Extensive non-clonal CAR T-cell expansion causing fatal hyperinflammatory syndrome with immune effector cell-associated hemophagocytic lymphohistiocytosis, cytokine release syndrome, and neurotoxicity syndrome.

Not available.

RAG recombinase expression discriminates the development of natural killer cells.

Introduction: V(D)J recombination, initiated by recombination-activating gene (RAG) endonucleases, is a crucial process for the generation of diversified antigen receptors of T and B lymphocytes but regarded dispensable for innate natural killer (NK) lymphocytes lacking clonotypic receptors.

Methods: To explore the impact of potential rearrangements on NK cell maturation, RAG-fate mapping reporter human induced pluripotent stem cell (iPSC) lines were generated by introduction of RSS-invEGFP constructs into the AAVS1 locus using CRISPR/Cas9 and differentiated into NK cells .

Results: GFP expression was observed in up to 14% of mature NK cells characterized by a CD45 CD56CD57NKG2CKIR phenotype and unproductive genetic rearrangements in the locus.

Long-read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons.

Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of three cell types commonly used to model brain disorders, human fibroblasts, induced pluripotent stem cells and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15 072 transcripts in stem cell-derived cortical neurons, 13 048 in fibroblasts and 12 759 in induced pluripotent stem cells. Our analyses uncovered 35 519 differential transcript expression events and 5135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types.

Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease whose exact disease pathogenesis is not yet fully understood. We performed a genetic in-depth analysis of ataxin-2 (ATXN2), a gene that has already been described as a modulator of neurodegenerative diseases. We focused on the influence of an intermediate CAG repeat, a 9bp duplication (9bp), and isoform expression of ATXN2 on the pathogenesis of SCA3.

Single-cell RNA-sequencing highlights a curtailed NK cell function in convalescent COVID-19 pregnant women.

Introduction: During gestation the immune system undergoes dramatic remodelling to protect the maternal-fetal dyad from infections whilst also preventing fetal rejection. We investigated how SARS-CoV-2 modifies the immune landscape during infection and in recovered pregnant women.

Methods: We immunophenotyped our two independent geographical cohorts using a 14-colour flow cytometry panel (surface and intracellular staining).

Cryogenic mouse tissue homogenization as an alternative to fresh-frozen biopsy use for genomics, transcriptomics, proteomics and metabolomics.

The classical approach of using adjacent pieces of fresh-frozen tissue for various omics analysis from the same sample possesses a risk of biological mismatch between arising from intrinsic tissue heterogeneity. We propose an alternative approach of tissue cryogenic pulverization and lyophilization before distribution for omics studies for a more reliable analysis. Here, we compare individual omics layer readouts from fresh-frozen adjacent tissue pieces and homogenized powder in mouse brain, kidney, and liver.

Unravelling axonal transcriptional landscapes: insights from induced pluripotent stem cell-derived cortical neurons and implications for motor neuron degeneration.

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment-specific analysis. In this study, we employ a robust RNA-sequencing approach, using microfluidic devices, to generate high-quality axonal transcriptomes from induced pluripotent stem cells-derived cortical neurons (CNs).

TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice.

TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin.

Clinical genome sequencing in patients with hereditary breast and ovarian cancer: Concept, implementation and benefits.

Hereditary breast and ovarian cancer (HBOC) is one of the most frequent genetic cancer predisposition syndromes. Individuals at risk are identified mainly by family history and histopathological criteria. The current standard genetic testing is exome or panel sequencing.

sc-MULTI-omics approach in nano-rare diseases: understanding the pathophysiological mechanism of Mulvihill-Smith Syndrome.

Mulvihill-Smith Syndrome (MSS) is a clinically complex and genetically unsolved nano-rare disorder with only 12 patients reported in the literature. Most patients (91%) have immunological impairments, succumb to infection, and might develop cancer later in life. Its pathogenesis remains elusive and therapeutic options are limited.

Genome-wide CRISPR-Cas9 screens identify BCL family members as modulators of response to regorafenib in experimental glioma.

Background: Registered systemic treatment options for glioblastoma patients are limited. The phase II REGOMA trial suggested an improvement of median overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE.

Systematic assessment of COVID-19 host genetics using whole genome sequencing data.

Courses of SARS-CoV-2 infections are highly variable, ranging from asymptomatic to lethal COVID-19. Though research has shown that host genetic factors contribute to this variability, cohort-based joint analyses of variants from the entire allelic spectrum in individuals with confirmed SARS-CoV-2 infections are still lacking. Here, we present the results of whole genome sequencing in 1,220 mainly vaccine-naïve individuals with confirmed SARS-CoV-2 infection, including 827 hospitalized COVID-19 cases.

Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.

Background: Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations.

Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein.

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes.

Compound Heterozygous Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive -Related Myopathy.

Pathogenic variants in the ryanodine receptor 1 () gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype-phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees.

Resequencing the complete SNCA locus in Indian patients with Parkinson's disease.

The genetic loci implicated in familial Parkinson's disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations.

Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration.

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs).

Genomes in clinical care.

In the era of precision medicine, genome sequencing (GS) has become more affordable and the importance of genomics and multi-omics in clinical care is increasingly being recognized. However, how to scale and effectively implement GS on an institutional level remains a challenge for many. Here, we present Genome First and Ge-Med, two clinical implementation studies focused on identifying the key pillars and processes that are required to make routine GS and predictive genomics a reality in the clinical setting.

Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease.

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls.

Augmenting MEK inhibitor efficacy in BRAF wild-type melanoma: synergistic effects of disulfiram combination therapy.

Background: MEK inhibitors (MEKi) were shown to be clinically insufficiently effective in patients suffering from BRAF wild-type (BRAF WT) melanoma, even if the MAPK pathway was constitutively activated due to mutations in NRAS or NF-1. Thus, novel combinations are needed to increase the efficacy and duration of response to MEKi in BRAF WT melanoma. Disulfiram and its metabolite diethyldithiocarbamate are known to have antitumor effects related to cellular stress, and induction of endoplasmic reticulum (ER) stress was found to synergize with MEK inhibitors in NRAS-mutated melanoma cells.