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Article
| Open AccessRepurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Three drugs initially developed for other conditions, 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat and varespladib, have shown promise in preventing the lethality of snakebite envenoming. Here, Hall et al., show that a combination of these drugs can combat the local dermonecrotic effects caused by diverse cytotoxic venoms.
- Steven R. Hall
- , Sean A. Rasmussen
- & Nicholas R. Casewell
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Article
| Open AccessA phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.
- Linong Ji
- , Hongwei Jiang
- & Lei Qian
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Article
| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessTemperature-related death burden of various neurodegenerative diseases under climate warming: a nationwide modelling study
Examining non-optimal temperatures’ influence on neurodegenerative diseases amid climate warming is vital for public health. Here, the authors project a notable net increase of death burden from neurodegenerative diseases after the mid-21st century.
- Peng Yin
- , Ya Gao
- & Haidong Kan
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Comment
| Open AccessAccelerating African neuroscience to provide an equitable framework using perspectives from West and Southern Africa
Drawing on perspectives from West and Southern Africa, this Comment critically examines the current state of neuroscience progress in Africa, describing the unique landscape and ongoing challenges as embedded within wider socio-political realities. Distinct research opportunities in the African context are explored to include genetic and bio-diversity, multilingual and multicultural populations, life-course development, clinical neuroscience and neuropsychology, with applications to machine learning models, in light of complex post-colonial legacies that often impede research progress. Key determinants needed to accelerate African neuroscience are then discussed, as well as cautionary underpinnings that together create an equitable neuroscience framework.
- Sahba Besharati
- & Rufus Akinyemi
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessProstate cancer genetic risk and associated aggressive disease in men of African ancestry
Most genetic studies for prostate cancer have been performed outside the context of Sub-Saharan Africa. Here, the authors interrogate 247,780 exomic variants for 798 Black South African men and identify genes associated with aggressive disease.
- Pamela X. Y. Soh
- , Naledi Mmekwa
- & Vanessa M. Hayes
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Article
| Open AccessYoung infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations
Our understanding of the infant immune responses to routine vaccines remains limited. Here, the authors show that administration of routine vaccines to 2-month-old infants is associated with highly variable but limited antibody responses and mostly naïve-like immune cells with robust and transient expression of interferon genes.
- Nima Nouri
- , Raquel Giacomelli Cao
- & Octavio Ramilo
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Article
| Open AccessHealth-related quality of life is linked to the gut microbiome in kidney transplant recipients
Here, Swarte et al. use metagenomics to investigate the association between the gut microbiome and Health-Related Quality of Life (HRQoL) in kidney transplant recipients, showing evidence for the association of multiple taxonomic, metabolic and neuroactive pathways (gut brain modules) with lower HRQoL, together suggesting potential modifiable gut microbial factors to improve HRQoL.
- J. Casper Swarte
- , Tim J. Knobbe
- & Rinse K. Weersma
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Article
| Open AccessExplainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies
Therapeutic antibodies are crucial in treating severe diseases. Here, the authors introduce scifAI, an open-source explainable AI framework for analyzing imaging flow cytometry data, enabling rapid screening of therapeutic antibody candidates.
- Sayedali Shetab Boushehri
- , Katharina Essig
- & Fabian Schmich
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Article
| Open AccessUtilizing river and wastewater as a SARS-CoV-2 surveillance tool in settings with limited formal sewage systems
COVID-19 has impacted health systems unequally and widespread SARS-CoV-2 testing for community surveillance has been limited globally. This work in Malawi highlights how river and wastewater can be used to detect emerging SARS-CoV-2 waves, identify variants of concern, and provide an early warning system.
- Kayla G. Barnes
- , Joshua I. Levy
- & Nicholas Feasey
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Article
| Open AccessTransformEHR: transformer-based encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records
Using AI to predict disease can improve interventions slow down or prevent disease. Here, the authors show that generative AI models built on the framework of Transformer, the model that also empowers ChatGPT, can achieve state-of-the-art performance on disease predictions based on longitudinal electronic records.
- Zhichao Yang
- , Avijit Mitra
- & Hong Yu
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Article
| Open AccessPlasma proteomic profiles predict individual future health risk
The predictive capability of future health risk using plasma proteomic profiles remains largely unexplored. Using 1461 proteins collected from 50k individuals, authors show proteins can derive much better or equivalent performance than established clinical indicators for more than 40 endpoints.
- Jia You
- , Yu Guo
- & Jin-Tai Yu
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Article
| Open AccessNR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open AccessAdults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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Article
| Open AccessPersistent humoral immune response in youth throughout the COVID-19 pandemic: prospective school-based cohort study
Understanding the immune responses of school-aged children to SARS-CoV-2 is important for designing public health measures. Here, the authors report findings from cross-sectional and longitudinal anti-SARS-CoV-2 antibody measurements in a school-based study in Zurich, Switzerland, from 2020-2022.
- Alessia Raineri
- , Thomas Radtke
- & Susi Kriemler
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Article
| Open AccessSequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine
Seasonal influenza vaccines typically fail to induce cross-protective antibody responses. Here, Van Reeth et al. sequentially vaccinate pigs with diverse H1N1 viruses and show that this strategy induces antibodies against a panel of H1N1 strains from swine and humans and protects against antigenically mismatched strains.
- Kristien Van Reeth
- , Anna Parys
- & Elien Vandoorn
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Article
| Open AccessTamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.
- Zijian Fang
- , Giuditta Corbizi Fattori
- & Simón Méndez-Ferrer
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Article
| Open AccessEpidemiology, mortality, and health service use of local-level multimorbidity patterns in South Spain
Multimorbidity—the occurrence of chronic diseases together—represents a major challenge for healthcare systems. Here, the authors characterise multimorbidity patterns in a large dataset of patients residing in southern Spain and show the unequal distribution of multimorbidity patterns along different socioeconomic areas at the local level.
- Javier Alvarez-Galvez
- , Esther Ortega-Martin
- & Jesus Carretero-Bravo
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Article
| Open AccessSLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling
White adipose tissue is closely associated with energy expenditure and obesity. Here, the authors show that SLC35D3 promotes white adipose tissue browning through the NOTCH1 signalling pathway and SLC35D3 may be a potential therapeutic target for obesity and related complications.
- Hongrui Wang
- , Liang Yu
- & Yibo Wang
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Article
| Open AccessMultifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis
The presence of antibodies to citrullinated protein antigens (ACPA) in peripheral blood represents a risk a state that is ‘at-risk’ for subsequent development of rheumatoid arthritis (RA). Here authors compare multiple molecular and immunological parameters in individuals who are ACPA positive without inflammatory arthritis, ACPA negative controls and patients diagnosed with ACPA positive early-stage RA to conclude that complex immunopathological processes are present in an ACPA positive state which may be targeted by future preventive approaches for RA.
- Eddie A. James
- , V. Michael Holers
- & Kevin D. Deane
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Article
| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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Article
| Open AccessAsymmetric CRISPR enabling cascade signal amplification for nucleic acid detection by competitive crRNA
New strategies are being developed to simplify CRISPR-based nucleic acid detection. By investigating the competitive reaction between a full-sized crRNA and split crRNA for CRISPR-Cas12a, the authors develop an asymmetric CRISPR assay for amplification-free, cascade signal amplification detection of nucleic acids.
- Jeong Moon
- & Changchun Liu
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Article
| Open AccessMutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.
- Shujuan Zhao
- , Kedous Y. Mekbib
- & Kristopher T. Kahle
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Article
| Open AccessMinimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL
While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. Here, the authors investigate it using a next generation sequencing approach.
- Haipin Chen
- , Miner Gu
- & Xiaojun Xu
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Article
| Open AccessTh17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets
The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.
- Monika Ettinger
- , Teresa Burner
- & Wolfram Hoetzenecker
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Article
| Open AccessCircadian disturbances and frailty risk in older adults
The relationship between circadian function and frailty is not well understood. Here, the authors show that disturbances in circadian rest-activity rhythms were associated with an elevated frailty risk and faster progress of frailty in older adults.
- Ruixue Cai
- , Lei Gao
- & Peng Li
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Article
| Open AccessJoint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape
The genetic architecture of normal-range cranial vault shape in humans is poorly understood. Here, the authors extract cranial vault shape from MRI and conduct a multi-ancestry GWAS, identifying 30 independently associated genomic loci of which 29 are novel.
- Seppe Goovaerts
- , Hanne Hoskens
- & Peter Claes
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Article
| Open AccessEvaluation of pragmatic oxygenation measurement as a proxy for Covid-19 severity
There is a need for an accurate measure of pulmonary oxygenation function that can be used as an intermediate endpoint in pragmatic clinical trials, to increase statistical power and efficiency. Here, the authors show that the S/F94, a modification of the S/F ratio, is a simple, meaningful and effective intermediate outcome measure.
- Maaike C. Swets
- , Steven Kerr
- & J. Kenneth Baillie
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Article
| Open AccessThe Imageable Genome
The impact of genomic discoveries on global health depends on their efficient translation into clinically applicable testing. Here, the authors present the Imageable Genome - the part of the human genome whose expression can be assessed via molecular imaging - to accelerate translation and to bridge the fields of genomics and molecular imaging.
- Pablo Jané
- , Xiaoying Xu
- & Martin A. Walter
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Article
| Open AccessDostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial
Several PD-(L)1 inhibitors have been approved or are in development for the treatment of NSCLC, showing promising efficacy and tolerable safety profiles. Here, the authors present a randomized phase II clinical trial comparing two different anti-PD-1 antibodies, dostarlimab and pembrolizumab, both combined with chemotherapy as first-line treatment in patients with metastatic NSCLC.
- Sun Min Lim
- , Solange Peters
- & Filippo de Marinis
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Article
| Open AccessA standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. Here, the authors show the implementation of such a metric using type 1 diabetes trial data, reassess and compare results from these trials, and extend its use to define response to therapy.
- Alyssa Ylescupidez
- , Henry T. Bahnson
- & Carla J. Greenbaum
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Article
| Open AccessTargeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides
In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.
- Tomas Sneideris
- , Nadia A. Erkamp
- & Tuomas P. J. Knowles
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Article
| Open AccessA generative adversarial network model alternative to animal studies for clinical pathology assessment
Generative AI has the potential to transform the way chemical and drug safety research is conducted. Here the authors show AnimalGAN, a model developed using Generative Adversarial Networks, which simulates virtual animal experiments to generate multidimensional rat clinical pathology measurements.
- Xi Chen
- , Ruth Roberts
- & Weida Tong
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Article
| Open AccessLensAge index as a deep learning-based biological age for self-monitoring the risks of age-related diseases and mortality
Age is closely related to health, but chronologically defined age often disagrees with biological age. Here, the authors develop an indicator of biological age - LensAge index - to reveal individuals’ aging level, and it can be implemented with smartphones, showing potential for self-monitoring of aging.
- Ruiyang Li
- , Wenben Chen
- & Haotian Lin
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Article
| Open AccessAerosol delivery of SARS-CoV-2 human monoclonal antibodies in macaques limits viral replication and lung pathology
Here the authors deliver aerosolized human monoclonal antibodies to SARS-CoV-2-infected rhesus macaques and show that the treatment significantly reduces viral RNA and infectious virus in the respiratory tracts, limits lung pathology, and decreases inflammatory cytokines.
- Daniel N. Streblow
- , Alec J. Hirsch
- & Nancy L. Haigwood
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Article
| Open AccessProduction of leishmanin skin test antigen from Leishmania donovani for future reintroduction in the field
As leishmaniasis control programs and new vaccines are advancing, it is necessary to re-introduce the leishmanin skin test to monitor transmission and immunity. This study describes the generation and validation of a new leishmanin skin test antigen for future re-introduction into endemic countries.
- Ranadhir Dey
- , Jalal Alshaweesh
- & Greg Matlashewski
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Comment
| Open AccessThe counterintuitive implications of superspreading diseases
The superspreading that characterized SARS and now COVID-19 can be rapidly quantified; however, its implications for outbreak control were never well understood. Recent studies point to its profound impact on outbreak dynamics and prospects for effective control of a future Disease X. These insights necessitate research into the mechanisms, impact and different modes of superspreading more widely.
- Bjarke Frost Nielsen
- , Kim Sneppen
- & Lone Simonsen
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Article
| Open AccessInferring bacterial transmission dynamics using deep sequencing genomic surveillance data
Studying rare genetic changes that arose as an infectious bacterium spread between lab mice, here the authors show that using the relative abundance of any changes rather than just whether they occurred can more precisely identify who likely infected who.
- Madikay Senghore
- , Hannah Read
- & Siouxsie Wiles
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Article
| Open AccessProteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Precise biomarkers for multiple sclerosis prognosis are vital for treatment decisions. Here, the authors identify specific proteins in cerebrospinal fluid that can predict short-term disease activity and long-term disability outcomes in persons with multiple sclerosis.
- Julia Åkesson
- , Sara Hojjati
- & Mika Gustafsson
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Article
| Open AccessImpact of COVID-19 on mortality in coastal Kenya: a longitudinal open cohort study
SARS-CoV-2-associated mortality estimates for sub-Saharan Africa are uncertain due to lack of comprehensive surveillance systems. Here, the authors analyse data from a detailed surveillance system in Kilifi, Kenya and find that excess mortality rates were relatively low, except for older adults.
- M. Otiende
- , A. Nyaguara
- & J. A. G. Scott
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Article
| Open AccessMitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
Exhaustion is the functional deterioration of T cells following chronic stimulation. Here, Wu et al. show that mitochondrial dysfunction drives T cell exhaustion by inhibiting HIF-1α degradation and transcriptional metabolic reprogramming.
- Hao Wu
- , Xiufeng Zhao
- & Martin Vaeth
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Article
| Open AccessReconstructing disease dynamics for mechanistic insights and clinical benefit
Understanding disease progression dynamics is critical for diagnostics and treatment, but capturing dynamics is difficult. Here, the authors present a method for modelling disease progression from high dimensional molecular data that enables patient stratification and high-risk disease state identification, showcased in bladder cancer.
- Amit Frishberg
- , Neta Milman
- & Shai S. Shen-Orr
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Article
| Open AccessZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production
Insulin receptor levels are closely related to insulin sensitivity. Here, the authors show that ZFYVE28 is involved in insulin resistance by promoting the degradation of phosphorylated insulin receptor and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.
- Liang Yu
- , Mengchen Xu
- & Yibo Wang
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Article
| Open AccesslesSDRF is more: maximizing the value of proteomics data through streamlined metadata annotation
Public proteomics data often lack essential metadata, limiting their potential. To address this, the authors developed lesSDRF, a tool to simplify the process of metadata annotation, thereby ensuring that data leave a lasting, impactful legacy well beyond their initial publication.
- Tine Claeys
- , Tim Van Den Bossche
- & Lennart Martens
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Article
| Open AccessNivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.
- Maria Pouyiourou
- , Bianca N. Kraft
- & Alwin Krämer
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Article
| Open AccessGenome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease
Thyroid hormones play a critical role in regulation of multiple physiological functions. Here the authors via meta-analyses and detailed variant-to-gene mapping strategies implicate novel genes, pathways and associations for thyroid function and disease.
- Alexander T. Williams
- , Jing Chen
- & Catherine John
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Article
| Open AccessTelomouse—a mouse model with human-length telomeres generated by a single amino acid change in RTEL1
Telomeres are the protective caps of the chromosomes, which shorten with age. Smoom and colleagues developed a mouse strain with human-size telomeres. This mouse, termed Telomouse, is therefore an invaluable tool for studying human aging and cancer.
- Riham Smoom
- , Catherine Lee May
- & Yehuda Tzfati