictive food-drug interaction analysis.
Age-related differences in psychopathology within sex chromosome trisomies
Authors: Roybal Melissa R. , Liu Siyuan , Larsen Isabella G. , Wass Anastasia , Schaffer Lukas , Ajumobi Tiffany , Whitman Ethan T. , Warling Allysa , Clasen Liv , Blumenthal Jonathan , Rau Srishti , Raznahan Armin
Published: November 2024

Sex chromosome trisomies (SCTs) are a group of genetic disorders characterized by presence of a supernumerary sex chromosome, resulting in karyotypes other than XX or XY. These include XXX (Trisomy X), XXY (Klinefelter syndrome), and XYY (Jacobs syndrome). Sex chromosome trisomies have been linked to increased risk for psychopathology; however, this relationship warrants additional research. Specifically, little is known regarding potential age-related variation in risk for psychopathology and how this may differ across karyotypes and subdomains of psychopathology, which has relevance for psychoeducation, personalized care, and mechanistic research. Thus, we used the Child Behavior Checklist (CBCL) to estimate age-related variation in psychopathology in a large cross-sectional sample of individuals with SCTs (n = 201) and euploidic controls (n = 304) spanning the age range of 5-18 years. We found that elevations of psychopathology in SCT were significantly associated with age in a manner that varied as a combined function of the karyotype and CBCL scale being considered. Post hoc tests revealed there is a uniquely pronounced age-associated increase in severity of social problems in XYY, alongside a lack of statistical evidence for age-related variation in the severity of psychopathology for other CBCL domains and SCT karyotypes. Our findings are relevant for advancing the personalization of clinical assessment and monitoring in SCTs. They also highlight potential windows of dynamic risk emergence for closer clinical and biological study, as well as opportunities to provide intervention to mitigate future risk.
A multi-model analysis of risk factors influencing hippocampus degree centrality in Han Chinese adults who lost their only child
Authors: Cao Yang , Guo Min , Wang Yuxin , Luo Yifeng
Published: November 2024

Objective

This study explores the relationship between Hippocampus Degree Centrality (DC) values and various risk factors in Han Chinese adults who have lost their only child, a phenomenon known as “shidu”. Our goal is to develop statistical models that have the potential to predict DC values and enhance clinical diagnosis and intervention strategies for Post-Traumatic Stress Disorder (PTSD) in these parents.

Methods

Participants were recruited from a PTSD survey conducted in Jiangsu Province, China, between September 2016 and March 2017. The survey included Han Chinese parents who had lost their only child to causes such as traffic accidents, explosions, suicide, cancer, and sudden death. Of the 237 participants, we focused on PTSD cases that met specific criteria, excluding individuals with adrenal disorders to eliminate confounding effects. After obtaining informed consent for follow-up assessments, we analyzed data from 109 eligible participants, examining a range of statistical models - linear, flexible, LASSO, ridge, and logistic regression - to identify correlations between DC values and various risk factors.

Results

Cortisol, gender, BMI, and memory capability are key contributors associated with DC values in Han Chinese adults who have experienced the trauma of losing their only child. We found that cortisol levels are negatively correlated with DC values in males, and are positively correlated in females (p-value = 0.017), which forms a gender-specific correlation. Additionally, BMI (p-value = 0.011) and memory scores (p-value = 0.157) indicate that physiological and cognitive factors can influence the hippocampus.

Conclusion

Linear and logistic models incorporating cortisol, gender, BMI, and memory capability show the greatest potential for clinical application in diagnosing DC abnormalities. These abnormalities are key indicators of stress levels and neurocognitive function in “shidu” parents, offering valuable insights for PTSD diagnosis and intervention strategies.
Visual and auditory object representations in ventral visual cortex after restoring sight in humans
Authors: Rączy Katarzyna , Linke Madita , van den Hurk Job , Heitmann Carolin , Guerreiro Maria J. S. , Zhan Minye , Kekunnaya Ramesh , Goebel Rainer , Röder Brigitte
Published: November 2024

Visual category-selective representations in human ventral occipital temporal cortex (VOTC) seem to emerge early in infancy. Surprisingly, the VOTC of congenitally blind humans features category-selectivity for auditory and haptic objects. Yet it has been unknown whether VOTC would show category-selective visual responses if sight were restored in congenitally blind humans. Assuming competition for synaptic space during development, cross-modal activation of VOTC as a consequence of congenital blindness might interfere with visual processing in sight-recovery individuals. To test this hypothesis, we investigated adults who had suffered a transient phase of congenital blindness due to bilateral dense cataracts before their sight was restored by cataract-removal surgery. In a functional magnetic resonance imaging (fMRI) study, participants watched movies of faces, scenes, body parts and other objects in the visual condition, while in the auditory condition they listened to the corresponding sounds. The most prominent group difference was the reduced face-selectivity in individuals with reversed congenital cataracts compared to age- and sex-matched normally-sighted individuals. In addition, a double dissociation was found: only sight-recovery individuals demonstrated significant decoding accuracy of visual categories based on auditory category representations in VOTC, while only normally-sighted individuals’ VOTC decoded auditory categories based on visual category representations. The present results uncovered the neural mechanisms of previously observed face processing impairments in individuals with reversed congenital blindness. We suggest that lower face-selectivity in the sight recovery group might arise from selective deficits in the cortical representation of the central visual field in lower-tier visual areas. Additionally, we speculate that in higher-order visual areas cross-modal activity might facilitate – rather than interfere – with visual functional recovery after congenital blindness.