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SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides.
SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides (ASOs) targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.
Eomesodermin in conjunction with the BAF complex promotes expansion and invasion of the trophectoderm lineage.
The T-box transcription factor (TF) Eomesodermin/Tbr2 (Eomes) is essential for maintenance of the trophectoderm (TE) lineage, but the molecular mechanisms underlying this critical role remain obscure. Here, we show in trophoblast stem cells (TSCs) that Eomes partners with several TE-specific TFs as well as chromatin remodellers, including Brg1 and other subunits of the BAF complex. Degron-mediated Eomes protein depletion results in genome-wide loss of chromatin accessibility at TSC-specific loci. These overlap with a subset of sites that lose accessibility following Brg1 inhibition, suggesting that Eomes acts as a "doorstop" controlling TSC chromatin accessibility. Eomes depletion also causes transcriptional misregulation of TSC maintenance and early differentiation markers. An additional subset of Eomes-dependent genes encode intercellular/matricellular interaction and cytoskeletal components, likely explaining the implantation defects of Eomes-null embryos. Thus, Eomes promotes TE lineage maintenance by sustaining trophectoderm-specific chromatin accessibility, while promoting the gene regulatory networks that modulate expansion and cell behaviour during implantation.
Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A
Abstract Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q (‘chr. 21amp’) in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
Neuroserpin alleviates cerebral ischemia-reperfusion injury by suppressing ischemia-induced endoplasmic reticulum stress.
JOURNAL/nrgr/04.03/01300535-202601000-00037/figure1/v/2025-06-09T151831Z/r/image-tiff Neuroserpin, a secreted protein that belongs to the serpin superfamily of serine protease inhibitors, is highly expressed in the central nervous system and plays multiple roles in brain development and pathology. As a natural inhibitor of recombinant tissue plasminogen activator, neuroserpin inhibits the increased activity of tissue plasminogen activator in ischemic conditions and extends the therapeutic windows of tissue plasminogen activator for brain ischemia. However, the neuroprotective mechanism of neuroserpin against ischemic stroke remains unclear. In this study, we used a mouse model of middle cerebral artery occlusion and oxygen-glucose deprivation/reperfusion-injured cortical neurons as in vivo and in vitro ischemia-reperfusion models, respectively. The models were used to investigate the neuroprotective effects of neuroserpin. Our findings revealed that endoplasmic reticulum stress was promptly triggered following ischemia, initially manifesting as the acute activation of endoplasmic reticulum stress transmembrane sensors and the suppression of protein synthesis, which was followed by a later apoptotic response. Notably, ischemic stroke markedly downregulated the expression of neuroserpin in cortical neurons. Exogenous neuroserpin reversed the activation of multiple endoplasmic reticulum stress signaling molecules, the reduction in protein synthesis, and the upregulation of apoptotic transcription factors. This led to a reduction in neuronal death induced by oxygen/glucose deprivation and reperfusion, as well as decreased cerebral infarction and neurological dysfunction in mice with middle cerebral artery occlusion. However, the neuroprotective effects of neuroserpin were markedly inhibited by endoplasmic reticulum stress activators thapsigargin and tunicamycin. Our findings demonstrate that neuroserpin exerts neuroprotective effects on ischemic stroke by suppressing endoplasmic reticulum stress.
Genome-Wide Association Studies of Down Syndrome Associated Congenital Heart Defects Suggests a Genetically Heterogeneous Risk for CHD in DS.
Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40%-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n = 886: atrioventricular septal defects (AVSD), n = 438; atrial septal defects (ASD), n = 122; ventricular septal defects (VSD), n = 170; other types of CHD, n = 156) and DS with a structurally normal heart (DS + NH, n = 572). We performed four genome-wide association study (GWAS) for common variants (MAF > 0.05) comparing DS with CHD, stratified by CHD-subtype, to DS + NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p
Determination of resilience of a panel of broadly neutralizing mAbs to emerging variants of SARS-CoV-2 generated using reverse genetics
SARS-CoV-2 continues to evolve, and its emerging variants might escape the immune responses generated by existing vaccines and therapeutic mAbs. Accordingly, rapid analysis of their possible neutralization phenotype is essential and can be facilitated by reverse genetics (RGs) systems to regenerate viruses with variant-specific substitutions. Here, we efficiently generate a panel of recent variants of SARS-CoV-2 (Omicron XBB.1.16, EG.5.1, BA.2.86, and JN.1) using a substantially optimized circular polymerase extension reaction (CPER) RGs system. Neutralization potency was analyzed for mAbs targeting different regions of spike protein. mAbs P4-J15, C68.61, S2X259, and IY-2A IgG were able to neutralize all recent viruses. However, S309, which was previously used to treat infection and targets the outer face of RBD, showed ∼75-fold reduction in potency versus JN.1. Moreover, C68.59, which targets the SD1 region of the CTD, was unable to neutralize either BA.2.86 or JN1, which share the E554K substitution in SD1. CPER RGs system and microneutralization assays can be adopted as effective tools to evaluate the efficacy of therapeutic mAbs against emerging variants in a time-responsive manner.
Nutraceuticals: using food to enhance brain health by modulating postnatal neurogenesis in animal models and patient populations
Adult hippocampal neurogenesis, while occurring throughout life, decreases with age and in some neurodegenerative diseases. As decreased hippocampal neurogenesis is correlated with cognitive decline, efforts have been made to increase levels of neurogenesis, either through natural compounds, environmental interventions or novel pharmacological compounds. Nutraceuticals are food products with medical benefits such as antioxidation, anti-inflammation or neuroprotection. There has been increasing interest in these “functional foods” and their active compounds in recent years, providing natural alternatives to de novo pharmaceuticals. This review highlights key nutraceuticals that promote neurogenesis and/or improve cognitive outcomes. By outlining the effects of these compounds in the animal models employed and in clinical populations, we also suggest further investigations. We examine common targets and pathways through which these nutraceuticals are believed to exert pro-neurogenic effects. Most nutraceutical preparations contain multiple components, any of which may exert effects on neurogenesis. Identifying key active compounds in nutraceuticals may enable researchers to better understand their effects and standardize doses across studies. The less stringent regulatory requirements for nutraceuticals can be a double-edged sword. While allowing easier access to the beneficial effects, higher doses of these compounds may have detrimental effects. Hence, research in this field should not only aim to identify the benefits of these compounds but also to identify efficacious and safe dosages for them. Our aims are to provide understanding of nutraceuticals, provide evidence for their benefits on neurogenesis and neurogenesis-related behaviors and finally to summarize potential mechanisms and help guide future work.
A Revised Prognostic Model for Patients with Acute Myeloid Leukemia and First Relapse.
Most patients with acute myeloid leukemia (AML) may obtain remission upon induction chemotherapy, but relapse is frequent and associated with poor survival. Previous prognostic models for outcomes after relapse lacked analysis of comprehensive molecular data. A validated prognostic model integrating clinical, cytogenetic, and molecular variables may support treatment decisions. We studied 943 AML patients who relapsed after first-line intensive induction treatment in a development cohort (HOVON-SAKK). A random survival forest algorithm was used to evaluate the association of clinical parameters, cytogenetic abnormalities, and molecular variables at diagnosis with overall survival (OS). Relapsing patients (n=377) who were enrolled in the NCRI-AML18 trial were used for model validation. In the development cohort, the median age at relapse was 58 years, and patients were classified as 2022 ELN favorable (22%), intermediate (31%), and adverse (48%) risk. One-third underwent allogeneic transplantation in first complete remission. Variable selection yielded nine variables significantly associated with 1-year OS, including relapse-free interval, age, white blood cell count, mutated TP53, FLT3-ITD, core-binding factor abnormalities, t(v;11q23)/KMT2A-rearranged and complex/monosomal karyotype, which were assigned points according to their estimated hazard ratios. Three prognostic groups were defined with distinct 1-year OS in both development (favorable: 51±3%, intermediate: 29±3% and poor: 14±2%, respectively) and validation cohorts (51±4%, 26±5% and 14±3%, respectively). Independent validation confirmed the improved accuracy in predicting outcomes for AML patients in first relapse. The revised AML relapse model improved on previous classification systems for prognostication of outcomes after first AML relapse. It provides stratification which might support tailoring second line treatment.
Protocol for high-quality RNA sequencing, cell surface protein analysis, and genotyping in single cells using TARGET-seq.
Studying the consequences of somatic mutations in pre-malignant and cancerous tissues is challenging due to noise in single-cell transcriptome data and difficulty in identifying the clonal identity of single cells. We optimized TARGET-seq to develop TARGET-seq+, which combines RNA sequencing (RNA-seq), the analysis of cell surface protein expression, and genotyping in single cells with improved sensitivity. We describe the steps for cell isolation, the preparation of single-cell RNA-seq (scRNA-seq) and genotyping libraries, and sequencing. We also provide guidance on the analysis of single-cell genotyping, transcriptome pre-processing, and data integration. For complete details on the use and execution of this protocol, please refer to Jakobsen et al.1.
Clonal tracing with somatic epimutations reveals dynamics of blood ageing.
Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
Data from A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies
<div>Abstract<p>The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.</p></div>
Chronic silencing of Drd1a-Cre+ neurons impairs dopaminergic-driven cortical activation.
In the somatosensory cortex of transgenic mice, Cre-recombinase is expressed under the control of the dopamine receptor D1 (Drd1a) promoter in lower layer 6. These neurons selectively project to the higher-order thalamic nuclei and participate in the cortico-thalamo-cortical loops involved in sensory processing and stimulus representation. However, the role of dopaminergic modulation in activating this neuronal population during cortical arousal remains poorly understood. In this study, we examined the effects of D1 (SKF-81297) and D2 (Quinpirole) receptor agonists on cortical network activation. We further investigated the consequences of silencing these neurons using a Snap25 conditional knockout mouse model. We report a decrease in cellular and neuronal density in the subplate/L6b with normal development from P8 to adulthood. Conversely, the density of Drd1a-Cre+ neurons goes up in Snap25 cKO brains when comparing the same ages. Moreover, we observe that silencing of Drd1a-Cre+ neurons has no effect on microglial cells. Our results demonstrate that both D1 and D2 agonists require the Drd1a-Cre+ neurons to modulate cortical activity effectively. Our study provides new insights into the fundamental role of Drd1a-Cre+ neurons in cortical activation and sensory processing.
Progression and life expectancy in primary lateral sclerosis
Objectives To characterise the clinical characteristics and longitudinal outcomes in primary lateral sclerosis (PLS), including median survival from symptom onset and age at death. Methods The authors retrospectively reviewed electronic health records of patients diagnosed with PLS referred to a specialised motor neuron disorders clinic from 2002 to 2024, analysed longitudinal Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) assessments using joint models and used Kaplan-Meier methods and life tables to calculate median survival and age at death compared with population-based values. Results Of 52 patients, 34 (65%) were male, 41 (79%) first noted symptoms in the lower limbs and 10 (19%) in corticobulbar function. Median age of symptom onset was 53 years. The mean annual rate of functional decline was -1.92 ALSFRS-R points (95% CI -3.03 to -0.78), with equal highest rates of decline in fine and gross motor subscores. Five patients (10%) received gastrostomy and three (6%) non-invasive ventilation. Median survival from symptom onset was 23.1 years (22.7 to not reached), and median age at death was 79.5 years (77.8 to not reached) compared with a population-based reference mean of 81.9 years (81.1 to 82.8). Discussion PLS may be commensurate with near-normal life expectancy. Significant disability arises from limb motor dysfunction, with a minority of patients requiring nutritional or respiratory support. This has important implications for counselling and trial design.
A nonlocal-to-local approach to aggregation-diffusion equations
Over the past decades, nonlocal models have been widely used to describe aggregation phenomena in biology, physics, engineering, and the social sciences. These are often derived as mean-field limits of attraction-repulsion agent-based models, and consist of systems of nonlocal partial differential equations. Using differential adhesion between cells as a biological case study, we introduce a novel local model of aggregation-diffusion phenomena. This system of local aggregation-diffusion equations is fourth-order, resembling thin-film or Cahn-Hilliard type equations. In this framework, cell sorting phenomena are explained through relative surface tensions between distinct cell types. The local model emerges as a limiting case of short-range interactions, providing a significant simplification of earlier nonlocal models, while preserving the same phenomenology. This simplification makes the model easier to implement numerically and more amenable to calibration to quantitative data. Additionally, we discuss recent analytical results based on the gradient-flow structure of the model, along with open problems and future research directions.
FoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes.
BACKGROUND: The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localization of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and the type 2 diabetic heart. Posttranslational S-acylation controls protein trafficking, and in this study, we hypothesized that increased CD36 S-acylation may underpin the preferential sarcolemmal localization of CD36, driving metabolic and contractile dysfunction in diabetes. METHODS AND RESULTS: Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localization, FA oxidation rates, and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs, and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 using siRNA or lentiviral shRNA decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO (forkhead box O) 1, as FoxO1 binds to the promotor of zDHHC4 and induces its transcription, as assessed using chromatin immunoprecipitation-seq, chromatin immunoprecipitation-quantitative PCR, luciferase assays, and siRNA silencing. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates, and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the deacylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content, and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts. CONCLUSIONS: Activation of the FoxO1-zDHHC4-CD36 S-acylation axis in diabetes drives metabolic and contractile dysfunction in type 2 diabetic heart.
British Society of Gastroenterology guidelines on colorectal surveillance in inflammatory bowel disease.
Patients with inflammatory bowel disease (IBD) remain at increased risk for colorectal cancer and death from colorectal cancer compared with the general population despite improvements in inflammation control with advanced therapies, colonoscopic surveillance and reductions in environmental risk factors. This guideline update from 2010 for colorectal surveillance of patients over 16 years with colonic inflammatory bowel disease was developed by stakeholders representing UK physicians, endoscopists, surgeons, specialist nurses and patients with GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodological support.An a priori protocol was published describing the approach to three levels of statement: GRADE recommendations, good practice statements or expert opinion statements. A systematic review of 7599 publications, with appraisal and GRADE analysis of trials and network meta-analysis, where appropriate, was performed. Risk thresholding guided GRADE judgements.We made 73 statements for the delivery of an IBD colorectal surveillance service, including outcome standards for service and endoscopist audit, and the importance of shared decision-making with patients.Core areas include: risk of colorectal cancer, IBD-related post-colonoscopy colorectal cancer; service organisation and supporting patient concordance; starting and stopping surveillance, who should or should not receive surveillance; risk stratification, including web-based multivariate risk calculation of surveillance intervals; colonoscopic modalities, bowel preparation, biomarkers and artificial intelligence aided detection; chemoprevention; the role of non-conventional dysplasia, serrated lesions and non-targeted biopsies; management of dysplasia, both endoscopic and surgical, and the structure and role of the multidisciplinary team in IBD dysplasia management; training in IBD colonoscopic surveillance, sustainability (green endoscopy), cost-effectiveness and patient experience. Sixteen research priorities are suggested.
Loop-Mediated Isothermal Amplification (LAMP) for the Diagnosis of Sexually Transmitted Infections: A Review.
Sexually transmitted infections (STIs) remain a significant public health concern. Given the asymptomatic nature of many STIs, diagnostic testing is critical for determining the appropriate treatment, enabling effective tracing and reducing the risk of further transmission. Nucleic acid amplification tests (NAATs) are the most sensitive and the most widely used in well-resourced settings. The majority of available NAATs are based on polymerase chain reaction (PCR), which requires highly trained personnel and costly equipment, making it impractical for resource-limited settings. Loop-mediated isothermal amplification (LAMP) has emerged as a simple, rapid, sensitive and low-cost alternative for pathogen detection, particularly well-suited for point-of-care tests (POCT). In this review, we evaluate LAMP assays reported in the literature for the detection of pathogens linked to the high incidence STIs prioritised by the World Health Organization (WHO) for POCT in 2023. These include Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, T. pallidum subspecies pallidum, as well as other common STIs such as herpes simplex virus, hepatitis B virus and human immunodeficiency virus (HIV). For each LAMP assay, we identified and summarised the key elements such as the type and number of tested clinical specimens, chosen target gene, detection system, reference test and clinical outcomes. We highlight the advantages and limitations of these assays and discuss the gaps that should be addressed to improve their applicability for POCT.