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| 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 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 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 AccessPalmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation
The role and mechanisms for protein palmitoylation in renal fibrosis remain unclear. Here, the authors show that DHHC9 and APT1 catalysed β-catenin S-palmitoylation on Cys300 contributes to renal fibrosis, which may provide a new therapeutic strategy for chronic kidney diseases.
- Mengru Gu
- , Hanlu Jiang
- & Chunsun Dai
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Article
| Open AccessKetamine’s acute effects on negative brain states are mediated through distinct altered states of consciousness in humans
The neural mechanisms underlying ketamine-induced altered states of consciousness are not well understood. Here, the authors show that depersonalization and dissociative amnesia related to ketamine have opposing effects on the activity of the right anterior insula in response to social threat.
- Laura M. Hack
- , Xue Zhang
- & Leanne M. Williams
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Article
| Open AccessADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
Raynaud’s phenomenon is a common vasospastic disorder, but the genetic origins of the condition are not well understood. Here, the authors find common genetic variants associated with Raynaud’s phenomenon, and find genes putatively involved in the disorder.
- Sylvia Hartmann
- , Summaira Yasmeen
- & Claudia Langenberg
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Article
| Open AccessClinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
Malaria parasites from patients who fail atovaquone therapies are highly drug-resistant, with mutations at Y268 in cytochrome b. Here the authors show that this mutation results in multiple defects in the parasite’s development and prevents transmission from mosquitoes to mice.
- Victoria A. Balta
- , Deborah Stiffler
- & Theresa A. Shapiro
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| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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Article
| Open AccessInjectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment
The use of biomaterial scaffolds-based cartilage grafts could potentially innovate the Osteoarthritis (OA) treatment, but has been limited by toxicity concerns and invasive surgical procedures. Here, the authors report an injectable and biodegradable piezoelectric hydrogel with ultrasound activation to offer a minimally invasive approach for OA treatment.
- Tra Vinikoor
- , Godwin K. Dzidotor
- & Thanh D. Nguyen
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Article
| Open AccessHypersensitive MR angiography based on interlocking stratagem for diagnosis of cardiac-cerebral vascular diseases
Current contrast-enhanced magnetic resonance angiography approaches are sub-optimal. Here the authors present a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd), enabling sophisticated micro-vessel angiography of cardiac-cerebrovascular diseases with ultrahigh resolution.
- Peisen Zhang
- , Junwei Cheng
- & Yi Hou
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization
cfDNA is a promising tool to detect early cancer, however, it has been limited by detection limits and technological ability. Here, the authors develop a method for simultaneous cfDNA methylation, fragmentation and copy number alteration sequencing and apply to a cohort of healthy and cancer patients.
- Fenglong Bie
- , Zhijie Wang
- & Shugeng Gao
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Article
| Open AccessLarge-scale capture of hidden fluorescent labels for training generalizable markerless motion capture models
Deep learning-based models for tracking behavior are often constrained by manual annotation. Here, authors present GlowTrack, an approach using fluorescence to generate large and diverse training sets that improve model robustness and tracking coverage.
- Daniel J. Butler
- , Alexander P. Keim
- & Eiman Azim
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Article
| Open AccessCamel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours
Chimeric antigen receptor T (CAR-T) cells represent an emerging form of immune therapy but success, especially in solid tumors, is limited by the scarcity of suitable target epitopes. Here authors show that a distinct epitope motif on the transmembrane protein B7-H3, recognized by a camel nanobody, triggers robust activation and anti-tumor function in cognate CAR-T cells.
- Dan Li
- , Ruixue Wang
- & Mitchell Ho
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Article
| Open AccessGenotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures
Candida glabrata bloodstream infections are thought to be mostly caused by a single strain. Here, the authors describe genotypic and phenotypic diversity of Candida glabrata in ten individual blood cultures, and find diversity in drug susceptibility and virulence within patients.
- Hassan Badrane
- , Shaoji Cheng
- & M. Hong Nguyen
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Article
| Open AccessDecoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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| Open AccessTranslating genomic tools to Raman spectroscopy analysis enables high-dimensional tissue characterization on molecular resolution
Spatial transcriptomics of histological sections have revolutionized basic research, while the actual biomolecular composition of the sample has fallen behind. Here, the authors propose a novel approach to analyze untargeted spatiomolecular Raman spectroscopy data through bioinformatic tools developed for transcriptomic analyses, and integrate them with additional Omics techniques.
- Manuel Sigle
- , Anne-Katrin Rohlfing
- & Meinrad Paul Gawaz
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Article
| Open AccessAtezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open AccessSynthesize high-dimensional longitudinal electronic health records via hierarchical autoregressive language model
The paper presents HALO, a Hierarchical Autoregressive Language Model, for generating high-fidelity, longitudinal electronic health records (EHR) data. HALO maintains statistical property, supports machine learning modeling without privacy concerns.
- Brandon Theodorou
- , Cao Xiao
- & Jimeng Sun
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Article
| Open AccessPortosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry
Patients with liver disease undergoing transjugular intrahepatic portosystemic shunt (TIPS) are at a higher risk of hepatic encephalopathy (HE). Here, the authors show intrahepatic shunting and specific metabolites, especially bile acids, as potential biomarkers and treatment targets for HE.
- Ana Carolina Dantas Machado
- , Stephany Flores Ramos
- & Amir Zarrinpar
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| Open AccessAAV-mediated base-editing therapy ameliorates the disease phenotypes in a mouse model of retinitis pigmentosa
Base editing technology has great potential in treating pathogenic single-nucleotide variations. Using a dual-AAV base editing system, Wu et al. restored visual functions in a mouse model of retinitis pigmentosa.
- Yidong Wu
- , Xiaoling Wan
- & Xueli Zhang
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Article
| Open AccessDeep learning for obstructive sleep apnea diagnosis based on single channel oximetry
Obstructive sleep apnea (OSA) is a highly prevalent condition with a number of comorbidities, but it has a high misdiagnosis rate. In this retrospective study, the authors used six independent databases to develop and evaluate a deep learning model, denoted OxiNet, for the diagnosis of OSA from the sole oximetry signal.
- Jeremy Levy
- , Daniel Álvarez
- & Joachim A. Behar
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| Open AccessLong-term ex situ normothermic perfusion of human split livers for more than 1 week
Long-term machine perfusion of human livers outside the body is an emerging field with tremendous potential for the assessment, recovery, and modification of organs prior to transplantation. Here, the authors report the long-term ex situ perfusion of human livers and demonstrate the ability to split and perfuse these organs using a standardised protocol.
- Ngee-Soon Lau
- , Mark Ly
- & Carlo Pulitano
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Article
| Open AccessCas9-mediated knockout of Ndrg2 enhances the regenerative potential of dendritic cells for wound healing
Chronic wounds impose a significant burden to a broad patient population. Here, the authors use CRISPR/Cas9 to enhance the regenerative capacity of dendritic cells by knocking out the gene Ndrg2, and show that seeding these engineered dendritic cells on hydrogels constitutes an effective therapy for chronic wounds in diabetic and non-diabetic conditions.
- Dominic Henn
- , Dehua Zhao
- & Geoffrey C. Gurtner
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Article
| Open AccessProteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification
RNA variants derived from cancer-associated RNA editing events can be a source of neoantigens. Here, based on a proteogenomic pipeline combining DNA and RNA sequencing with MS-based immunopeptidomics, the authors identity and validate potential neoantigen candidates in patients with different tumor entities, highlighting RNA as important neoantigen source.
- Celina Tretter
- , Niklas de Andrade Krätzig
- & Angela M. Krackhardt
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| Open AccessTrimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage
Macrophages are increasingly recognized as key drivers of lung damage in acute pneumonia including COVID-19. Here, the authors report on a first-in-class, inhalable, carbohydrate-coupled microRNA-inhibitor for selective targeting of macrophages and that prevents pulmonary hyperinflammation.
- Christina Beck
- , Deepak Ramanujam
- & Stefan Engelhardt
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| Open AccessA gut feeling for drugs that have metabolic benefits
Resveratrol (REV) is a natural polyphenol with anti-obesity effects. However, the mechanisms remain unclear due to its low bioavailability and the lack of defined membrane-bound or nuclear receptors. Pang and colleagues reported that REV intervention (REV-I) alters gut microbiota and bile acid profile, leading to the inhibition of farnesoid X receptor (FXR) and attenuation of scavenger receptor class B type 1 (SR-B1)-mediated chylomicron secretion. This highlights a therapeutic potential of targeting gut microbiome and intestinal SR-B1 for obesity and diabetes treatment.
- Eryun Zhang
- , Alon Agua
- & Wendong Huang
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Article
| Open AccessAn osteoinductive and biodegradable intramedullary implant accelerates bone healing and mitigates complications of bone transport in male rats
Current limb salvage techniques for the treatment of the osteopathic non-unions still have several drawbacks that may prolong the duration of treatment. Here, Lin et al., propose using an osteoinductive (BMP-2 eluting) intramedullary and biodegradable implant to achieve early bony bridging and show that pin tract infection or docking site non-union can be avoided in experimental animal models of large bone defects.
- Sien Lin
- , Hirotsugu Maekawa
- & Yunzhi Peter Yang
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| Open AccessElastin stabilization prevents impaired biomechanics in human pulmonary arteries and pulmonary hypertension in rats with left heart disease
Pulmonary hypertension due to left heart disease is characterized by pulmonary arterial stiffening that results from extracellular matrix remodeling. Here, the authors show that elastin stabilization improves arterial biomechanics and attenuates pulmonary hypertension.
- Mariya M. Kucherenko
- , Pengchao Sang
- & Christoph Knosalla
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Article
| Open AccessAntiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
Human proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce viral infectivity. Here, the authors show that SERINC3 has architecture resembling non-ATP dependent lipid transporters and induces loss of membrane asymmetry correlated with changes in envelope conformation and loss of infectivity.
- Susan A. Leonhardt
- , Michael D. Purdy
- & Mark Yeager
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Article
| Open AccessA preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles.
- Jeffrey J. Sutherland
- , Dimitar Yonchev
- & Laszlo Urban
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| Open AccessTransplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity
The authors show in a preclinical large animal model that in utero delivery of FVIII-secreting human placental cells is feasible, safe, and yields elevated plasma FVIII activity for at least three years without triggering immunity, affirming prenatal treatment of hemophilia A.
- Martin Rodriguez
- , Brady Trevisan
- & Graça Almeida-Porada
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Article
| Open AccessThe RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer
CDK4/6 inhibition is a promising therapeutic approach to treat cancer, but it is challenged by resistance development. Here, the authors show that the RNA binding protein LRPPRC forms a positive feedback loop with CDK6 and inhibiting LRPPRC with the FDA-approved gossypol acetate overcomes CDK4/6 inhibition resistance.
- Wei Zhou
- , Wenxi Wang
- & Xiaohong Fang
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| Open AccessUltrasound-responsive low-dose doxorubicin liposomes trigger mitochondrial DNA release and activate cGAS-STING-mediated antitumour immunity
Chemotherapy-induced cytosolic DNA has been shown to activate the cGAS-STING pathway. Here, the authors demonstrate that the efficacy of low-dose doxorubicin to elicit a STING-mediated anti-tumour immune response can be enhanced by liposomal-loading with indocyanine green, resulting in ultrasound-activatable enhanced nuclear doxorubicin localisation and release of mitochondrial DNA.
- Chaoyu Wang
- , Ruoshi Zhang
- & Rui Kuai
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| Open AccessPersonalized aerosolised bacteriophage treatment of a chronic lung infection due to multidrug-resistant Pseudomonas aeruginosa
Köhler et al. document the treatment, and clinical improvement, of a male patient with a life-threatening chronic multi-drug resistant Pseudomonas aeruginosa infection with aerosolized personalized phage therapy, in combination with intravenous antibiotic treatment.
- Thilo Köhler
- , Alexandre Luscher
- & Christian van Delden
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| Open AccessA randomized non-inferiority trial of therapeutic strategy with immunosuppressants versus biologics for Vogt-Koyanagi-Harada disease
Different classes of biologic therapeutics have been assessed in the context of Vogt-Koyanagi-Harada disease. Here the authors compared cyclosporine immunosuppression or adalimumab in a randomised clinical trial for the treatment of patients with Vogt-Koyanagi-Harada disease and found non-inferiority upon treatment with cyclosporine.
- Zhenyu Zhong
- , Lingyu Dai
- & Peizeng Yang
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Article
| Open AccessSingle cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets
Fibroadenoma occurrence is linked to increased long-term risk of breast carcinoma, however, the lack of models has made understanding this mechanism unclear. Here, the authors use single cell RNA-seq to identify dysregulation of epithelial cells and develop organoid models to study treatment resistance.
- Zhigang Chen
- , Yi Zhang
- & Jian Huang
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Article
| Open AccessHost-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial
The gut microbiome is causally linked to body weight in preclinical models. Here, in a controlled feeding study, the authors show that greater delivery of gut-microbiome fermentable dietary substrates to the colon leads to a net negative energy balance that is accompanied by robust microbial and host responses.
- Karen D. Corbin
- , Elvis A. Carnero
- & Steven R. Smith
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Article
| Open AccessAn injectable liposome-anchored teriparatide incorporated gallic acid-grafted gelatin hydrogel for osteoarthritis treatment
Osteoarthritis is a common disease that causes pain and difficulty moving joints. Here the authors present an injectable gelatin-based hydrogel that slowly releases teriparatide drug to avoid frequent injections, offering a potential solution for patients with osteoarthritis.
- Guoqing Li
- , Su Liu
- & Hui Zeng
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Article
| Open AccessA blocking monoclonal antibody reveals dimerization of intracellular domains of ALK2 associated with genetic disorders
Mutant forms of the transmembrane receptor activin receptor-like kinase 2 are associated with different genetic diseases. Here, the authors report that disease-associated forms of this receptor cause intracellular domains to dimerize in response to ligand binding of extracellular domains.
- Takenobu Katagiri
- , Sho Tsukamoto
- & Kiyosumi Takaishi
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Article
| Open AccessPrimary somatosensory cortex bidirectionally modulates sensory gain and nociceptive behavior in a layer-specific manner
How the brain controls pain perception remains elusive. Here, authors show that layers 5 and 6 of the somatosensory cortex suppress or enhance nociception through cell-type-specific cortical and corticothalamic interactions.
- Katharina Ziegler
- , Ross Folkard
- & Alexander Groh
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Article
| Open AccessDynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.
- Danielle S. Potter
- , Ruochen Du
- & Anthony Letai
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Article
| Open AccessDNA methylation markers for kidney function and progression of diabetic kidney disease
Epigenetic markers are potential biomarkers for diabetes and related complications. Here, the authors identify CpG sites associated with kidney function and its subsequent decline using both single-site and multisite analyses, which are shown to have functional significance in the kidney.
- Kelly Yichen Li
- , Claudia Ha Ting Tam
- & Ronald C. W. Ma
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Article
| Open AccessImmune cell dynamics deconvoluted by single-cell RNA sequencing in normothermic machine perfusion of the liver
Normothermic machine perfusion (NMP) is a method of keeping transplant organs maintained closer to physiological conditions. Here the authors analyse the immune cell dynamics during NMP in human donor livers using scRNA sequencing as a way of assessing the effects of NMP upon the immune status of the organ.
- T. Hautz
- , S. Salcher
- & S. Schneeberger
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Article
| Open AccessA case study of percutaneous epidural stimulation to enable motor control in two men after spinal cord injury
Percutaneous spinal cord epidural stimulation (SCES) leads were implanted in two men with spinal cord injury (SCI) in an approved trial by the McGuire IRB committee. SCES decreased the assistance required from the exoskeleton. In one participant, SCES enabled standing and stepping in parallel bars and overground ambulation with a walker.
- Ashraf S. Gorgey
- , Robert Trainer
- & Timothy D. Lavis
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Article
| Open AccessThe IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Glypican-1 (GPC1) expression is elevated in pancreatic cancer and has been exploited as a therapeutic target. Here the authors report the development of VHH nanobody-based CAR-T cells targeting GPC1, showing anti-tumor activity in pancreatic cancer preclinical models.
- Nan Li
- , Alex Quan
- & Mitchell Ho
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Article
| Open AccessCorrection of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy
In a double homozygous mouse model of myotonic dystrophy type 1, Hu et al. use antisense oligonucleotide correction of myotonia to induce a therapeutic shift from an overabundance of oxidative muscle fibers to mechanically stronger glycolytic fibers.
- Ningyan Hu
- , Eunjoo Kim
- & Thurman M. Wheeler
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Article
| Open AccessMultiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19
In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.
- Samuel Druzak
- , Elizabeth Iffrig
- & Cheryl L. Maier
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Article
| Open AccessSmad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma
TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models.
- Jeff Yat-Fai Chung
- , Philip Chiu-Tsun Tang
- & Patrick Ming-Kuen Tang
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Article
| Open AccessLacking mechanistic disease definitions and corresponding association data hamper progress in network medicine and beyond
Large-scale disease-association data are widely used for pathomechanism mining, even if disease definitions used for annotation are mostly phenotype-based. Here, the authors show that this bias can lead to a blurred view on disease mechanisms, highlighting the need for close-up studies based on molecular data for well-characterized patient cohorts.
- Sepideh Sadegh
- , James Skelton
- & David B. Blumenthal