Featured
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| Open AccessIlluminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans
The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.
- Joakim Lehrstrand
- , Wayne I. L. Davies
- & Ulf Ahlgren
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| Open AccessConsistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs
Xenotransplantation is an imminent clinical reality but concerns remain around the logistics of procurement and the experimental immunosuppression regimens required to achieve long-term xenograft survival. Here the authors show more than 6 month survival of genetically modified porcine kidneys in baboons after regulatory compliant organ procurements, clinically relevant organ preservation times and FDA-approved immunosuppressive reagents.
- Daniel Eisenson
- , Yu Hisadome
- & Kazuhiko Yamada
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| Open AccessAn esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus with unclear immune cell involvement. Here the authors generate a single cell transcriptomic dataset with 400k cells from the esophageal mucosa of active EoE patients, remission EoE patients, and healthy individuals to characterise esophageal cellular composition, phenotype and interaction in this disease.
- Jiarui Ding
- , John J. Garber
- & Ramnik J. Xavier
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Article
| Open AccessMonkeypox virus genomic accordion strategies
The 2023 monkeypox outbreak was caused by a subclade IIb monkeypox virus (MPXV). Here, using advanced sequencing techniques, the authors identify variations on low-complexity regions of the MPXV genome and describe their potential as evolutionary drivers.
- Sara Monzón
- , Sarai Varona
- & Gustavo Palacios
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Article
| Open AccessStructural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A
SV2A is a receptor for botulinum neurotoxin (BoNT) and new generation antiepileptic drugs (AEDs). Here the authors report cryo-EM structures of SV2A in complex with BoNT receptor binding domain and AEDs highlighting the difference in the binding affinity between AEDs.
- Atsushi Yamagata
- , Kaori Ito
- & Mikako Shirouzu
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| Open AccessMalnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial
Childhood malnutrition in Africa is a glaring example of global inequality, and mortality remains high. Here, the authors report the results of the TAME randomized phase II clinical trial, in which intestinal healing was the target of four potential interventions in malnourished children in Zambia and Zimbabwe.
- Kanta Chandwe
- , Mutsa Bwakura-Dangarembizi
- & Paul Kelly
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| Open AccessInflammation and cytomegalovirus viremia during pregnancy drive sex-differentiated differences in mortality and immune development in HIV-exposed infants
HIV exposed but uninfected infants may face an increased risk of serious infection and mortality. In this work, the authors utilise a cohort from rural Zimbabwe to explore the biological mechanisms underlying infant mortality.
- Ceri Evans
- , Kuda Mutasa
- & Andrew J. Prendergast
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Article
| Open AccessNeoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
| Open AccessUveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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| Open AccessThe physiological interactome of TCR-like antibody therapeutics in human tissues
The use of bispecific antibodies to target tumour-specific epitopes presented by MHC molecules in tumour tissue is a promising avenue for cancer immunotherapy. Here the authors use a mass-spectrometry guided analysis to identify off-target MHC-peptide complexes that bind to TCR-like antibodies next to the target peptide, enabling a novel approach to monitoring of antibody specificity during clinical maturation and development.
- Estelle Marrer-Berger
- , Annalisa Nicastri
- & Nicola Ternette
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Article
| Open AccessUltrasensitive single-step CRISPR detection of monkeypox virus in minutes with a vest-pocket diagnostic device
The recent monkeypox outbreak highlighted the need for rapid and accurate diagnosis of this disease. Here, authors develop an ultrasensitive and streamlined CRISPR assay using miniaturized device, which can detect monkeypox virus in rash fluid swab, oral swab, saliva, and urine within 15 minutes.
- Yunxiang Wang
- , Hong Chen
- & Shengqi Wang
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Article
| Open AccessBacterial peptidoglycan acts as a digestive signal mediating host adaptation to diverse food resources in C. elegans
Here, by using a food digestion model in C. elegans, the authors identify a mechanism by which bacterial peptidoglycan (PGN) interacts with Bacterial Colonization Factor-1 (BCF-1) triggering C. elegans to expand its ability to consume a wide range of foods in their natural environment.
- Fanrui Hao
- , Huimin Liu
- & Bin Qi
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Article
| Open AccessEmerging variants develop total escape from potent monoclonal antibodies induced by BA.4/5 infection
Many emerging SARS-CoV-2 variants partially escape the humoral immune response. Here, Liu et al. characterize 28 antibodies from BA.4/5 breakthrough infections and find attrition of neutralization and complete loss of function for variants with Spike mutations at positions 455 and 456.
- Chang Liu
- , Raksha Das
- & Gavin R. Screaton
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Article
| Open AccessMechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2
The biogenesis of iron-sulfur proteins in eukaryotes is initiated by the mitochondrial core ISC complex. Here, the authors provide structural, biochemical and spectroscopic data to characterize sulfur transfer intermediates in the core ISC complex.
- Vinzent Schulz
- , Ralf Steinhilper
- & Roland Lill
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| Open AccessPerinatal outcomes after admission with COVID-19 in pregnancy: a UK national cohort study
The impacts of maternal SARS-CoV-2 infection on newborns are not well understood. Here, the authors perform a national cohort study using data on births in the UK from March 2020—March 2022 and find that moderate to severe maternal COVID-19 was associated with adverse perinatal outcomes.
- Hilde Marie Engjom
- , Rema Ramakrishnan
- & Marian Knight
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| Open AccessDonor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease
Graft-versus-Host disease is a major complication after allogeneic bone marrow transplantation and is ameliorated by adoptively transferred donor regulatory T cells. Here, the authors apply transcriptomic and TCR profiling to assess regulatory T cell organ-specific adaptation in murine bone marrow transplantation models.
- David J. Dittmar
- , Franziska Pielmeier
- & Michael Rehli
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Article
| Open AccessNerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints
Osteoarthritis is a painful and debilitating condition. Here, the authors show that NGFR, a receptor for NGF, restricts NF-κB activation and its deficiency in skeletal cells impairs the remodeling and repair of osteoarthritic joints.
- Lan Zhao
- , Yumei Lai
- & Jian Huang
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| Open AccessInhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence
Here the author reveal that histone crotonylation (including H3K9cr) exert a role in kidney fibrosis, where ACSS2 represents a potential target to slow fibrotic kidney disease progression.
- Lingzhi Li
- , Ting Xiang
- & Liang Ma
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| Open AccessPositive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution
SARS-CoV-2 constantly evolves but the roles of resulting mutations are not always clear. In this study, the authors report that ORF8 knockout confers a fitness advantage to SARS-CoV-2 using genomic surveillance data, highlighting how different types of adaptations across the SARS-CoV-2 genome can drive variant fitness.
- Cassia Wagner
- , Kathryn E. Kistler
- & Trevor Bedford
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| Open AccessInfluenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children
In this study, the authors assessed influenza-specific antibody responses in a cohort of seasonally vaccinated children and report that seasonal vaccination is beneficial by enhancing pandemic influenza virus-specific antibodies and cross-reactive effector functions.
- Janice Z. Jia
- , Carolyn A. Cohen
- & Sophie A. Valkenburg
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| Open AccessLipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis
Oxidative stress triggers lipid accumulation in cells by sequestering triglycerides in lipid droplets. Here, the authors show that lipopolysaccharide-binding protein interacts with redox sensor PRDX4 to control lipid-redox balance and promotes triglyceride accumulation in droplets by capturing unsaturated lipids.
- Qilun Zhang
- , Xuting Shen
- & Haoshu Fang
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Article
| Open AccessEpidemiological, clinical, and genomic landscape of coccidioidomycosis in northeastern Brazil
Coccidioidomycosis, a WHO-listed mycosis, is neglected in South America. Analysis of 292 cases in Brazil, often tied to armadillo hunting, unveils unique disease patterns, environmental factors and pathogen genetics causing the disease.
- Kelsen Dantas Eulálio
- , Daniel R. Kollath
- & Marcus de Melo Teixeira
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| Open AccessUtility of polygenic scores across diverse diseases in a hospital cohort for predictive modeling
Here, the authors analyze polygenic scores for 457 phenotypes, finding 49 with robust polygenic score predictive models ( > 0.6 AUC). They find that population diversity and environmental factor integration are key considerations to improving the model’s performance.
- Ting-Hsuan Sun
- , Chia-Chun Wang
- & Kai-Cheng Hsu
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Article
| Open AccessSubthalamic stimulation modulates context-dependent effects of beta bursts during fine motor control
How movement speed is neurally modulated remains poorly understood. Here, the authors recorded invasive brain signals in Parkinson’s disease patients during drawing and deep brain stimulation, showing a context-dependent relationship between reductions of movement acceleration and dynamic activity of the basal ganglia.
- Manuel Bange
- , Gabriel Gonzalez-Escamilla
- & Sergiu Groppa
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| Open AccessIntegrated proteogenomic and metabolomic characterization of papillary thyroid cancer with different recurrence risks
Papillary thyroid cancers (PTC) generally have good prognosis, but their recurrence rate remains high. Here, the authors use proteogenomics and metabolomics to identify molecular features in PTC tumours and determine PTC subtypes that are associated with prognosis and potential targeted therapies.
- Ning Qu
- , Di Chen
- & Rongliang Shi
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Article
| Open AccessSplice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat
Somatic expansion of a CAG repeat in HTT drives onset of Huntington’s disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.
- Zachariah L. McLean
- , Dadi Gao
- & James F. Gusella
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Article
| Open AccessEnhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights
Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.
- Sheeba J. Sujit
- , Muhammad Aminu
- & Jia Wu
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| Open AccessDeficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion
The mechanisms of bifurgation, a key step in thyroid development, are largely unknown. Here, Fang et al. find that HGF/Met is indispensable for the bifurgation of the thyroid primordium during zebrafish thyroid development.
- Ya Fang
- , Jia-Ping Wan
- & Huai-Dong Song
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Article
| Open AccessMultisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
Repetitive audio-visual stimulation, or sensory flicker, can modulate oscillations in a non-invasive manner. Here the authors demonstrate the potential of flicker in individuals with epilepsy undergoing intracranial seizure monitoring.
- Lou T. Blanpain
- , Eric R. Cole
- & Annabelle C. Singer
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| Open AccessSpatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant
Xenotransplantation in humans using pig organs could improve the transplant organ supply. Here the authors transplant pig kidneys into a brain-dead recipient and monitor the human immune cell response early after transplantation using spatial and single cell transcriptomics and show early myeloid cell infiltration.
- Matthew D. Cheung
- , Rebecca Asiimwe
- & Paige M. Porrett
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| Open AccessEarly-life exercise induces immunometabolic epigenetic modification enhancing anti-inflammatory immunity in middle-aged male mice
Exercise could affect the immune system, but whether early-life exercise could benefit immune health in adulthood is not fully understood. Here the authors show that early-life exercise promotes epi-metabolic changes in the liver to potentially benefit immunity in older age and characterise the involvement of pipecolic acid in this process.
- Nini Zhang
- , Xinpei Wang
- & Feng Gao
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| Open AccessImmunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection
In this study, Giron et al. find that people living with chronic HIV experience accelerated aging-associated alterations in antibody glycans. These alterations, attributed to senescence enzymes, predict comorbidities and reduce the antiviral function of antibodies.
- Leila B. Giron
- , Qin Liu
- & Mohamed Abdel-Mohsen
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| Open AccessAntigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis
Although many autoimmune diseases are characterized by the presence of autoantibodies, complete characterisation of autoantibody repertoires is lacking. Here, the authors introduce an autoantigen-specific Fab profiling method to show that the autoantibody repertoire in rheumatoid arthritis is diverse yet dominated only by a few clones.
- Eva Maria Stork
- , Danique M. H. van Rijswijck
- & Albert Bondt
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| Open AccessThe genomic evolutionary dynamics and global circulation patterns of respiratory syncytial virus
This study on respiratory syncytial virus (RSV) reveals global genomic gaps. Using INFORM-RSV data, it uncovers selection’s impact on RSVA and RSVB diversity. Analysing full genomes, it highlights non-neutral epidemic processes. The research emphasises air travel’s influence on global spread, underscoring the need for comprehensive RSV genomic surveillance.
- Annefleur C. Langedijk
- , Bram Vrancken
- & Shabir A. Madhi
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| Open AccessReporting outcome comparisons by sex in oncology clinical trials
Many aspects of human health and disease are influenced by sex as a biological variable and gender as a social construct. A recent study from Nature Communications reported the landscape of outcome comparisions by sex in oncology clinical trials, highlighting the need for a more thorough reporting of sex differences.
- Guo Zhao
- , Yuning Wang
- & Ning Li
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| Open AccessMolecular patterns of resistance to immune checkpoint blockade in melanoma
A large fraction of patients with melanoma still does not benefit from immune checkpoint blockade, associated with both primary and acquired resistance. Here the authors report genetic and immunological patterns of resistance in patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy.
- Martin Lauss
- , Bengt Phung
- & Göran Jönsson
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Article
| Open AccessDHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells
Inflammatory bowel disease (IBD) is featured with epithelial barrier dysfunction, however, the underlying mechanism is less clear. Here, the authors show that DHX9 deficiency in intestinal stem cells (ISCs) induces accumulation of abnormal R-loops and subsequent genomic instability, leading to impairment of ISCs and development of IBD.
- Xingxing Ren
- , Qiuyuan Liu
- & Shu Zhu
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Article
| Open AccessSARS-CoV-2-specific cellular and humoral immunity after bivalent BA.4/5 COVID-19-vaccination in previously infected and non-infected individuals
Prior infection or exposure to SARS-CoV-2 may influence immunogenicity and effectiveness of subsequent vaccination to new strains of virus. Here the authors show that immunogenicity of a BA.4/5 mRNA vaccine differed in recipients depending on whether they had been exposed to or infected with an earlier strain of virus.
- Rebecca Urschel
- , Saskia Bronder
- & Martina Sester
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Article
| Open AccessImmunoregulatory role of the gut microbiota in inflammatory depression
Inflammatory depression is a treatment-resistant subtype of depression. Here, the authors show that patients with inflammatory depression exhibit a disrupted microbiota, which upon FMT in mice leads to increased peripheral and central inflammatory factors, intestinal mucosal permeability, and depressive and anxiety-like behaviors. Probiotic administration ameliorates the disease phenotype.
- Penghong Liu
- , Zhifen Liu
- & Kerang Zhang
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| Open AccessComparative characterization of the infant gut microbiome and their maternal lineage by a multi-omics approach
Here, the authors employ multi-omics on a cohort comprising three generations of family members, showing that fecal microbiota populations, functions, and metabolome of infants vary greatly from their maternal lineage, exhibiting a less diverse microbiota and differences in various metabolite classes including short- and branched-chain fatty acids.
- Tomás Clive Barker-Tejeda
- , Elisa Zubeldia-Varela
- & Alma Villaseñor
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Article
| Open AccessDermal injury drives a skin to gut axis that disrupts the intestinal microbiome and intestinal immune homeostasis in mice
The microbial community in the intestine can affect other organs such as the skin but it is not clear if the opposite can occur. Here the authors show that skin wounding affects the microbial composition of the intestinal flora which then enhances DSS induced colitis and intestinal inflammation.
- Tatsuya Dokoshi
- , Yang Chen
- & Richard L. Gallo
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Article
| Open AccessIntegration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment
Risk prediction for prognosis in colorectal cancer is an important tool. Here, the authors utilise GWAS from 5 cohorts of colorectal cancer patients, and show a healthy lifestyle is associated with a 7.6% improvement in overall survival among patients with high pathologic and genetic risk.
- Junyi Xin
- , Dongying Gu
- & Meilin Wang
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Article
| Open Accessp53 promotes revival stem cells in the regenerating intestine after severe radiation injury
The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.
- Clara Morral
- , Arshad Ayyaz
- & David G. Kirsch
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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| Open AccessThe secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation
Microbiome-secreted proteins act as key modulators of host-microbiome crosstalk. Here, the authors show that Amuc_1409 protein, secreted from Akkermansia muciniphila, plays a key role in intestinal homeostasis by regulating intestinal stem cells through interaction with E-cadherin, indicating its potential as a biomolecule for improving gut health.
- Eun-Jung Kang
- , Jae-Hoon Kim
- & Chul-Ho Lee
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Article
| Open AccessPaternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring
The dietary factors causing varying intergenerational responses are not fully identified. Here, the authors show that the relative proportion of protein, fats, and carbohydrates in paternal diets before conception differentially influences the phenotype of the next-generation offspring on energy metabolism and behaviour.
- Angela Jane Crean
- , Alistair McNair Senior
- & Stephen James Simpson
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Article
| Open AccessGadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms
Different gene mutations have been reported as drivers for myeloproliferative neoplasms (MPN). Here, the authors show that Gadd45g insufficiency induces MPN in mouse models and associates with MPN in patients.
- Peiwen Zhang
- , Na You
- & Xiaotong Ma
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Article
| Open AccessTargeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis
CD8 + T cells play an important role in primary biliary cholangitis (PBC). In this study, the authors demonstrate that PD-1-expressing CD8+ liver-resident T cells are pathogenic in murine PBC and that targeting these cells using a chimaeric antigen receptor reduces disease severity.
- Hao-Xian Zhu
- , Shu-Han Yang
- & Zhe-Xiong Lian
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Article
| Open AccessSenescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice
In their previous study, the researchers systematically revealed that endplate sclerosis is a significant aspect of spine degeneration or aging and a primary source of spinal pain. However, the underlying mechanisms of endplate sclerosis remained unclear. In their current report, it is shown that senescent cells accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging mouse models. The clearance of these senescent cells was found to restrain angiogenesis coupled with endplate sclerosis. Notably, macrophages were identified as undergoing senescence in the sclerotic endplates. The specific knockout of cdkn2a (p16) in macrophages abrogated LSI or aging-induced angiogenesis and sclerosis in the endplates. Moreover, both in vivo and in vitro studies indicated that IL-10 mediates the effects of senescent macrophages on angiogenesis and sclerosis in the endplates. Overall, these findings suggest that senescent macrophages orchestrate angiogenesis coupling with endplate sclerosis via the IL-10/pSTAT3 axis. This study enhances the understanding of the connection between immune senescence and endplate sclerosis and uncovers senescent macrophage-initiated endplate sclerosis as potential therapeutic targets for spinal degeneration.
- Yonggang Fan
- , Weixin Zhang
- & Shuangfei Ni