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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Inflammation is gradually compartmentalized and restricted to specific tissue niches such as the lesion rim. However, the precise cell type composition of such niches, their interactions and changes between chronic active and inactive stages are incompletely understood. We used single-nucleus and spatial transcriptomics from subcortical MS and corresponding control tissues to map cell types and associated pathways to lesion and nonlesion areas. We identified niches such as perivascular spaces, the inflamed lesion rim or the lesion core that are associated with the glial scar and a cilia-forming astrocyte subtype. Focusing on the inflamed rim of chronic active lesions, we uncovered cell-cell communication events between myeloid, endothelial and glial cell types. Our results provide insight into the cellular composition, multicellular programs and intercellular communication in tissue niches along the conversion from a homeostatic to a dysfunctional state underlying lesion progression in MS., (© 2024. The Author(s).)

The human hippocampus and prefrontal cortex play critical roles in learning and cognition 1,2 , yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3) 3 . The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci., Competing Interests: Competing interests J.R.E. serves on the scientific advisory board of Zymo Research. A.D.S. is an employee of Arima Genomics., (© 2024. The Author(s).)

The UCSC Genome Browser (https://genome.ucsc.edu) is a widely utilized web-based tool for visualization and analysis of genomic data, encompassing over 4000 assemblies from diverse organisms. Since its release in 2001, it has become an essential resource for genomics and bioinformatics research. Annotation data available on Genome Browser includes both internally created and maintained tracks as well as custom tracks and track hubs provided by the research community. This last year's updates include over 25 new annotation tracks such as the gnomAD 4.1 track on the human GRCh38/hg38 assembly, the addition of three new public hubs, and significant expansions to the Genome Archive[GenArk) system for interacting with the enormous variety of assemblies. We have also made improvements to our interface, including updates to the browser graphic page, such as a new popup dialog feature that now displays item details without requiring navigation away from the main Genome Browser page. GenePred tracks have been upgraded with right-click options for zooming and precise navigation, along with enhanced mouseOver functions. Additional improvements include a new grouping feature for track hubs and hub description info links. A new tutorial focusing on Clinical Genetics has also been added to the UCSC Genome Browser., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Our ability to generate sequencing data and assemble it into high quality complete genomes has rapidly advanced in recent years. These data promise to advance our understanding of organismal biology and answer longstanding evolutionary questions. Multiple genome alignment is a key tool in this quest. It is also the area which is lagging: today we can generate genomes faster than we can construct and update multiple alignments containing them. The bottleneck is in considerable computational time required to generate accurate pairwise alignments between divergent genomes, an unavoidable precursor to multiple alignments. This step is typically performed with lastZ, a very sensitive and yet equally slow tool. Here we describe an optimized GPU-enabled pairwise aligner KegAlign. It incorporates a new parallelization strategy, diagonal partitioning, with the latest features of modern GPUs. With KegAlign a typical human/mouse alignment can be computed in under 6 hours on a machine containing a single NVidia A100 GPU and 80 CPU cores without the need for any pre-partitioning of input sequences: a ~150× improvement over lastZ. While other pairwise aligners can complete this task in a fraction of that time, none achieves the sensitivity of KegAlign's main alignment engine, lastZ, and thus may not be suitable for comparing divergent genomes. In addition to providing the source code and a Conda package for KegAlign we also provide a Galaxy workflow that can be readily used by anyone.

Background:  Patients with lissencephaly typically present with severe psychomotor retardation and drug-resistant seizures. The aim of this study was to characterize the epileptic phenotype in a genotypically and radiologically well-defined patient cohort and to evaluate the response to antiseizure medication (ASM). Therefore, we retrospectively evaluated 47 patients of five genetic forms ( LIS1/PAFAH1B1 , DCX , DYNC1H1 , TUBA1A , TUBG1 ) using family questionnaires, standardized neuropediatric assessments, and patients' medical reports., Results:  All but two patients were diagnosed with epilepsy. Median age at seizure onset was 6 months (range: 2.1-42.0), starting with epileptic spasms in 70%. Standard treatment protocols with hormonal therapy (ACTH or corticosteroids) and/or vigabatrin were the most effective approach for epileptic spasms, leading to seizure control in 47%. Seizures later in the disease course were most effectively treated with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, resulting in seizure freedom in 20%. Regarding psychomotor development, lissencephaly patients presenting without epileptic spasms were significantly more likely to reach various developmental milestones compared to patients with spasms., Conclusion:  Classic lissencephaly is highly associated with drug-resistant epilepsy starting with epileptic spasms in most patients. The standard treatment protocols for infantile epileptic spasms syndrome lead to freedom from seizures in around half of the patients. Due to the association of epileptic spasms with an unfavorable course of psychomotor development, early and reliable diagnosis and treatment of spasms should be pursued. For epilepsies occurring later in childhood, ASM with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, appears to be most effective., Competing Interests: None declared., (Thieme. All rights reserved.)

Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways., (© 2024. The Author(s).)