Featured
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| Open AccessCharacterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria
mRNA therapeutics delivered via lipid nanoparticles are being developed for the treatment of metabolic diseases caused by protein deficiency. Here, the authors use preclinical data to develop translational PK/PD models, which scaled allometrically to humans to predict starting doses for first-in-human clinical studies for in propionic acidemia, methylmalonic acidemia, and phenylketonuria.
- Rena Baek
- , Kimberly Coughlan
- & Paolo G. V. Martini
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Article
| Open AccessA patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis
Most people affected by Alcohol Use Disorder do not develop cirrhosis. Here, the authors show that induced pluripotent stem cell-derived hepatocytes from patients with Alcohol Cirrhosis, have impaired cell energy production and were more susceptible to oxidative stress, which is partially reversed by treatment with Aramchol.
- Bani Mukhopadhyay
- , Cheryl Marietta
- & David Goldman
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Article
| Open AccessPrimary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma
Cutaneous squamous cell carcinoma is more frequent and more aggressive in the organ transplanted and represent a therapeutic challenge due to the ongoing transplantrelated immune suppression. Here, the authors present a case report of a patient whose T cell responses were successfully strengthened via primary prophylactic therapy with mammalian target of rapamycin inhibition and intra-lesion injection of the oncolytic herpesvirus T-VEC.
- Victor Joo
- , Karim Abdelhamid
- & Michel Obeid
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Article
| Open AccessDynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19
In this study, the authors report the case of a patient who underwent lung transplantation and subsequently developed COVID-19 that resulted in persistent infection. Following antiviral treatment, SARS-CoV-2 (BA.5) showed dynamic genetic diversity with remdesivir resistant mutations leading to enhanced fusogenicity.
- Hidetoshi Igari
- , Seiichiro Sakao
- & Eiji Ido
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Article
| Open AccessAntiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment
Viral infection is a common risk for immune-compromised individuals, particularly pediatric patients receiving hematopoietic stem cell transplants. Here the authors report a phase II trial testing adoptive transfer of third party, virus-specific T cells on the feasibility, safety, clinical responses, as well as homeostasis of antiviral immunity in the recipients.
- Michael D. Keller
- , Patrick J. Hanley
- & Michael A. Pulsipher
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Article
| Open AccessDupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells
Dupilumab-associated head and neck dermatitis has been described in a subset of patients treated with the IL4R-blocker dupilumab. Here the authors characterise the immune cell composition and single-cell transcriptome in comparison with untreated forms of atopic dermatitis in a small cohort showing increases in IL-22-associated genes.
- Christine Bangert
- , Natalia Alkon
- & Patrick M. Brunner
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Article
| Open AccessClinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung
Authors utilise a murine model of infection to provide mechanistic insight into how antimicrobial therapy may be a predisposing risk factor for hospital-acquired pneumonia. They show that antibiotic-induced microbiota perturbations compromise inflammatory monocytes and thereby impair antibacterial defence.
- Patrick J. Dörner
- , Harithaa Anandakumar
- & Bastian Opitz
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessEnzymatic conversion of human blood group A kidneys to universal blood group O
ABO blood group compatibility restrictions limit the availability of organs for patients awaiting transplantation. Here, the authors show the rapid enzymatic removal of blood group A antigens from the vasculature of human kidneys using normothermic and hypothermic machine perfusion technologies to make universal blood group O organs for transplantation.
- Serena MacMillan
- , Sarah A. Hosgood
- & Michael L. Nicholson
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessProinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy
Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.
- Yanan Xue
- , Xiaojie Yan
- & Yuan Ping
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Article
| Open AccessInhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2
Inhibiting SARS-CoV-2 interaction with ACE2 is a promising antiviral strategy. Here, the authors show that exosomes derived from human lung spheroid cells expressing hACE2 accumulate in the lung following prophylactic inhalation to bind and neutralize SARS-CoV-2 and protect mice from SARS-CoV-2-induced disease.
- Zhenzhen Wang
- , Shiqi Hu
- & Ke Cheng
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Article
| Open AccessNeoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial
Neoadjuvant chemo-immunotherapy represents a therapeutic option for resectable head and neck squamous cell carcinoma (HNSCC). Here the authors report the results of a phase II trial of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced HNSCC.
- Di Wu
- , Yong Li
- & Xuekui Liu
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Article
| Open AccessTissue engineered vascular grafts are resistant to the formation of dystrophic calcification
Advancements in congenital heart surgery stress the need for durable biomaterials. Here, the authors compare tissue-engineered vascular grafts (TEVGs) with traditional polytetrafluoroethylene grafts, revealing TEVGs’ superior durability and reduced calcification, promising improved long-term success for surgeries.
- Mackenzie E. Turner
- , Kevin M. Blum
- & Christopher K. Breuer
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Article
| Open AccessEffect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial
Here, the authors present the results of the PROMOTe trial, reporting improved cognition with prebiotic vs placebo in twins over 60 years old, probing that remote trials are feasible in older adults, and suggesting that the gut microbiota may represent a therapeutic target for age-associated morbidity.
- Mary Ni Lochlainn
- , Ruth C. E. Bowyer
- & Claire J. Steves
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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Article
| Open AccessBiomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation
Loss of communication between the brain and the body severely impacts the sensorimotor abilities of disabled individuals. Here, the authors design and test a neuroscience-driven framework for advancing bionic devices that leverages biomimetic stimulation to induce physiologically plausible information flow in animals and enhances patient performance with neuroprostheses.
- Giacomo Valle
- , Natalija Katic Secerovic
- & Stanisa Raspopovic
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Article
| Open AccessMolecular co-assembled strategy tuning protein conformation for cartilage regeneration
The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures. Here the authors develop a “molecular velcro”-inspired amphiphilic supramolecular co-assembly strategy, which improves the mechanical strength and cartilaginous regeneration efficiency through conformation transition.
- Chengkun Zhao
- , Xing Li
- & Yong Sun
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Article
| Open AccessTGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques.
- Jinhee Kim
- , Deepanwita Bose
- & Elena Martinelli
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Article
| Open AccessThe molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2.
Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.
- Stephan Spahn
- , Fabian Kleinhenz
- & Michael Bitzer
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Article
| Open AccessEfficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM
Post-stroke walking impairment is a significant public health concern. Here, the authors perform an interventional, randomized controlled trial evaluating the efficacy and safety of InTandem™, an autonomous neurorehabilitation system utilizing auditory-motor entrainment to improve walking after stroke.
- Louis N. Awad
- , Arun Jayaraman
- & Sabrina R. Taylor
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Article
| Open AccessThe impact of reproductive factors on the metabolic profile of females from menarche to menopause
Here, the authors explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank to explore whether reproductive factors are likely to impact females’ metabolic profile later in life.
- Gemma L. Clayton
- , Maria Carolina Borges
- & Deborah A. Lawlor
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Article
| Open AccessPathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production
Gain-of-function mutations in NLRP3 result in Cryopyrin-Associated Periodic Syndrome in human patients. Here authors show that although these NLRP3 variants are constitutively active, they preserve their responsiveness to external pro-inflammatory stimuli, and they interfere with the immune-metabolic inflammatory pathways in monocytes.
- Cristina Molina-López
- , Laura Hurtado-Navarro
- & Pablo Pelegrin
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Article
| Open AccessMechanically resilient hybrid aerogels containing fibers of dual-scale sizes and knotty networks for tissue regeneration
Aerogels are suitable for soft tissue engineering, but often come with brittleness. Here the authors develop a hybrid aerogel with micro- and nanofiber networks that optimizes tensile moduli and fracture energies and show that these materials are super-elastic, fostering rapid tissue ingrowth and allowing minimally invasive procedures.
- S. M. Shatil Shahriar
- , Alec D. McCarthy
- & Jingwei Xie
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Article
| Open AccessPangenome graphs improve the analysis of structural variants in rare genetic diseases
A pangenomic approach, where genome sequences are related to each other in a graph, facilitates analysis of genomic variation between individuals. Here, the authors explore the benefits of using such an approach to characterize structural variation (e.g., deletions or duplications of more than 50 base pairs) in a rare disease cohort.
- Cristian Groza
- , Carl Schwendinger-Schreck
- & Tomi Pastinen
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Article
| Open AccessHHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant
Lower respiratory tract disease is a common complication after allogeneic hematopoietic cell transplant (HCT), but underlying reasons remain unclear. Here the authors show that HHV-6B detection in the lungs of allogeneic HCT recipients is associated with increased risk for death and distinct host gene expression profiles, implicating HHV-6B as a pulmonary pathogen in these patients.
- Joshua A. Hill
- , Yeon Joo Lee
- & Michael Boeckh
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Article
| Open AccessROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.
- Kristina Maas-Bauer
- , Anna-Verena Stell
- & Robert Zeiser
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Article
| Open AccessSingle-sided magnetic resonance-based sensor for point-of-care evaluation of muscle
Magnetic resonance imaging is a useful clinical tool, but its widespread use is constrained by size, cost, and time. Here, the authors report the development of a magnetic resonance sensor for the clinical detection of muscle tissue, allowing for new point-of-care quantitative diagnostic measurements
- Sydney E. Sherman
- , Alexa S. Zammit
- & Michael J. Cima
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Article
| Open AccessLevels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Complement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.
- M. A. Zouache
- , B. T. Richards
- & G. S. Hageman
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Article
| Open AccessNeutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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| Open AccessFrom lab to life: how wearable devices can improve health equity
Wearable devices can provide personalised medicine at the point of need, potentially increasing access to health services and therefore improving health equity. Here the authors discuss their experiences developing wearable devices for vulnerable patient populations, including neonates and pregnant individuals.
- Jessica R. Walter
- , Shuai Xu
- & John A. Rogers
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Article
| Open AccessThe antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients
Here, by performing tracheal aspirate RNA sequencing of critically ill patients, the authors find that older age associates with a greater number of detectably expressed antimicrobial resistance genes in the lower respiratory tract microbiome.
- Victoria T. Chu
- , Alexandra Tsitsiklis
- & Charles R. Langelier
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Article
| Open AccessBCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination
Bacillus Calmette-Guèrin vaccination prevents tuberculosis but some individuals control infection without immunization. Here the authors employ functional assessment of effector responses against mycobacteria to find that distinct gene expression profiles for pre-existing capacity to control and control induced by BCG vaccination.
- Krista E. van Meijgaarden
- , Wenchao Li
- & Simone A. Joosten
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Article
| Open AccessIntegrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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Article
| Open AccessRevealing hidden patterns in deep neural network feature space continuum via manifold learning
Existing feature visualisation methods are not well-suited for regression tasks. Here, authors introduce a method to learn the manifold topology related to deep neural network output and target labels and provide insightful visualisations of the high-dimensional features while preserving the local geometry.
- Md Tauhidul Islam
- , Zixia Zhou
- & Lei Xing
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Article
| Open AccessDistinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination
The ability of BCG vaccination to prevent pulmonary tuberculosis could be improved by targeting mucosal immunity within the lung. Here the authors compare latent Mtb-infected donors with intradermal or oral BCG vaccine recipients to show distinct systemic and pulmonary immune responses are induced by differing routes of natural infection or vaccination.
- Richard F. Silver
- , Mei Xia
- & Daniel F. Hoft
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Article
| Open AccessA pilot study of alternative substrates in the critically Ill subject using a ketogenic feed
Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.
- Angela McNelly
- , Anne Langan
- & Zudin A. Puthucheary
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessHealth-related quality of life is linked to the gut microbiome in kidney transplant recipients
Here, Swarte et al. use metagenomics to investigate the association between the gut microbiome and Health-Related Quality of Life (HRQoL) in kidney transplant recipients, showing evidence for the association of multiple taxonomic, metabolic and neuroactive pathways (gut brain modules) with lower HRQoL, together suggesting potential modifiable gut microbial factors to improve HRQoL.
- J. Casper Swarte
- , Tim J. Knobbe
- & Rinse K. Weersma
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Article
| Open AccessPlasma proteomic profiles predict individual future health risk
The predictive capability of future health risk using plasma proteomic profiles remains largely unexplored. Using 1461 proteins collected from 50k individuals, authors show proteins can derive much better or equivalent performance than established clinical indicators for more than 40 endpoints.
- Jia You
- , Yu Guo
- & Jin-Tai Yu
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Article
| Open AccessSequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine
Seasonal influenza vaccines typically fail to induce cross-protective antibody responses. Here, Van Reeth et al. sequentially vaccinate pigs with diverse H1N1 viruses and show that this strategy induces antibodies against a panel of H1N1 strains from swine and humans and protects against antigenically mismatched strains.
- Kristien Van Reeth
- , Anna Parys
- & Elien Vandoorn
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Article
| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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Article
| Open AccessAsymmetric CRISPR enabling cascade signal amplification for nucleic acid detection by competitive crRNA
New strategies are being developed to simplify CRISPR-based nucleic acid detection. By investigating the competitive reaction between a full-sized crRNA and split crRNA for CRISPR-Cas12a, the authors develop an asymmetric CRISPR assay for amplification-free, cascade signal amplification detection of nucleic acids.
- Jeong Moon
- & Changchun Liu
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Article
| Open AccessTh17-associated cytokines IL-17 and IL-23 in inflamed skin of Darier disease patients as potential therapeutic targets
The use of IL-17/IL-23 blocking therapy for rare inflammatory skin diseases needs proof of principle data for larger clinical trials. Here the authors show that patients with Darier disease have enhanced Th17 cells and, using IL-17/IL-23 blockers, they show that the immune gene signatures are altered in localised skin biopsies.
- Monika Ettinger
- , Teresa Burner
- & Wolfram Hoetzenecker
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Article
| Open 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