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Anti-NMDA-receptor GluN1 antibody serostatus is robust in acute severe stroke
Get PDFBACKGROUND: Anti-N-methyl-D-aspartate IgM and IgA antibodies (NMDAR1-abs) are associated with unfavorable stroke outcomes and may be risk factors thereof. However, to utilize NMDAR1-abs serostatus for risk assessment in acute stroke, it is crucial to understand the robustness of serostatus during this phase. Therefore, we investigated the robustness of NMDAR1-abs serostatus and titer levels up to seven days after stroke. MTEHODS: In this exploratory analysis of the multicenter STRAWINSKI trial (identifier: NCT01264549), patients with severe ischemic stroke (NIHSS ≥ 9) in the middle cerebral artery territory were included. The first blood sample was taken within 36 h and then daily from day two to seven after stroke. NMDAR1-abs immunoglobulin (Ig)A and IgM were assessed in serum using cell-based assays. We initially measured NMDAR1-abs in the total cohort on day 1. Subsequently, in samples from seropositive and matched seronegative patients, we measured NMDAR1-abs on each following day. Titer dilutions started from 1:10 up to 1:1000. Seropositivity was defined as any titer > 0. RESULTS: Out of 171 patients (mean age = 76 [SD = 11], median NIHSS = 15 [IQR = 12–18]), 16 (9%) individuals were seropositive. Seropositive patients remained seropositive and matched seronegative participants remained seronegative over sequential measurements. Although titer levels remained largely unchanged, some patients showed fluctuating titers. CONCLUSIONS: The status of NMDAR1-abs seropositivity is stable during acute stroke, with little to no variation in titer levels
Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Get PDFHypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management
Guiding clinical management of patients with CNS lymphomas by minimal-invasive detection of ctDNA in cerebrospinal fluid
Get PDFCAMK2D causes heart failure in RBM20 cardiomyopathy
No full textAlthough heart disease can arise from different etiologies, current treatment is not tailored to the different underlying causes but is rather a one-size-fits-all approach. Importantly, not all patients benefit from this treatment regimen, which means the number needed to treat is very high. Moreover, this makes clinical trials large and costly, limiting clinical translation. Thus, there is a high medical need to develop a first etiology-specific therapy. Mutations in RBM20, a splicing factor that targets multiple pivotal cardiac genes including TTN and CAMK2D, cause a clinically aggressive form of dilated cardiomyopathy (DCM) with a high risk of malignant ventricular arrhythmias. Here, we hypothesized that CAMK2D is the heart disease-causing target of RBM20. We crossed Camk2d - to Rbm20 -deficient mice and found that double knockout (DKO) mice were protected from heart failure and sudden cardiac death. Phosphorylation of multiple CAMK2D targets was increased in Rbm20 -deficient mouse hearts, which was reverted in DKO hearts, confirming that CAMK2D is not only misspliced but also overactivated. AAV9-mediated re-expression of single CAMK2D splice variants in DKO mice reintroduced cardiac dysfunction irrespective of the splice variant, unmasking that overactivation rather than missplicing underlies the detrimental phenotype. To test whether heart failure could pharmacologically be reversed, we treated heterozygous Rbm20 -R636Q knock-in (KI) mice with hesperadin, a potent CAMK2 inhibitor, which rescued both cardiac function and ventricular geometry. These data demonstrate that overactivation of CAMK2D underlies heart failure in RBM20 cardiomyopathy. Pharmacological inhibition of CAMK2D could therefore become the first cause-directed DCM therapy
Bidirectional editing unveils gene interactions in human brain evolution
No full textComparative genomic studies between contemporary humans and extinct hominins have revealed key evolutionary modifications, but their roles in scaffolding our species’ distinctive traits remain poorly understood. The sheer number of sapiens-specific genetic variants uncovered so far makes it challenging to investigate the mechanisms underlying these recent evolutionary changes at scale. To address this, we developed a scalable gene-editing framework implemented in cortical brain organoids. We prioritized 15 candidate genes among the few carrying nearly fixed protein-coding mutations that distinguish us from other hominins, and developed a CRISPR-Cas9 dual-screen strategy to systematically interrogate the genes’ roles and, above all, their interactions. Combining overexpression and downregulation effects within the same cell, for all possible gene pairs, we mapped the genes’ impacts on single-cell transcriptomic profiles and differentiation potential in cortical brain organoids. We reconstructed the regulatory architecture among genes predicted to have a significant impact on corticogenesis. Pooling all perturbation pairs, we observe marked cell type-specific effects, alternative cell fates favoring neurons or glia, as well as the timing of emergence of interneuron populations. A core subnetwork made up of KIF15, NOVA1, RB1CC1 and SPAG5 was found to be a central regulator across cortex cell types
Phantom validation data for the paper: Simultaneous T2, T2*, and R2′ mapping for multiple sclerosis using model-based reconstruction of undersampled radial RARE-EPI MRI
No full textThis dataset supports a manuscript currently under review. Information will be updated upon acceptanc
Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming [ES_ChIP_seq_H3K9ac_H3K27ac_LA]
No full textSpatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here, we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naïve mouse pluripotent stem cells leads to upregulation of the cysteine generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naïve to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature aging, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Importantly, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity, and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases
Anthropogenic land use exerts selection pressures on the resistome of a wild rodent
Get PDFAntimicrobial resistance poses a significant global health challenge. However, the factors maintaining antimicrobial resistance genes (ARGs) in wildlife microbiomes remain unclear particularly in species inhabiting human-dominated landscapes. We analysed 875 gut metagenomes from wild house mice (Mus musculus) on German farms between 2016 and 2022 to identify environmental and host determinants of ARG occurrence. Using joint species distribution models, we quantified the influence of landscape, climate and mouse associated characteristics on the occurrence of individual ARGs and on trait dependence among genes. Environmental variables and livestock farming intensity explained more than 21% of ARG variation, whereas host characteristics accounted for less than 10%. Analysis of ARG traits revealed that agricultural land use and exposure to livestock increased the occurrence of mobile ARGs. Pig density was strongly associated with integron-encoded sulfonamide resistance genes and genes conferring tetracycline and beta-lactam resistance. Consistent with these findings, mouse resistomes closely resembled those of livestock manure. Taken together, our results show that landscape conditions, particularly farming intensity, shape the distribution of specific ARGs and mobile ARGs in house mice microbiomes. Understanding the factors impacting ARGs prevalence in wildlife is crucial for determining transmission of antimicrobial resistant microorganisms from animal and environmental reservoirs
Polygenic risk for psychiatric disorders and its association with neuropsychiatric symptoms in dementia
Get PDFNeuropsychiatric symptoms are common in Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), yet their genetic underpinnings remain unclear. To gain insight into biological processes related to neuropsychiatric symptoms in dementia, we investigated whether polygenic risk scores (PRS) for psychiatric disorders – major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) – are associated with neuropsychiatric symptoms in dementia. Data included genetic and neuropsychiatric data of 6240 AD patients, 428 FTD patients and 390 DLB patients from five European cohorts (ADC, GR@ACE, DELCODE, AgeCoDe, and DCN). PRS for MDD, BD, SCZ, and ASD were calculated using LDpred2. Neuropsychiatric symptoms were assessed using total scores from the Neuropsychiatric Inventory (NPI) (NPI-12 and NPI-Q) and Geriatric Depression scale (GDS). Associations between PRS and symptoms were examined using linear regression models, followed by meta-analyses. In FTD, higher SCZ-PRS associated with lower NPI scores in the meta-analysis (β = −0.12, p = .001). No associations were found in AD and DLB. This is the first study to show that genetic liability for SCZ associates with lower NPI in FTD, warranting further investigation
