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| Open AccessMultiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer
Intratumoral heterogeneity has been documented in multiple cancer types, and can be linked to treatment resistance. Here, the authors analyse multiregional samples from colorectal cancers and show gene expression subtypes which are less vulnerable to heterogeneity and may partly contribute to differential patient survival.
- Jonas Langerud
- , Ina A. Eilertsen
- & Anita Sveen
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Article
| Open AccessPriming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells
Phenotypic changes in exhausted T cells are linked to chromatin remodeling. Here the authors show that pharmacological inhibition of the H3K4me1/2 demethylase LSD1 promotes the persistence and enhances the therapeutic activity of adoptively transferred T cells for cancer therapy.
- Fengqi Qiu
- , Peishan Jiang
- & Wanqiang Sheng
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Article
| Open AccessDevelopment of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality
Identifying biomarkers associated with risk of severe COVID-19 disease could inform clinical management. Here, the authors identify a long noncoding RNA associated with severe disease using data from three European countries, and validate their finding in data from Canada.
- Yvan Devaux
- , Lu Zhang
- & Hüseyin Firat
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Article
| Open AccessMedical history predicts phenome-wide disease onset and enables the rapid response to emerging health threats
Preventive interventions often require strategies to identify high-risk individuals. Here, the authors illustrate the potential utility of medical history in predicting the onset risk for thousands of diseases across clinical specialties including COVID-19.
- Jakob Steinfeldt
- , Benjamin Wild
- & Roland Eils
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Article
| Open AccessProduction of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism
Secondary bile acids are microbially produced metabolites linked to metabolic diseases. A challenge in microbiota research is to understand how bacteria collaborate to produce such bioactive molecules. Here, the authors show that adding a single low-abundance bacterial species to a community can significantly affect the metabolic output and host physiology.
- Annika Wahlström
- , Ariel Brumbaugh
- & Fredrik Bäckhed
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Article
| Open AccessInflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis
Inflammatory and degenerative processes are thought to play a role in the pathophysiology of multiple sclerosis. Here, the authors identified twenty serum proteins associated with increased clinical and radiographic disease activity.
- Tanuja Chitnis
- , Ferhan Qureshi
- & Sergio E. Baranzini
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Perspective
| Open AccessPlacing engineering in the earthquake response and the survival chain
This Perspective provides insightful discussion in how engineers can aid human health and safety during earthquake disasters. From search and rescue, helping mobilize patients, and securing medical facilities and treatment engineering can work towards bettering earthquake response.
- Luis Ceferino
- , Yvonne Merino
- & Baturalp Ozturk
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Article
| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessTargeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open AccessThe sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of Aspergillus fumigatus, and its repression reduces the virulence of this fungal pathogen in an animal model of infection.
- Jinhong Xie
- , Jeffrey M. Rybak
- & Jarrod R. Fortwendel
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Article
| Open AccessHomozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility
Here the authors show that a homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters the accessibility of variant-distal methylation sites in EPRS1 mRNA, revealing a new RNA-dependent mechanism by which genetic variants can influence gene expression and disease.
- Debjit Khan
- , Iyappan Ramachandiran
- & Paul L. Fox
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Article
| Open AccessHistopathologic image–based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer
Predicting the response to platinum-based chemotherapy in high-grade serous ovarian carcinoma (HGSOC) remains challenging. Here, the authors develop the histopathology image-based Pathologic Risk Classifier for HGSOC - PathoRiCH - to predict and stratify HGSOC patient response to therapy, especially when combined with molecular biomarkers.
- Byungsoo Ahn
- , Damin Moon
- & Eunhyang Park
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Article
| Open AccessAI-enhanced integration of genetic and medical imaging data for risk assessment of Type 2 diabetes
Type 2 diabetes is a global health threat demanding precise healthcare methods. Here, the authors show that their AI-driven risk assessment models, integrating genetic, imaging, and demographic data, achieve high accuracy in identifying high-risk groups, promising advancements in prevention strategies.
- Yi-Jia Huang
- , Chun-houh Chen
- & Hsin-Chou Yang
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Article
| Open AccessSpatial disparities in the mortality burden of the covid-19 pandemic across 569 European regions (2020-2021)
Excess mortality can be used as an indicator of the impacts of the COVID-19 pandemic. Here, the authors estimate excess mortality in 569 European regions in 25 countries for 2020 and 2021 and describe how impacts changed over time.
- Florian Bonnet
- , Pavel Grigoriev
- & Carlo-Giovanni Camarda
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Article
| Open AccessCerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue
After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition with neurological symptoms. Here, the authors show symptom-specific brain microstructure alterations in these patients, providing insights into the underlying pathophysiology.
- Jonas A. Hosp
- , Marco Reisert
- & Alexander Rau
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Article
| Open AccessStimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse
Despite initial treatment with surgical resection, glioblastoma multiforme (GBM) frequently recurs. Here the authors report the design of an immunostimulatory autolysing Salmonella based-nanocapsule delivery system, promoting anti-tumor immune responses and preventing postoperative relapse in preclinical GBM models.
- Yulin Zhang
- , Kaiyan Xi
- & Shilei Ni
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Article
| Open AccessHsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
Hsc70 (heat shock protein family A member 8) is a cytoplasmic chaperone protein involved in endosomal micro-autophagy and chaperone-mediated autophagy. Here the authors report that Hsc70 promotes lysosomal degradation of PD-L1 and that its overexpression promotes anti-tumor immune responses in preclinical cancer models.
- Xiaoyan Xu
- , Tingxue Xie
- & Hongguang Xia
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Article
| Open AccessEnhanced CD95 and interleukin 18 signalling accompany T cell receptor Vβ21.3+ activation in multi-inflammatory syndrome in children
Multi-Inflammatory Syndrome in Children (MIS-C) is a severe post-infectious presentation related to SARS-CoV-2 infection. Here authors used multi-omics approaches to characterise MIS-C cases and found increased CD95 and IL-18 signalling accompanying the expansion of TCR Vβ 21.3+ T cells.
- Zhenguang Zhang
- , Iain R. L. Kean
- & Nazima Pathan
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Article
| Open AccessEnhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys
Targeted drug delivery in vivo is a complex challenge, and understanding the characteristics that define the behavior of delivery vehicles in vivo is vital for advancing delivery vehicle design. Here the authors use a library of polymeric delivery vehicles and high-throughput tools to study the structure-function relationships guiding the physiological fate of nanomedicines.
- Alexandra S. Piotrowski-Daspit
- , Laura G. Bracaglia
- & W. Mark Saltzman
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Article
| Open AccessOriginal COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters
Waning immunity and the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness and required vaccine updates. Here, the authors assess how different priming regimens affect the immunogenicity of BA.1 and BA.5 bivalent boosters.
- Luca M. Zaeck
- , Ngoc H. Tan
- & Rory D. de Vries
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Article
| Open AccessMycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine
In this work, authors mechanistically investigate the reduced induction of antimicrobial peptides in Mycobacterium tuberculosis infected macrophages.
- Cheng Peng
- , Yuanna Cheng
- & Lin Wang
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Article
| Open AccessLiver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling
The peroxisomal β-oxidation enzyme ACOX1 increases in liver with obesity, but the physiological significance is unclear. Here, the authors show that liver-specific knockout of Acox1 leads to accumulation of omega-3 VLCFAs that promote metabolic health through activation of GPR120 in adipose tissue.
- Dongliang Lu
- , Anyuan He
- & Irfan J. Lodhi
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Article
| Open AccessGenomic insights unveil the plasmid transfer mechanism and epidemiology of hypervirulent Klebsiella pneumoniae in Vietnam
Hypervirulent Klebsiella pneumoniae (hvKp) is a significant cause of severe community-acquired infection, primarily in Asia. Here, the authors characterise the genetic profile, phylogenetic structure, and plasmid features of hvKp in Vietnam.
- Quynh Nguyen
- , Nguyen Yen Thi Phuong
- & Duy Thanh Pham
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Article
| Open AccessFerritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
| Open AccessImpacts of human mobility on the citywide transmission dynamics of 18 respiratory viruses in pre- and post-COVID-19 pandemic years
Population mobility is associated with SARS-CoV-2 transmission but its impacts on other respiratory viruses are not well understood. Here, the authors investigate associations between mobile phone-derived mobility metrics and the dynamics of 18 respiratory viruses in Seattle, Washington from 2018 to 2022.
- Amanda C. Perofsky
- , Chelsea L. Hansen
- & Cécile Viboud
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Article
| Open AccessImportance of social inequalities to contact patterns, vaccine uptake, and epidemic dynamics
Contact patterns influence the spread of infectious diseases, but mathematical models of epidemics typically only account for age differences in contacts. Here, the authors investigate the importance of other sociodemographic characteristics in shaping contact patterns and vaccine uptake using survey data from Hungary.
- Adriana Manna
- , Júlia Koltai
- & Márton Karsai
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Article
| Open AccessTDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Amyotrophic Lateral Sclerosis is characterized by TDP-43 proteinopathy in the brain. Here, the authors find TDP-43 aggregation might be mediated by the loss of Asparaginase-like 1, an enzyme that degrades detrimental isoaspartates and is downregulated by the endogenous retrovirus HML-2.
- Marta Garcia-Montojo
- , Saeed Fathi
- & Avindra Nath
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Article
| Open AccessBone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes
Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).
- Moritz Binder
- , Raphael E. Szalat
- & Nikhil C. Munshi
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Article
| Open AccessThe vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans
The transition between yeast and hyphae is crucial for the pathogenicity of Candida albicans. Here, Liu et al. show that vacuole fusion is active during hyphal extension and that large vacuoles increase the mechanical forces of hyphae penetrating into organs.
- Yu Liu
- , Ruina Wang
- & Lan Yan
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Article
| Open AccessDynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy
Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.
- Maxime Mistretta
- , Mena Cimino
- & Giulia Manina
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Article
| Open AccessMechanically robust and personalized silk fibroin-magnesium composite scaffolds with water-responsive shape-memory for irregular bone regeneration
The regeneration of critical-size bone defects, especially those with irregular shapes, remains a clinical challenge. Here, the authors report a shape-memory, tailorable, self-adaptive and bioactive silk fibroin/magnesium composite scaffold that can quickly match irregular defects by simple trimming and lead to good interface integration.
- Zhinan Mao
- , Xuewei Bi
- & Yufeng Zheng
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Article
| Open AccessSerological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea
In a serological analysis, Bore et al. utilise serum samples, collected from a cohort of individuals associated with bushmeat hunting and butchering, in the forested region of Guinea, a region close to the epicentre of the 2013–2016 West Africa Ebola virus disease epidemic.
- Joseph Akoi Boré
- , Joseph W. S. Timothy
- & Miles W. Carroll
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Article
| Open AccessE-cardiac patch to sense and repair infarcted myocardium
Infarted myocardium hampers the synchronous electroactivity of the cardiac tissue. Here, the authors showcase a battery-free conductive cardiac patch made of reduced graphene and its therapeutic efficacy for cardiac repair.
- Renjie Qiu
- , Xingying Zhang
- & Leyu Wang
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Article
| Open AccessSevere drought exposure in utero associates to children’s epigenetic age acceleration in a global climate change hot spot
The study suggests a positive association between in utero drought exposure and faster biological aging in children in a global climate change hot spot. Drought experienced during pregnancy may reduce life expectancy.
- Xi Qiao
- , Bilinda Straight
- & Belinda L. Needham
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Article
| Open AccessFOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation
FOXC1 transcription factor plays a role in vascular development, but its mechanism is not well defined. Here, the authors show FOXC1 regulates retinal angiogenesis by promoting CD98 amino acid transporter expression to activate mTOR signalling, and also by promoting blood-retina barrier formation.
- Teena Bhakuni
- , Pieter R. Norden
- & Tsutomu Kume
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Article
| Open AccessIdentifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank
Plasma proteins are a potential diagnostic tool to detect multiple diseases, including cancer. Here, the authors leverage multi-omics data to identify 1,463 proteins associated with 19 common cancers in UK Biobank participants. Reviewer Recognition:
- Keren Papier
- , Joshua R. Atkins
- & Ruth C. Travis
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Article
| Open AccessComparison of intramyocellular lipid metabolism in patients with diabetes and male athletes
Endurance athletes and sedentary type 2 diabetes patients swapped their lifestyle for 8 weeks. Athletes store and utilise saturated fat intensely for performant physical activity, and type 2 diabetes patients reversed their dysmetabolic lipid state after endurance training.
- Alice M. Mezincescu
- , Amelia Rudd
- & Dana Dawson
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Article
| Open AccessThree stepwise pH progressions in stratum corneum for homeostatic maintenance of the skin
Previous studies of the skin have suggested a neutral-to-acidic pH gradient in the outermost layer. Here, the authors perform quantitative intravital pH imaging of the stratum corneum, the outermost epidermal layer, and demonstrate three distinct pH zones - rather than a gradient - with different biological functions.
- Keitaro Fukuda
- , Yoshihiro Ito
- & Masayuki Amagai
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Article
| Open AccessCD5L as a promising biological therapeutic for treating sepsis
Authors explore the utility of CD5L for treating experimental sepsis. CD5L deficiency exacerbates experimental sepsis. Conversely, administration of recombinant CD5L in WT mice augments neutrophil function, enhances bacterial control, and mitigates inflammation, leading to substantial improvements in disease outcomes.
- Liliana Oliveira
- , M. Carolina Silva
- & Alexandre M. Carmo
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Article
| Open AccessIRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis
The endoplasmic reticulum (ER) is a major site of lipid peroxidation during ferroptosis. Here authors show that the ER protein IRE1α determines ferroptosis induction via regulating glutathione synthesis independent of the unfolded protein response.
- Dadi Jiang
- , Youming Guo
- & Albert C. Koong
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Article
| Open AccessCEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials
Cibisatamab is a T-cell bispecific antibody targeting the carcinoembryonic antigen (CEA) on tumor cells and CD3 epsilon chain on T cells. Here the authors report the results of two clinical trials of cibisatamab as monotherapy (NCT02324257) and in combination with atezolizumab (anti-PD-L1; NCT02650713) in patients with CEA-positive solid tumors.
- Neil H. Segal
- , Ignacio Melero
- & Guillem Argilés
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Article
| Open AccessHepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture
Hepatocytes dedifferentiate into progenitor-like cells in culture. Here, authors elucidate the dynamics and mechanisms of hepatocyte dedifferentiation and find an unexpected differentiation potential of hepatocytes into intestinal epithelial cells.
- Shizuka Miura
- , Kenichi Horisawa
- & Atsushi Suzuki
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Article
| Open AccessCell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment
Cell-mediated cytotoxicity observed in untreated SMA patients’ CSF and brain parenchyma. Spatial transcriptomic and multiplex immunohistochemistry linked cytotoxicity near affected motoneurons. Nusinersen treatment showed no impact on this profile.
- I-Na Lu
- , Phyllis Fung-Yi Cheung
- & Gerd Meyer zu Horste
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Article
| Open AccessA burden of proof study on alcohol consumption and ischemic heart disease
Alcohol use is commonplace and ischemic heart disease (IHD) the leading cause of death globally, yet their relationship is unclear. Here we show that study type determines whether research finds alcohol reduces IHD risk or is unrelated, arguing for new approaches to settle this critical debate.
- Sinclair Carr
- , Dana Bryazka
- & Emmanuela Gakidou
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Article
| Open AccessSevere outcomes of malaria in children under time-varying exposure
Severe pediatric malaria remains a concern in many countries. Here, the authors use an individual-based modeling approach to evaluate the relationship between malaria prevalence and incidence of malaria pediatric hospitalizations, and show how unsteady transmission patterns affect hospitalization rates.
- Pablo M. De Salazar
- , Alice Kamau
- & Melissa A. Penny
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Article
| Open AccessDysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation
The impact of obesity on cancer remains insufficiently explored. Here the authors show that in mouse models, dysfunctional adipocytes exhibit low levels of BECN1 which induce YAP/TAZ activity to promote breast and colorectal tumor progression.
- Yaechan Song
- , Heeju Na
- & Han-Woong Lee
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Article
| Open AccessPremature skewing of T cell receptor clonality and delayed memory expansion in HIV-exposed infants
Here, Dzanibe et al show that in utero HIV/ARV exposure sequentially disrupts infant immunologic trajectories, beginning with NK cells that predict vaccine antibody responses and followed by delayed T cell memory maturation linked to skewed TCR clonality.
- Sonwabile Dzanibe
- , Aaron J. Wilk
- & Clive M. Gray
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Article
| Open AccessdsRNAi-mediated silencing of PIAS2beta specifically kills anaplastic carcinomas by mitotic catastrophe
Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly.
- Joana S. Rodrigues
- , Miguel Chenlo
- & Clara V. Alvarez
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Article
| Open AccessSystematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types
Single-cell sequencing has enabled detailed analyses of the tumour microenvironment (TME). Here, the authors perform an integrative analysis of the TME using single-cell and spatial transcriptomics data from over a thousand tumours across thirty cancer types, identifying interferon-enriched community states predictive of immunotherapeutic responses.
- Junho Kang
- , Jun Hyeong Lee
- & Jong-Eun Park