bluuebunny/crossref_metadata_2025 huggingface dataset:
The benefit of a complete reference genome for cancer structural variant analysis
Authors: Paulin Luis F , Fan Jeremy , O’Neill Kieran , Pleasance Erin , Porter Vanessa L. , Jones Steven J.M , Sedlazeck Fritz J.
Published: March 2024

The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remains challenging.

We hypothesized that use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumour/normal matched benchmark sample and two patient samples show that the CHM13-T2T improves SV detection and prioritization accuracy compared to GRCh38, with a notable reduction in false positive calls. We also overcame the lack of annotation resources for CHM13-T2T by lifting over CHM13-T2T-aligned reads to the GRCh38 genome, therefore combining both improved alignment and advanced annotations.

In this process, we assessed the current SV benchmark set for COLO829/COLO829BL across four replicates sequenced at different centers with different long-read technologies. We discovered instability of this cell line across these replicates; 346 SVs (1.13%) were only discoverable in a single replicate. We identify 49 somatic SVs, which appear to be stable as they are consistently present across the four replicates. As such, we propose this consensus set as an updated benchmark for somatic SV calling and include both GRCh38 and CHM13-T2T coordinates in our benchmark. The benchmark is available at: 10.5281/zenodo.10819636 Our work demonstrates new approaches to optimize somatic SV prioritization in cancer with potential improvements in other genetic diseases.
ACUTE SEIZURES AFTER SPONTANEOUS INTRACEREBRAL HEMORRHAGE IN YOUNG INDIVIDUALS: 11-YEAR TRENDS AND ASSOCIATION WITH MORTALITY
Authors: Lekoubou Alain , Cohrs Austin , Dejuk Mariana , Hong Jinpyo , Sen Souvik , Bonilha Leonardo , Chinchilli Vernon M.
Published: March 2024

OBJECTIVE

To describe trends in acute seizures (AS) among young individuals with spontaneous intracerebral hemorrhage (sICH) and association with mortality.

BACKGROUND

Acute seizures are frequent complications of sICH. The rate of sICH is rising among young Americans (18 to 60 years). Trends in AS incidence in this age group is largely unknown. Further, the association of AS with mortality has not been reported among young Americans.

DESIGN/METHODS

The Merative MarketScan® Commercial Claims and Encounters database, for the years 2005 through 2015, served as the data source for this study. This period was chosen as spontaneous ICH incidence increased among young individuals between 2005 and 2015. Our study population included patients aged 18 to 64 years with ICH identified using the International Classification of Diseases, Ninth and Tenth Revision (ICD-9/10) codes 430, 431, 432.0, 432.1, 432.9, I61, I61.0, I61.1, I61.2, I61.3, I61.4, I61.5, I61.6, I61.8, and I61.9, excluding those with a prior diagnosis of seizures (ICD-9/10 codes 345.x,780.3x, G40, G41, and R56.8). We computed yearly AS incidence, mortality (in patients with and without seizures), and analyzed trends. We applied a logistic regression model to determine the independent association of AS with mortality accounting for demographic and clinical variables.

RESULTS

Of 81,878 sICH patients, 7,611 (9.3%) developed AS. AS incidence increased linearly between 2005 (incidence rate: 8.1%) and 2015 (incidence rate: 11.0%), which represents a 26% relative increase (P for trends <0.0001. In-hospital mortality rate was 14.3% among those who developed AS and 11.5% among those who did not. Between 2005 and 2015, overall, in-hospital mortality decreased from 13.0% to 9.7% among patients without AS but remained unchanged among those with AS. Patients who developed AS were 10% more likely to die than those who did not (OR: 1.10, 95% confidence interval: 1.02-1.18).

CONCLUSIONS

Between 2005 and 2015, AS incidence increased by nearly 26% among young Americans with sICH. In-patient mortality remained unchanged among those who developed seizures but declined among those who did not. The occurrence of AS was independently associated with a 10% higher risk of in-hospital death. Future studies will test the benefit of treating AS to reduce mortality after sICH.
The evolutionary and molecular history of a chikungunya virus outbreak lineage
Authors: Krambrich Janina , Mihalič Filip , Gaunt Michael W. , Bohlin Jon , Hesson Jenny , Lundkvist Åke , de Lamballerie Xavier , Li Cixiu , Shi Weifeng , Pettersson John H.-O.
Published: March 2024

In 2018–2019, Thailand experienced a nationwide spread of chikungunya virus (CHIKV), with approximately 15,000 confirmed cases of disease reported. Here, we investigated the evolutionary and molecular history of the East/Central/South African (ECSA) genotype to determine the origins of the 2018–2019 CHIKV outbreak in Thailand. This was done using newly sequenced clinical samples from travellers returning to Sweden from Thailand in late 2018 and early 2019 and previously published genome sequences. Our phylogeographic analysis showed that before the outbreak in Thailand, the Indian Ocean lineage (IOL) found within the ESCA, had evolved and circulated in East Africa, South Asia, and Southeast Asia for about 15 years. In the first half of 2017, an introduction occurred into Thailand from another South Asian country, most likely Bangladesh, which subsequently developed into a large outbreak in Thailand with export to neighbouring countries. Based on comparative phylogenetic analyses of the complete CHIKV genome and protein modelling, we also identified amino acid substitutions that may be associated with immune evasion, increased spread, and virulence. We identified several mutations in the E1/E2 spike complex, such as E1 K211E and E2 V264A, which are highly relevant as they may lead to changes in vector competence, transmission efficiency and pathogenicity of the virus. A number of mutations (E2 G205S, Nsp3 D372E, Nsp2 V793A), that emerged shortly before the outbreak of the virus in Thailand in 2018 may have altered antibody binding and recognition due to their position. This study not only improves our understanding of the factors contributing to the epidemic in Southeast Asia, but also has implications for the development of effective response strategies and the potential development of new vaccines.

Author Summary

We investigated the evolutionary and molecular history of the East/Central/South African (ECSA) genotype to determine the origins of the 2018–2019 chikungunya virus (CHIKV) outbreak in Thailand. We used newly sequenced clinical samples from travellers returning to Sweden from Thailand in late 2018 and early 2019 together with previously published genome sequences. Our phylogeographic analysis shows that the Indian Ocean lineage (IOL), found within ECSA, evolved in Eastern Africa, Southern Asia, and Southeast Asia for about 15 years before the outbreak in Thailand in 2018. We have also identified amino acid substitutions that may be associated with immune evasion, increased spread, and higher virulence that occurred prior to the outbreak and may have played a critical role in the rapid spread of the virus. Our study concludes that monitoring and understanding CHIKV dynamics remains critical for an effective response to the previously unpredictable outbreaks of the virus.
Alpha7 nicotinic acetylcholine receptor agonist PHA 568487 dampens inflammation in PBMCs from patients with newly discovered coronary artery disease
Authors: Mjörnstedt Filip , Wilhelmsson Rebecka , Ulleryd Marcus , Hammarlund Maria , Bergström Göran , Gummesson Anders , Johansson Maria E
Published: March 2024

Background

The alpha7 nicotinic acetylcholine receptor (α7nAChR) controls inflammation in experimental models. The α7nAChR is expressed in human peripheral blood mononuclear cells (PBMCs) as well as in human atherosclerotic plaques, yet, its role in regulating inflammation in patients with cardiovascular disease remains unknown. In this study we aim to investigate whether stimulation of the α7nAChR can dampen the immune response in patients with newly discovered coronary artery disease (CAD).

Methods

Human peripheral blood mononuclear cells (PBMCs) extracted from patients with verified CAD (n=38) and control participants with healthy vessels (n=38) were challenged in vitro with lipopolysaccharide (LPS) in combination with α7nAChR agonist PHA 568487. Supernatants were analyzed for cytokines using multiplex immunoassay. The CAD group was re-examined after 6 months.

Results

α7nAChR stimulation decreased TNF-α in all groups, in control participants and in CAD patients, both at the first visit as well as the follow-up visit after 6 months. The most pronounced effect of α7nAChR stimulation was seen in CAD patients at their first visit, where 12 of 17 cytokines were decreased (TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-7, IL-10, IL-17A, GM-CSF, MCP-1, MIP-1β and IL12(p70)).

Conclusions

Stimulation of α7nAChR dampens the inflammatory response in human PBMCs. This suggests that the anti-inflammatory properties of the α7nAChR may have a role in treating CAD.
Sustainable and Ecofriendly Nanoparticle Synthesis Using Microbial Strains Isolated From Heavy Metal Rich Industrial Effluent
Authors: Nathan Soshina , Mathunny Soumya , Anjana J
Published: March 2024

Given the enormous potential of metal nanomaterials, their sustainable production is of paramount importance and is a key area of focus worldwide. In this regard, bacteria are highly valued because of their potential for rapid, cost-effective and eco-friendly metal nanomaterial synthesis. In this study, culture supernatants ofBacillus cereusandCurvulariasp isolated from heavy metal rich Titanium industry effluent effectively synthesised cobalt and copper nanoparticles of narrow size range at room temperature, neutral pH and static conditions within 2-7 days. This was verified by visible colour changes, UV-Vis spectroscopy and FT-IR. The UV-Visible spectra of the biosynthesized cobalt and copper nanoparticles exhibited sharp narrow peaks at 341 and 342 nm. This suggested that the cobalt and copper nanoparticles were not only small but also had a narrow size distribution, a feature rarely reported in biosynthesis studies. Furthermore, our approach was conducted at room temperature using cell-free supernatant, eliminating the need for additional heating or cooling, and minimising processing thus making the process energy-efficient, cost effective and sustainable. This is a first report on the production of monodisperse cobalt and copper nanoparticles by microbes isolated from this novel extreme environment.

Graphical abstract
Single-cell RNA sequencing unraveled the expression heterogeneity of hematopoietic stem and progenitor cells and lymphoid cell development dysregulation in childhood asthma
Authors: Zhu Danying , Li Guang , Yuan Lang , Zeng Zeyu , Dong Na , Wang Chao , Chen Ming , Xie Lijian , Ding Guohui , Shen Libing , Dong Xiaoyan
Published: March 2024

Asthma is a long-term inflammatory disease affecting airways and lungs with usual onset in childhood. Its cause is not fully understood up to now. Here, using single-cell RNA sequencing, we profile peripheral blood mononuclear cells (PBMCs) from three pediatric patients with onset asthma and four age-matched healthy controls to investigate the cellular etiology of childhood asthma. The overall expression features among three asthma patients’ PBMCs demonstrate that innate immunity is commonly upregulated while adaptive immunity is commonly downregulated in childhood asthma, but each patient has different molecular phenotypes. The analyses of the expression profiles of hematopoietic stem and progenitor cells (HSPCs) further show that the HSPCs of asthma patients have heterogeneous expression backgrounds with more specific differentially expressed genes (DEGs) in each patient than common DEGs and a common feature of low S100 protein binding gene expression. S100A8, S100A9, S100A12, and RETN are universally upregulated in various cell types of asthma patients. The cell developmental trajectories in three asthma cases exhibit an abnormal immune cell development pattern compared to that in health control. The dysregulated lymphoid lineage development is observed in all 3 patients, but there is no identical abnormal pattern for each patient. The pseudo-time analyses of gene expression show that the expression dynamics of two proto-oncogenes, JUN and SPI1, and six inflammatory response related genes (S100A8, S100A9, S100A12, IL7R, IL32, CCL5) are relevant to abnormal immune cell development in asthma patients. The cell-cell communication analyses reveal the contribution of incoming annexin signal towards dendritic cells and the outgoing resistin signal from dendritic cells to asthma heterogeneity. Interestingly, the plasma blast cells of asthma patient 3 with severe symptoms exhibit dual cell identities of both plasma blast cells and T cells. Our scRNA-Seq analyses for three asthma patients reveal a complex cellular etiology for childhood asthma and provide a new research direction for the comprehensive and systematic understanding of key molecular mechanisms of childhood asthma.
Mental Health Trends in India from 2020 to 2022: Association with Financial Stress, Food Insecurity, and COVID-19-related Illness Concerns
Authors: Yang Youqi , Sun Anqi , Zimmermann Lauren , Mukherjee Bhramar
Published: March 2024

This study examines the impact of pandemic-related worries on mental health in the Indian general adult population from 2020 to 2022. Using data from the Global COVID-19 Trends and Impact Survey (N = 2,576,174 respondents aged≥18 years in India; an average weekly sample size of around 25,000), it explores the associations between worry variables (namely financial stress, food insecurity, and COVID-19-related health worries) and self-reported symptoms of depression and nervousness. The statistical analysis was conducted using complete cases only (N = 747,996). Our analysis used survey-weighted models, focusing on the three pandemic-related worries as the exposures, while also adjusting for various other covariates, including demographics and calendar time. The study finds significant associations between these worries and mental health outcomes, with financial stress being the most significant factor affecting both depression (adjusted odds ratio: 2.36, 95% confidence interval: [2.27, 2.46]) and nervousness (adjusted odds ratio: 1.91, 95% confidence interval: [1.81, 2.01]) during the first phase of the study period (June 27, 2020, to May 19, 2021). The fully adjusted models also identify additional factors related to mental health, including age, gender, residential status, geographical region, occupation, and education. Moreover, the research highlights that males and urban residents had higher odds ratios for self-reported mental health problems regarding the worry variables than females and rural residents, respectively. Furthermore, the study reveals a rise in the prevalence of self-reported depression and nervousness and their association with COVID-19-related health worries during the lethal second wave of the pandemic in May 2021 compared to the onset of the pandemic. This study shows that social media platforms like Facebook can deploy surveys to a large number of participants globally and can be useful tools in capturing mental health trends and uncovering associations during a public health crisis.
Recapitulation of Cellular Senescence, Inflammation, and Fibrosis in Human Kidney-Derived Tubuloids by Repeated Cisplatin Treatment
Authors: Nakao Yuki , Mori Yutaro , Mori Makiko , Mandai Shintaro , Fujiki Tamami , Kikuchi Hiroaki , Ando Fumiaki , Susa Koichiro , Mori Takayasu , Waseda Yuma , Yoshida Soichiro , Fujii Yasuhisa , Sohara Eisei , Uchida Shinichi
Published: March 2024

In the pursuit of more accurate pathophysiological models for assessing renal drug response, the development of kidney organoids derived from human pluripotent stem cells represents a significant step forward. However, recapitulating aging/senescence-associated pathophysiology within these models remains challenging. Here, we present an innovative approach to generate more homogeneous epithelial-like structures known as “tubuloid” using primary human renal proximal tubular epithelial cells (hRPTECs) cultured from human resected kidneys, as a refined alternative. We evaluated the efficacy of tubuloids using cisplatin treatment at three different concentrations: 0.2, 2.0, and 20.0 µg/mL. Tubuloids showed highly differentiated structures with proximal tubular epithelial cells that expressed lotus tetragonolobus lectin and LRP2/Megalin. Upon exposure to cisplatin, γH2AX expression increased in a dose-dependent manner, indicating DNA damage. Cisplatin treatment also resulted in the expression of Kidney Injury Molecule-1 (KIM-1) and Cleaved Caspase-3, which are indicators of kidney injury and apoptotic signaling, respectively. Repeated cisplatin administration resulted in upregulation of the cellular senescence marker p16, alongside increased secretion of inflammatory cytokines IL-1β and IL-6, indicating the induction of a senescence-associated secretory phenotype (SASP). Furthermore, supernatant collected from cisplatin-treated tubuloids induced myofibroblast activation, indicating the onset of renal fibrosis. We successfully established a tubuloid-based model of cisplatin-induced kidney injury using hRPTECs. Tubuloids provide a novel platform for studying the response of renal epithelial cells to toxins and therapeutics. Tubuloids can replicate cellular senescence, SASP, and fibrosis, making them a promising pathophysiological model for chronic kidney disease (CKD), providing insights into the disease’s fibrotic mechanisms.

Translational Statement

Recapitulating aging/senescence-associated pathophysiological reaction in kidney organoids remains challenging. Our study reveals that tubuloids could be novel candidate for chronic kidney disease (CKD) model.
Sex-dependent associations between human milk oligosaccharides and malaria outcomes in breastfeeding Ugandan children
Authors: Mwangi Victor Irungu , Owalla Tonny Jimmy , Moukarzel Sara , Okurut Emmanuel , Yonemitsu Chloe , Bode Lars , Egwang Thomas G.
Published: March 2024

Human milk oligosaccharides (HMOs), whose compositions vary between secretor and non-secretor mothers, protect breastfeeding children against various diseases. We investigated the relationship between HMOs in Ugandan secretor mothers and malaria outcomes in their children. Malaria outcomes in breastfeeding children followed up over seven months were classified as malaria-free and asymptomatic, mild, or severe malaria. A single human milk sample collected from each mother was analyzed for HMOs. Significantly higher 2’fucosyllactose (2’FL) and lacto-N-fucopentaose I (LNFP I) concentrations were observed in mothers of malaria-free children, and significantly higher lacto-N-tetraose (LNT) concentrations were observed in mothers of children with asymptomatic malaria. Concentrations of five HMOs, 3-fucosyllactose (3 FL), 3’sialyllactose (3’SL), difucosyllactose (DFLac), lacto-N-fucopentaose II (LNFP II), and sialyllacto-N-tetraose b (LSTb); and two HMOs, difucosyllacto-N-tetrose (DFLNT) and fucosyllacto-N-hexaose (FLNH) were significantly higher in mothers of malaria-infected children and children with severe malaria, respectively. Sex-dependent associations were observed for some HMOs.
Evaluating public and patient involvement in interventional research – a newly developed checklist (EPPIIC) with application to the COB-MS feasibility trial
Authors: Pyne Elise , Joyce Robert , Dwyer Christopher P. , Hynes Sinéad M.
Published: March 2024

Public and patient involvement (PPI) has been identified as an increasingly desired and, often, required component of trial methodology – leading to higher quality, more accessible and relevant clinical research, alongside increased recruitment, funding success and insight into research impact. However, despite the great variety of frameworks and checklists available for assessing PPI, most are limited with respect to important features (e.g. applicable in specific contexts only, fail to clarify what should be assessed and reported, lack the necessary comprehensiveness or are biased in favour of researcher reporting). Thus, the current research aimed to address such limitations through the development of a new checklist, the EPPIIC, through review, thematic analysis and ‘meta-evaluation’ in conjunction with PPI engagement. A further aim was to pilot the EPPIIC through its application to and reporting on the COB-MS trial, which utilised PPI throughout the research’s life-cycle. Upon completion of the EPPIIC, three thematic ‘sub-scales’ emerged: (1) Policy & Practice, (2) Participatory Culture and (3) Influence & Impact. All findings are presented and discussed in light of theory and research. Notably, findings recommend EPPIIC as a useful means of assessing PPI in future trials.
Initial respiratory support outcomes and associated factors among preterm neonates with respiratory distress syndrome admitted at Moi Teaching and Referral hospital Eldoret, Kenya
Authors: Ndeto Joyce Kalekye , Nyandiko Winstone M , Chepkemoi Audrey K , Mwangi Ann W
Published: March 2024

Background

Respiratory distress syndrome (RDS) is the single most important cause of morbidity and mortality in preterm neonates. Early management of RDS is crucial in determining short- and long-term outcomes and studies have established initial respiratory support (IRS) among other factors as an important determinant. Despite preexisting guidelines and advancements in the management of RDS, IRS failure with noninvasive ventilation is common and is associated with unfavorable outcomes.

Objective

This study evaluated the non-invasive initial respiratory support outcomes and associated factors among preterm neonates with respiratory distress syndrome admitted in the newborn unit (NBU) at Moi Teaching and Referral Hospital Eldoret (MTRH), Kenya

Methods

Using a prospective observational hospital-based study, preterm neonates ≤ 35weeks admitted at the newborn unit with clinical RDS were followed up for 28 days. The primary outcome was IRS success or failure characterized by not stepping up or stepping up the respiratory support respectively within 72 hours of life and associated maternal and neonatal factors. Descriptive statistics was described using mean ± (SD) for continuous variables and frequencies and percentages for categorical variables. Simple and multinomial regression analysis was performed to evaluate relationship between different IRS methods with outcome variables and a p-value of < 0.05 was considered significant.

Results

We enrolled 320 neonates, 172(53.8%) were male with a mean (SD) gestation age of 30.9 (2.95) weeks. The mothers mean age was 27 years, ranging (15–43). 70(22.4%) 95%CI:17.95,27.47] had IRS failure and 243(77.6%) had IRS success. On multivariate analysis IRS success was associated with primiparity (AOR=2.81;95%CI: 1.42, 7.99), birthweight > 1300g (AOR= 5.04;95%CI 1.81, 14.6), low modified Downes score (AOR=26.395%CI 3.37, 230) and normal admission temperatures (AOR=0.32;95%CI 0.12, 0.72) (p= <0.001).

Conclusion

Noninvasive ventilation had a high initial respiratory support success. Primiparity, birthweight >1300g, normal admission temperatures and low Downes score were associated with IRS success.
Assessing Red Blood Cell Distribution Width in Vietnamese Heart Failure Patients: A Cross-Sectional Study
Authors: Dang Hai Nguyen Ngoc , Luong Thang Viet , Cao Mai Thi Thu , Bui Vinh Trung , Tran Thanh Thien , Nguyen Hung Minh
Published: March 2024

Heart failure (HF) is a growing public health concern, with red cell distribution width (RDW) gaining recognition as a cost-effective marker for predicting HF onset and progression. This study, conducted from February 2022 to February 2024 at Hue Central Hospital, aimed to assess RDW levels in hospitalized Vietnamese HF patients and its predictive value for HF severity, involving a cross-sectional analysis of 351 patients categorized into HF and non-HF groups. HF patients exhibited higher median RDW levels (14.90% [13.70% - 17.00%]) compared to non-HF individuals (13.10% [12.23% - 13.78%]). RDW was higher in HF patients with left ventricular ejection fraction (LVEF) < 50% (15.30%) than LVEF ≥ 50% (14.70%). ROC curve analysis for acute heart failure (AHF) prediction yielded an AUC of 0.651 (p < 0.001), with a cutoff point of 13.85%, sensitivity of 86.05%, and specificity of 36.94%. Elevated RDW levels were associated with HF risk (OR: 1.844, p < 0.001) and AHF (OR: 3.612, p < 0.001). Multivariate analysis identified associations between RDW and hemoglobin (Hb) (β = 2.431, p = 0.040) and hematocrit (HCT) (β = −3.355, p = 0.007) in HF. RBC and RDW > 13.85% were independent risk factors for AHF. This suggests that RDW levels can serve as biomarkers for diagnosing HF and predicting its severity. Their accessibility and cost-effectiveness indicate the potential utility of RDW in managing HF, particularly in settings with limited resources.
Training-free Design of Deep Networks as Ensembles of Clinical Experts
Authors: Wu Tinghui , Wu Jieke , Zhang Zijun , Chen Wuyang
Published: March 2024

Artificial intelligence (AI) techniques such as deep learning hold tremendous potential for improving clinical practice. However, clinical data complexity and the need for extensive specialized knowledge represent major challenges in the current, human-driven model design. Moreover, as human interpretation of a clinical problem is inherently encoded in the model, the conventional single model paradigm is subjective and cannot fully capture the prediction uncertainty. Here, we present a fast and accurate framework for automated clinical deep learning, TEACUP (training-free assembly as clinical uncertainty predictor). The core of TEACUP is a newly developed metric that faithfully characterizes the quality of deep networks without incurring any cost for training of these networks. When compared to conventional, training-based approaches, TEACUP reduces computation costs by more than 50% while achieving improved performance across distinct clinical tasks. This efficiency allows TEACUP to create ensembles of expert AI models, contributing to recommendations in clinical practice by mimicking the approach of using multiple human experts when interpreting medical data. By combining multiple perspectives, TEACUP provides more robust predictions and uncertainty quantification, paving the way for more reliable clinical AI.
Prevalence and Sociodemographic Covariates of Human Papillomavirus in the United States: Findings from the 2008 to 2020 National Inpatient Sample Database
Authors: Dantes Emily , Bhuiyan Mohammad Alfrad Nobel , Bourg Margaret , Smith Corey D. , Bhuiyan Md. Shenuarin , Smith Deborah G
Published: March 2024

Human papillomavirus (HPV) infection is widespread worldwide, leading to a significant burden of HPV-related cancers. This study aimed to identify the prevalence of HPV infection in the United States based on a large nationwide inpatient sample database. We used the Nationwide Inpatient Sample (NIS) database from 2008 to 2020 and identified HPV cases using the International Classification of Diseases, Ninth (ICD-9) and Tenth Revision (ICD-10) codes. Pearson’s chi-square and independent-sample t-test were used for the analysis. The prevalence ratio was calculated using logistic regression models and the Cochran Armitage trend test to examine trends. A total of 47,506 HPV infections were identified from 2008 to 2020 among adults aged >18 years. Most patients were female (99.72%), with a higher prevalence among the 26-40 age group and white individuals. HPV infections were more prominent among low-income individuals and in the southern region of the United States. From 2008 to 2020, HPV increased from 6.76% to 10.91%. This study provides insights into the epidemiology of HPV infection in the United States. Understanding the trends and characteristics of HPV infection can contribute to public health interventions aimed at prevention and early detection.
IDRWalker: A Random Walk based Modeling Tool for Disordered Regions in Proteins
Authors: Chen Guanglin , Zhang Zhiyong
Published: March 2024

Motivation

With the advancement of structural biology techniques, the elucidation of increasingly large protein structures has become possible. However, the structural modeling of intrinsically disordered regions in proteins remains challenging. Particularly in the case of large protein complexes, it is difficult to rapidly construct models for all intrinsically disordered regions using existing methods. In the nuclear pore complex, a gigantic protein machine of interest, intrinsically disordered regions play a crucial role in the function of the nuclear pore complex. Therefore, there is a need to develop a modeling tool suitable for intrinsically disordered regions in large protein complexes.

Results

We have developed a program named IDRWalker based on self-avoiding random walks, enabling convenient and rapid modeling of intrinsically disordered regions in large protein complexes. Using this program, modeling of all disordered regions within the nuclear pore complex can be completed in a matter of minutes. Furthermore, we have addressed issues related to peptide chain connectivity and knot that may arise during the application of random walks.

Availability and implementation

IDRWalker is an open-source Python package. Its source code is publicly accessible on GitHub (https://github.com/zyzhangGroup/IDRWalker).
Binding of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition
Authors: Fahoum Jamal , Billan Maria , Varga Julia K , Padawer Dan , Elgrably-Weiss Maya , Basu Pallabi , Stolovich-Rain Miri , Baraz Leah , Cohen-Kfir Einav , Kumari Sujata , Oiknine-Dijan Esther , Kumar Manoj , Zelig Orly , Mayer Guy , Isupov Michail N , Wolf Dana G , Altuvia Shoshy , Wiener Reuven , Schueler-Furman Ora , Rouvinski Alexander
Published: March 2024

SARS-CoV-2 infection triggers strong antibody response toward Nucleocapsid-Protein (NP), suggesting extracellular presence beyond its intra-virion RNA binding. Interestingly, NP was found to decorate infected and proximal uninfected cell-surfaces. Here, we propose a new mechanism through which extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated linear-glycosaminoglycans by spatial rearrangement of its RNA-binding sites facilitated by the flexible, positively charged, linker. Coating of uninfected lung-derived cells with purified NP attracted anti-NP-IgG from lung fluids and sera collected from COVID-19 patients. The magnitude of this immune recognition was significantly elevated in moderate compared to mild COVID-19 cases. Importantly, binding of anti-NP-IgG present in sera generated clusters that triggered C3b deposition by the classical complement pathway. Heparin analog enoxaparin outcompeted NP-binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings unveil how extracellular NP may exacerbate COVID-19 tissue damage, and suggest leads for preventative therapy.

Abstract Figure

Highlights

IgG from patients’ sera target NP-bound cells resulting in complement activation

The flexible linker allows NP to both bind linear sulfated GAGs and wrap around RNA

Heparin analogs prevent NP surface binding and alleviate complement activation

Cell-ELISA anti-NP IgG levels differ between mild and moderate COVID-19
Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC
Authors: Zhu Qian , Balasubramanian Akhila , Asirvatham Jaya Ruth , Piyarathna Badrajee , Kaur Jaspreet , Mohamed Nada , Wu Ling , Chatterjee Megha , Wang Stacy , Pourfarrokh Niloufar , Rasaily Uttam , Xu Yitian , Zheng Junjun , Jebakumar Deborah , Rao Arundathi , Chen Shu-hsia , Li Yi , Chang Eric , Li Xiaoxian , Aneja Ritu , Zhang Xiang H.-F. , Sreekumar Arun
Published: March 2024

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be “immune cold” and hence immunotherapy resistant tumors, and EA TNBC as ‘inflamed’ tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Statement of Significance

We have uncovered distinct tumor-promoting and immunosuppressive microenvironments that may contribute to the observed disparities in patient outcomes. Our findings lay the groundwork for developing race-specific therapeutic interventions, potentially improving outcomes for patients with TNBC. Given that chemotherapy and anti-PD1 therapy are currently available treatments for TNBC, our finding of race-specific spatial multicellular niche-associated cell-cell interactions suggest that these treatments may have racially distinct response profiles among TNBC patients. Hence, our novel insights on molecular and cellular interactions in TNBC stratified by race has the potential to inform personalized treatment strategies.
Biguanide-PROTACs: Modulating Mitochondrial Proteins in Pancreatic Cancer Cells
Authors: Vatté Julie , Bourdeau Véronique , Ferbeyre Gerardo , Schmitzer Andreea R.
Published: March 2024

This study focuses on the synthesis of Biguanide-PROTACs, formed by conjugating the biguanide motif with diverse E3 enzyme ligands and spacers. Evaluation of their activity on pancreatic cancer cell (KP4) proliferation established a correlation between membrane permeability and median effective concentration. Mechanistic insights revealed that only two compounds exhibited biguanide-like AMPK activation, while only one hydrophobic compound uniquely altered mitochondrial protein levels. The prospect of developing and expanding the Biguanide-PROTAC library holds promises, offering potential insights into biguanide mechanisms and the creation of more potent anticancer agents. This study contributes to understanding the intricate interplay between compound structure, permeability, and anticancer activity, paving the way for targeted drug development in pancreatic cancer treatment.
Characterization of the murine spine for spaceflight studies
Authors: Lim Shiyin , Veres Joanna E. , Almeida Eduardo A.C. , O’Connell Grace D.
Published: March 2024

Rodents provide a useful analog for understanding the effects of spaceflight on the human body, offering opportunities for investigations into the relationship between microgravity and the musculoskeletal system. In particular, rodents have often been utilized to improve our understanding of the effects of spaceflight on the spine, including intervertebral disc and vertebral body health. However, there are a number of experimental factors that differ between existing works, including mission duration, animal housing, and anatomical location of interest, making it difficult to draw holistic conclusions. Additionally, the quadrupedal nature of the murine spine results in different biomechanical loading than in a bipedal organism. Thus, the objective of this study was to more fully define the bulk properties of the murine lumbar spine model after 28 days of spaceflight. Additionally, the proximal tibia was analyzed to provide insight into the skeletal site-specificity of gravitational unloading in space. Results indicated that the effects of spaceflight on vertebral body bone microarchitecture, intervertebral disc biochemistry, and intervertebral disc joint mechanics were statistically insignificant, while large and significant bone loss was observed in the proximal tibia of the same animals. We hypothesize that this may be due to site-specific loading changes in space. Specifically, vigorous ambulatory behaviors observed in this experiment after initial acclimation to spaceflight may increase axial load-bearing in the lumbar spine, while maintaining microgravity induced mechanical unloading in the tibia. In total, this work shows that the rodent spine, unlike the weight bearing tibia in the same mice, is not affected by gravitational unloading, suggesting the tissue degenerative effects of spaceflight are site- and load-specific and not systemic. This study also highlights the importance of considering experimental variables such as habitat acclimation, physical activity, and experiment duration as key factors in determining musculoskeletal and spine health outcomes during spaceflight.
Reconstructed influenza A/H3N2 infection histories reveal variation in incidence and antibody dynamics over the life course
Authors: Hay James A. , Zhu Huachen , Jiang Chao Qiang , Kwok Kin On , Shen Ruiyin , Kucharski Adam , Yang Bingyi , Read Jonathan M. , Lessler Justin , Cummings Derek A. T. , Riley Steven
Published: March 2024

Humans experience many influenza infections over their lives, resulting in complex and varied immunological histories. Although experimental and quantitative analyses have improved our understanding of the immunological processes defining an individual’s antibody repertoire, how these within-host processes are linked to population-level influenza epidemiology remains unclear. Here, we used a multi-level mathematical model to jointly infer antibody dynamics and individual-level lifetime influenza A/H3N2 infection histories for 1,130 individuals in Guangzhou, China, using 67,683 haemagglutination inhibition (HI) assay measurements against 20 A/H3N2 strains from repeat serum samples collected between 2009 and 2015. These estimated infection histories allowed us to reconstruct historical seasonal influenza patterns and to investigate how influenza incidence varies over time, space and age in this population. We estimated median annual influenza infection rates to be approximately 18% from 1968 to 2015, but with substantial variation between years. 88% of individuals were estimated to have been infected at least once during the study period (2009-2015), and 20% were estimated to have three or more infections in that time. We inferred decreasing infection rates with increasing age, and found that annual attack rates were highly correlated across all locations, regardless of their distance, suggesting that age has a stronger impact than fine-scale spatial effects in determining an individual’s antibody profile. Finally, we reconstructed each individual’s expected antibody profile over their lifetime and inferred an age-stratified relationship between probability of infection and HI titre. Our analyses show how multi-strain serological panels provide rich information on long term, epidemiological trends, within-host processes and immunity when analyzed using appropriate inference methods, and adds to our understanding of the life course epidemiology of influenza A/H3N2.
Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury
Authors: Anandakrishnan Nanditha , Yi Zhengzi , Sun Zeguo , Liu Tong , Haydak Jonathan , Eddy Sean , Jayaraman Pushkala , DeFronzo Stefanie , Saha Aparna , Sun Qian , Yang Dai , Mendoza Anthony , Mosoyan Gohar , Wen Huei Hsun , Schaub Jennifer A. , Fu Jia , Kehrer Thomas , Menon Rajasree , Otto Edgar A. , Godfrey Bradley , Suarez-Farinas Mayte , Leffters Sean , Twumasi Akosua , Meliambro Kristin , Charney Alexander W. , García-Sastre Adolfo , Campbell Kirk N. , Gusella G. Luca , He John Cijiang , Miorin Lisa , Nadkarni Girish N. , Wisnivesky Juan , Li Hong , Kretzler Matthias , Coca Steve G. , Chan Lili , Zhang Weijia , Azeloglu Evren U.
Published: March 2024

COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.
Diagnostic performance of multiplex lateral flow tests in ambulatory patients with acute respiratory illness
Authors: Murphy Caitriona , Mak Loretta , Cheng Samuel M. S. , Liu Gigi Y. Z. , Chun Alan M. C. , Leung Katy K. Y. , Sum Natalie Y. W. , Poukka Eero , Peiris Malik , Cowling Benjamin J.
Published: March 2024

Background

We assessed the performance of three different multiplex lateral flow assays which provide results for influenza, respiratory syncytial virus (RSV) and SARS-CoV-2.

Methods

Ambulatory patients 6 months and older presenting with two or more symptoms or signs of an acute respiratory illness were enrolled in an outpatient clinic in Hong Kong. Multiplex lateral flow tests manufactured by SureScreen, Microprofit and Goldsite were performed by trained research staff using the nasal swabs from each test kit, and separate swabs were collected for RT-PCR testing.

Results

Between 4 April and 20 October 2023, 1646 patients were enrolled and tested by at least one lateral flow test. The point estimates for all three multiplex tests had high sensitivity above 80% for influenza A and SARS-CoV-2, and the tests manufactured by Microprofit and Goldsite had sensitivity exceeding 84% to detect RSV. Test sensitivity increased with viral load. Specificity was higher than 97% for all three tests except for the SureScreen test which had specificity 86.2% (95% CI: 83.9% to 88.3%) for influenza A.

Conclusions

The multiplex lateral flow tests provided timely diagnosis of influenza, RSV and SARS-CoV-2 infection and can be used to inform clinical management and infection control such as isolation behaviours.
DentalSegmentator: robust deep learning-based CBCT image segmentation
Authors: Dot Gauthier , Chaurasia Akhilanand , Dubois Guillaume , Savoldelli Charles , Haghighat Sara , Azimian Sarina , Rahbar Taramsari Ali , Sivaramakrishnan Gowri , Issa Julien , Dubey Abhishek , Schouman Thomas , Gajny Laurent
Published: March 2024

Objectives

Segmentation of anatomical structures on dento-maxillo-facial (DMF) computed tomography (CT) or cone beam computed tomography (CBCT) scans is increasingly needed in digital dentistry. The main aim of this research was to propose and evaluate a novel open source tool called DentalSegmentator for fully automatic segmentation of five anatomic structures on DMF CT and CBCT scans: maxilla/upper skull, mandible, upper teeth, lower teeth, and the mandibular canal.

Methods

A retrospective sample of 470 CT and CBCT scans was used as a training/validation set. The performance and generalizability of the tool was evaluated by comparing segmentations provided by experts and automatic segmentations in two hold-out test datasets: an internal dataset of 133 CT and CBCT scans acquired before orthognathic surgery and an external dataset of 123 CBCT scans randomly sampled from routine examinations in 5 institutions.

Results

The mean overall results in the internal test dataset (n= 133) were a Dice similarity coefficient (DSC) of 92.2 ± 6.3% and a normalised surface distance (NSD) of 98.2 ± 2.2%. The mean overall results on the external test dataset (n= 123) were a DSC of 94.2 ± 7.4% and a NSD of 98.4 ± 3.6%.

Conclusions

The results obtained from this highly diverse dataset demonstrate that this tool can provide fully automatic and robust multiclass segmentation for DMF CT and CBCT scans. To encourage the clinical deployment of DentalSegmentator, the pre-trained nnU-Net model has been made publicly available along with an extension for the 3D Slicer software.

Clinical Significance

DentalSegmentator open source 3D Slicer extension provides a free, robust, and easy-to-use approach to obtaining patient-specific three-dimensional models from CT and CBCT scans. These models serve various purposes in a digital dentistry workflow, such as visualization, treatment planning, intervention, and follow-up.
Unraveling the factors associated with digital health intervention uptake
Authors: Ruotsalainen Ilona , Valtanen Mikko , Kärsämä Riikka , Umer Adil , Liedes Hilkka , Parikka Suvi , Lundqvist Annamari , Aittola Kirsikka , Manninen Suvi , Pihlajamäki Jussi , Vuorinen Anna-Leena , Lindström Jaana
Published: March 2024

For preventing chronic diseases, reducing modifiable lifestyle risk factors is crucial. Digital health interventions (DHIs) hold promise for reaching large population groups, but raise health equity concerns. A subgroup (n=6978) of 20 to 74-year-old participants of the population-based Healthy Finland survey were offered an opportunity to start using a web-based DHI, aiming to support adoption of healthy lifestyle habits. We used adjusted logistic regression models to identify significant predictors of DHI uptake. Women (adjusted odds ratio [aOR] 1.69, 95% CI 1.49–1.93), middle-aged individuals (1.47, 1.21–1.79), and those with higher income (aORs between 1.76–1.97) and education (1.10, 1.08–1.12) had higher odds of DHI uptake. Moreover, healthier lifestyle indicated by better diet quality (1.07, 1.04– 1.10), less frequent or non-smoking (aORs between 1.59–2.29), sleep (0.58, 0.37–0.86), higher functional capacity (1.06, 1.02–1.11), and good overall current health (1.46, 1.15– 1.89) associated with increased likelihood of DHI uptake. Lastly, individuals with better internet connections, higher competence to use e-services (aORs between 2.00–4.10), low concerns about data security (aORs between 1.37–1.76), stronger belief in benefits of digital services (1.04, 1.02–1.05), and reporting to use e-services (aORs between 2.48–6.08) had higher odds of uptake. Our findings indicate that those with higher socioeconomic status, better health and healthier lifestyle are more likely to take up DHI. Our research also highlights the impact of digital literacy and positive attitudes towards online services in adopting DHIs. These insights will be valuable in shaping strategies for future DHI initiatives.