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Matters Arising
| Open AccessReply: Muscle abnormalities in Long COVID
- B. Appelman
- , B. T. Charlton
- & R. C. I. Wüst
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Article
| Open Access
CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease
Disturbed lipid metabolism is a feature of diabetic kidney disease (DKD). Here the authors report that ceramide synthase 6 (CerS6) in podocytes contributes to the pathogenesis of diabetic kidney disease (DKD) in male mice by inducing mitochondrial DNA leakage, activating the cGAS-STING pathway and promoting inflammation.
- Zijing Zhu
- , Yun Cao
- & Zhaowei Chen
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Article
| Open Access
BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma
Metabolic dysregulation in the development of clear cell renal cell carcinoma (ccRCC) remains to be understood. Here the authors identify that a carnitine synthesis enzyme BBOX1, which inhibits TBK1-mTORC1 signaling and glycolysis, is often lost in ccRCC.
- Chengheng Liao
- , Lianxin Hu
- & Qing Zhang
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Article
| Open Access
Multi-ancestry meta-analysis of genome-wide association studies discovers 67 new loci associated with chronic back pain
A multi-ancestry genome-wide association study meta-analysis of chronic back pain in 553,601 participants from the Million Veteran Program revealed 67 new genome-wide significant loci with gene enrichment in brain and pituitary tissues.
- Ian B. Stanaway
- , Pradeep Suri
- & Marianna Gasperi
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Article
| Open Access
FTO-associated osteoclastogenesis promotes alveolar bone resorption in apical periodontitis male rat via the HK1/USP14/RANK pathway
Alveolar bone resorption (ABR) is a key pathological manifestation in the development of apical periodontitis (AP) that contributes to the AP-associated tooth loss, and whose underlying mechanism is largely unknown. Here, the authors show a molecular mechanism on osteoclastogenesis-related ABR and provides a therapeutic target of AP via modulating the FTO/HK1/USP14/RANK axis.
- Yajie Qian
- , Jing Wu
- & Deyan Chen
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Article
| Open Access
The spatiotemporal transcriptional profiling of murine brain during cerebral malaria progression and after artemisinin treatment
By integrating single-cell and spatial transcriptomic analysis, Chen et al. profile the cellular disruptions in the murine brain during cerebral malaria and after artemisinin treatment.
- Jiayun Chen
- , Yunmeng Bai
- & Jigang Wang
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Article
| Open Access
Medical multimodal multitask foundation model for lung cancer screening
Lung cancer screening (LCS) requires effectively and efficiently mining big, multimodal datasets. Here, the authors develop a medical multimodal-multitask foundation model (M3FM) for LCS from 3D low-dose computed tomography and medical multimodal data, outperforming state-of-the-art methods and allowing the identification of informative data elements.
- Chuang Niu
- , Qing Lyu
- & Ge Wang
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Article
| Open Access
Regorafenib plus sintilimab as a salvage treatment for microsatellite stable metastatic colorectal cancer: a single-arm, open-label, phase II clinical trial
The combination of targeted therapeutic agents for metastatic colorectal cancer (mCRC) salvage treatment has potential in clinics. Here this group conducts a single-arm, open-label, phase II trial assessing the combination therapy of regorafenib (tyrosine kinase inhibitor) and sintilimab (PD-1 targeting) as a safe and effective salvage-line treatment for mCRC patients who have progressed upon second-line treatment.
- Rui Liu
- , Zhi Ji
- & Jihui Hao
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Article
| Open Access
Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV
Targeted protein degradation has so far been rarely applied as an antiviral strategy. Here, the authors report that macrocycle-based PROTACs targeting host protein cyclophilin A, exploited during viral infection, show potent and isoform-selective degradation resulting in antiviral activity against HIV-1 and HCV.
- Lydia S. Newton
- , Clara Gathmann
- & David L. Selwood
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Article
| Open Access
Enzymatic conversion of blood group B kidney prevents hyperacute antibody-mediated injuries in ABO-incompatible transplantation
The complexity of matching ABO blood groups presents a formidable barrier to successful transplantation. Here, the authors show that an enzymatic converted type B kidney was transplanted into a type O brain-dead recipient without hyperacute rejection.
- Jun Zeng
- , Ming Ma
- & Turun Song
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Article
| Open Access
Single-cell RNA sequencing defines distinct disease subtypes and reveals hypo-responsiveness to interferon in asymptomatic Waldenstrom’s Macroglobulinemia
The impact of tumor intrinsic and immune alterations on disease progression in patients with Waldenstrom’s Macroglobulinemia (WM) remains to be characterized. Here, the authors perform single-cell RNA-sequencing and identify distinct tumor subtypes, tumour microenvironment features and potential therapeutic vulnerabilities in patients with WM.
- Romanos Sklavenitis-Pistofidis
- , Yoshinobu Konishi
- & Irene M. Ghobrial
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Article
| Open Access
Non-catalytic mechanisms of KMT5C regulating hepatic gluconeogenesis
Gluconeogenesis produces glucose from non-carbohydrate carbon substrates, particularly occurs during fasting. Here, the authors show lysine methyltransferase KMT5C promotes gluconeogenesis by decreasing PGC-1α degradation, which is independent of its methyltransferase activity.
- Qingwen Zhao
- , Xuan Cui
- & Dongning Pan
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Article
| Open Access
Transdermal microneedle-assisted ultrasound-enhanced CRISPRa system to enable sono-gene therapy for obesity
Obesity, a surging global health challenge, needs effective and innovative therapeutic models. Here, the authors show in mice a microneedle drug delivery platform loaded with metal-organic frameworks (MOFs) and CRISPRa-UCP1 system to enable sono-gene therapy for obesity.
- Shaoyue Li
- , Jifeng Yu
- & Huixiong Xu
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Article
| Open Access
Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer
The molecular mechanisms underlying stage I non-small cell lung cancer (NSCLC) remain poorly understood. Here, the authors do multi-omics profiling of paired tumor and normal adjacent tissues from NSCLC patients, finding molecular processes and cell type proportions that are associated with recurrence.
- Chengdi Wang
- , Jingwei Li
- & Weimin Li
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Article
| Open Access
Prion protein promotes copper toxicity in Wilson disease
This study reveals that prion protein (PrP) promotes copper toxicity in Wilson disease by facilitating copper endocytosis. The authors demonstrate that suppressing PrP reduces copper overload and liver damage, offering a potential therapeutic strategy for this fatal inherited disorder.
- Raffaella Petruzzelli
- , Federico Catalano
- & Roman S. Polishchuk
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Article
| Open Access
Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease
Authors show that base editing can convert sickle hemoglobin (HbS) to the rare but naturally occurring variant G-Makassar (HbG). Purified HbG appears normal, but in a mouse model, HbGS red cells sickle under hypoxia, highlighting the importance of assessing red cell quality when evaluating novel gene editing strategies for hematologic disorders.
- Zachary Kostamo
- , Manuel A. Ortega
- & Vivien A. Sheehan
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Article
| Open Access
Biological age model using explainable automated CT-based cardiometabolic biomarkers for phenotypic prediction of longevity
The authors develop a model derived from an automated pipeline of explainable AI body composition tools applied to abdominal CT. They provide a tool for the personalized phenotypic assessment of biological aging that can be opportunistically derived, regardless of clinical indication.
- Perry J. Pickhardt
- , Michael W. Kattan
- & John W. Garrett
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Article
| Open Access
Retrotrans-genomics identifies aberrant THE1B endogenous retrovirus fusion transcripts in the pathogenesis of sarcoidosis
Sarcoidosis is an inflammatory systemic disorder characterized by the granulomas developed in epithelioid cells in various organs. Here, the authors identify ancient endogenous retrovirus THE1B fusion transcripts that are aberrantly expressed in sarcoidosis.
- Shunsuke Funaguma
- , Aritoshi Iida
- & Ichizo Nishino
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Article
| Open Access
Artificial intelligence links CT images to pathologic features and survival outcomes of renal masses
Distinguishing benign renal masses from malignant renal tumours, and further differentiating indolent from aggressive renal cancers, on computed tomography (CT) scans remains challenging. Here, the authors develop deep learning models for distinguishing benign from malignant renal masses, and differentiating indolent from aggressive renal tumours in a large cohort of preoperative CT scans, obtaining high accuracy and a strong association with clinical outcomes.
- Ying Xiong
- , Linpeng Yao
- & Shuo Wang
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Article
| Open Access
The anti-PD-L1/CTLA-4 bispecific antibody KN046 plus lenvatinib in advanced unresectable or metastatic hepatocellular carcinoma: a phase II trial
KN046 is a bispecific antibody targeting PD-L1 and CTLA4. Here the authors report the results of a phase II trial of KN046 combined with lenvatinib in patients with advanced hepatocellular carcinoma.
- Da Xu
- , Hongwei Wang
- & Baocai Xing
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Article
| Open Access
A multistage drug delivery approach for colorectal primary tumors and lymph node metastases
Lymph node (LN) metastases after primary treatment may end up with disease recurrence and poor survival rate. Here this group designs a phospholipase A2 (sPLA2)-responsive nanosystem delivering doxorubicin for in vivo inhibition of both primary colorectal tumor progression and LN metastasis.
- Yihang Yuan
- , Quanjun Lin
- & Chao Fang
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Article
| Open Access
WNT11 Promotes immune evasion and resistance to Anti-PD-1 therapy in liver metastasis
Activation of the WNT/β-catenin signaling pathway has been associated with immune evasion in several cancer types. Here the authors show that expression of WNT11, a member of the non-canonical WNT signaling pathway, is associated with CD8 + T cell exclusion and resistance to immune checkpoint inhibitors in liver metastasis.
- Weiliang Jiang
- , Bingjie Guan
- & Senlin Zhao
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Article
| Open Access
D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming
The oncometabolite D-2-HG has been implicated in compromising DNA repair pathway. Here the authors show D-2-HG leads to genome-wide DNA hypermethylation and loss of CTCF coverage, which impairs the assembly of the homologous recombination DNA repair machinery and associated topology adjustment.
- Fengchao Lang
- , Karambir Kaur
- & Chunzhang Yang
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Article
| Open Access
Triglyceride levels and its association with all-cause mortality and cardiovascular outcomes among patients with heart failure
The association between triglyceride (TG) and mortality remains controversial in individuals with heart failure (HF). Here the authors show a U-shaped association where high TG levels are associated with ASCVD-related admission or death and lower TG levels are associated with HF-related readmission or death.
- Qing-Wen Ren
- , Tiew-Hwa Katherine Teng
- & Kai-Hang Yiu
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Article
| Open Access
The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model
CAR and PXR receptors are known to regulate metabolism, however, there is no dual human ligand suitable for therapy. Here, the authors show a CAR agonist/PXR antagonist, MI-883, which regulates cholesterol/bile acid homeostasis by leveraging CAR and PXR activations in plasma cholesterol regulation.
- Jan Dusek
- , Ivana Mejdrová
- & Petr Pavek
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Article
| Open Access
Single-cell atlas of human pancreatic islet and acinar endothelial cells in health and diabetes
The pancreatic vasculature displays significant heterogeneity, with the islets perfused by a specialized microcirculation with greater density than the surrounding acinar tissue. Using single-cell RNA sequencing of human pancreases and integration with further data, the authors reveal the vascular transcriptomic heterogeneity in the healthy and diabetic pancreas.
- Rebecca Craig-Schapiro
- , Ge Li
- & David Redmond
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Article
| Open Access
Neurovascularization inhibiting dual responsive hydrogel for alleviating the progression of osteoarthritis
Treating osteoarthritis associated pain is challenging. Here, the authors on a hydrogel for extracellular RNA scavenging and releasing bevacizumab to block angiogenesis and neurogenesis at the osteochondral interface, mitigating pain and disease progression.
- Wenpin Qin
- , Zhangyu Ma
- & Kai Jiao
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Article
| Open Access
Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer
Determining the causal variants at GWAS loci is crucial for understanding genetic disease mechanisms. Here, the authors apply MPRA to perform non-small cell lung cancer (NSCLC) variant-to-function mapping at scale and propose distinct genetic architectures underlying NSCLC susceptibility.
- Congcong Chen
- , Yang Li
- & Hongbing Shen
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Article
| Open Access
A quantitative spatial cell-cell colocalizations framework enabling comparisons between in vitro assembloids and pathological specimens
Comparing spatial omics data across samples remains elusive. Here, the authors develop a quantitative spatial framework, termed as colocatome analysis, by combining pairwise cell-cell colocalization, spatial permutation and normalization approaches for comparing features across conditions and studies.
- Gina Bouchard
- , Weiruo Zhang
- & Sylvia K. Plevritis
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Article
| Open Access
A covalent peptide-based lysosome-targeting protein degradation platform for cancer immunotherapy
LYTAC strategies often face challenges in solid tumor penetration and synthesis. Here, the authors introduce Pep-TACs, a modular TFRC-based covalent peptide degradation platform that effectively degrades membrane protein PD-L1. This approach significantly suppresses both anti-PD-1-responsive and -resistant tumor growth, particularly in brain tumors.
- Youmei Xiao
- , Zhuoying He
- & Yanfeng Gao
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Article
| Open Access
Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis involving evasion of immune control. Here, the authors perform a comprehensive analysis of single-cell multi-omic data revealing either a myeloid-enriched or adaptive-enriched tumour microenvironment, linked to distinct B and T cell clonal selection and differentiation, distinct overall survival, and potential therapeutic approaches.
- Shivan Sivakumar
- , Ashwin Jainarayanan
- & Rachael Bashford-Rogers
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Article
| Open Access
Distributed cross-learning for equitable federated models - privacy-preserving prediction on data from five California hospitals
Medical predictive analytics can enhance quality improvement, clinical research, and patient care. D-CLEF, a privacy-preserving model, integrates patient data across centers and performs comparably to centralized models, enabling collaboration without sharing patient records.
- Tsung-Ting Kuo
- , Rodney A. Gabriel
- & Lucila Ohno-Machado
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Article
| Open Access
Testosterone exacerbates neutrophilia and cardiac injury in myocardial infarction via actions in bone marrow
Men develop larger myocardial infarction (MI) sizes than women. Here, the authors show that male sex and testosterone, via bone marrow stroma, exacerbates MI-induced neutrophilia and cardiac injury and that response to anti-inflammatory treatment in MI is greater in men than women
- Elin Svedlund Eriksson
- , Marta Lantero Rodriguez
- & Åsa Tivesten
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Article
| Open Access
Brd7 loss reawakens dormant metastasis initiating cells in lung by forging an immunosuppressive niche
Metastasis-initiating cells can reawaken from a dormant state that initially allowed them to survive, triggering metastatic outgrowth. Here, authors show that loss of Brd7 promotes an immunosuppressive tumor microenvironment that drives breast cancer metastatic reawakening from dormancy in the lung.
- Jayanta Mondal
- , Junfeng Zhang
- & Filippo G. Giancotti
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Article
| Open Access
A truncated pre-F protein mRNA vaccine elicits an enhanced immune response and protection against respiratory syncytial virus
Here the authors design an mRNA based RSV vaccine, expressing a truncated membrane-anchored version of the stabilized pre-F protein, and demonstrate strong humoral and Th1-skewed T-cell responses in small animal models without signs of vaccine-enhanced respiratory disease.
- Min Lin
- , Yifan Yin
- & Zizheng Zheng
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Article
| Open Access
A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations
STX16 microdeletions cause pseudohypoparathyroidism type-1B only on the maternal allele. Here, the authors show that the allele-specific pathogenicity reflects differential conformations of a biallelically active enhancer dictating GNAS imprinting.
- Yorihiro Iwasaki
- , Monica Reyes
- & Murat Bastepe
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Article
| Open Access
Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics
Medulloblastoma in children is a difficult cancer to treat and the immune response to this tumour is not fully understood. Here the authors characterise and validate T cell epitopes from these cancers using an immunopeptidomics approach, comparing different molecular subtypes.
- Julia Velz
- , Lena K. Freudenmann
- & Marian C. Neidert
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Article
| Open Access
Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis
Targeting Ceramide Transfer Protein (CERT) is known to sensitize solid cancer cells to chemotherapy. Here this groups reports targeting CERT can effectively inhibit the growth and promote apoptosis of acute myeloid leukemia cells carrying FLT3-ITD mutation.’
- Xiaofan Sun
- , Yue Li
- & Hui Zeng
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Article
| Open Access
Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation
Here, the authors show that reduced transport of UDP-GlcNAc to the endoplasmic reticulum and Golgi leads to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. This, in turn, stabilizes the transcription factor GATA4, promoting the senescence-associated secretory phenotype and exacerbating osteoarthritis.
- Donghyun Kang
- , Jeeyeon Lee
- & Jin-Hong Kim
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Article
| Open Access
Differential transport pathways of saturated and unsaturated fatty acid esters in male mouse hepatocytes
Saturated fatty acid (SFA) and unsaturated fatty acid (UFA) have distinct impacts on health. Here the authors demonstrate that the secretion of UFA esters from the liver requires PDI-MTP, while secretion of SFA esters could be PDI-MTP-independent.
- Fengwu Chen
- , Aizhen Yang
- & Yi Wu
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Article
| Open Access
NAPTUNE: nucleic acids and protein biomarkers testing via ultra-sensitive nucleases escalation
Rapid detection of diverse biomarkers is crucial for public health. Here, the authors develop NAPTUNE, a versatile platform that identifies multiple nucleic acids and proteins targets within 45 minutes using a nuclease cascade.
- Tao Hu
- , Xinxin Ke
- & Chunyi Hu
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Article
| Open Access
Fucosylated haptoglobin promotes inflammation via Mincle in sepsis: an observational study
Haptoglobin (Hp) scavenges cell-free haemoglobin and is associated with the prognosis of human sepsis. Here, the authors characterize the association of fucosylated Hp in sepsis progression and identify a macrophage population expressing a receptor for fucosylated Hp, highlighting its inflammation-amplifying effects in in vitro human cell cultures and in vivo using a mouse model.
- Taylor Roh
- , Sungeun Ju
- & Eun-Kyeong Jo
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Article
| Open Access
Multi-omic spatial effects on high-resolution AI-derived retinal thickness
Retinal morphology is emerging as a key biomarker for disease. Here, using AI to create a high-resolution map of retinal thickness from optical coherence tomography images, the authors demonstrate spatial associations with genetic variation, metabolites and disease, with the parafovea showing the highest enrichment
- V. E. Jackson
- , Y. Wu
- & M. Bahlo
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Perspective
| Open Access
Reward signals in the motor cortex: from biology to neurotechnology
The primary motor cortex (M1) not only drives movement but also responds to rewards. In this Perspective, the authors discuss the functional roles of M1’s reward signals and propose how they could transform neurotechnologies like brain-computer interfaces and brain stimulation for movement recovery.
- Gerard Derosiere
- , Solaiman Shokur
- & Pierre Vassiliadis
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Article
| Open Access
Cloned airway basal progenitor cells to repair fibrotic lung through re-epithelialization
Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis patients causes high mortality worldwide, with no lung repair approaches available currently. Here, the authors show that cloned human airway basal progenitor cells could repair the fibrotic lung through re-epithelialization of the damaged alveolar area.
- Yu Zhao
- , Yueqing Zhou
- & Wei Zuo
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Perspective
| Open Access
Duchenne muscular dystrophy: recent insights in brain related comorbidities
Duchenne muscular dystrophy is characterised by progressive muscle weakness and variable brain involvement. In this review the authors describe the molecular underpinning of this brain involvement, and how genetic therapies improve behavioural outcomes in the dystrophic mouse models.
- Cyrille Vaillend
- , Yoshitsugu Aoki
- & Francesco Muntoni
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Article
| Open Access
Plant-nanoparticles enhance anti-PD-L1 efficacy by shaping human commensal microbiota metabolites
The impact of diet on gut microbiota and metabolites in context of cancer immunotherapy remains elusive. Here the authors reveal ginger-derived exosome-like nanoparticle (GELN) aly-miR159a-3p enhances anti-PD-L1 therapy by increasing microbiota-dependent docosahexaenoic acid (DHA) level thus limiting tumor cell PD-L1 expression.
- Yun Teng
- , Chao Luo
- & Huang-Ge Zhang
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Article
| Open Access
Stimulus-activated ribonuclease targeting chimeras for tumor microenvironment activated cancer therapy
Off-target effects have limited RNA degradation approaches. Here, the authors develop a tumor microenvironment-activated ribonuclease targeting chimera (RiboTAC) demonstrating H2O2 and acid activated degradation of pre-miR-21, which was effective in restoring radiosensitivity in lung cancer.
- Yuqi Zhang
- , Jinfeng Zhu
- & Haibin Shi
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Article
| Open Access
USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation
The m6A binding protein YTHDF1 is frequently upregulated in cancer. Here the authors report that USP5 deubiquitinates and stabilizes YTHDF1, associated with cancer growth and immune evasion, and that targeting USP5 potentiates response to anti-PD-L1 in preclinical models.
- Na Shao
- , Lei Xi
- & Chungang Liu
