A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

SummaryAlternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide “microexons” display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism

Conserved functional antagonism of CELF 1 and MBNL proteins controls stem cell-specific alternative splicing in planarians

In contrast to transcriptional regulation, the function of alternative splicing (AS) in stem cells is poorly understood. In mammals, MBNL proteins negatively regulate an exon program specific of embryonic stem cells; however, little is known about the in vivo significance of this regulation. We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea. We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators. We show that functional antagonism between CELF and MBNL factors directly controls stem cell-specific AS in planarians, placing the origin of this regulatory mechanism at the base of Bilaterians. Knockdown of CELF or MBNL factors lead to abnormal regenerative capacities by affecting self-renewal and differentiation sets of genes, respectively. These results highlight the importance of AS in animal stem cell regulation across metazoans

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel CaV1.2. We show that CACNA1C’s transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets

Eosinophilic fascitis following Sars-Cov2 Vaccination

Table 1. Eosinophilic-associated diseases following vaccination against COVID-19 reported in the literature.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Eosinophilic fasciitis following Sars-Cov2 Vaccination

Eosinophilic fasciitis (EF) is a rare scleroderma-like syndrome considered an autoimmune disease (1,2). It was first described by Shulman in 1974 (3) characterized by induration of the skin, peripheral eosinophilia, hypergammaglobulinemia and elevated erythrocyte sedimentation rate (ESR). The disorder occurs equally in males and females and the average age of onset has been reported between 40 and 50 years, although it can appear from childhood to older ages (4).The etiology of EF remains unknown. Multiple triggers have been suggested such as muscle trauma, drugs (statins, phentytoin, ramipril, subcutaneous heparin or trichloroethylene), infections (Borrelia burgdorferi, Mycoplasma arginini), hematologic disorders, solid neoplasms, autoimmune diseases or physical factors such as radiotherapy and burns (1).Clinically, EF is characterized by an abrupt onset of pain and swelling on the affected extremities, mainly with a symmetrical presentation. The edema is followed by the thickening of the skin, showing the two characteristic signs of the disease: Peau d’orange appearance and the “groove sign”, a depression along the course of superficial veins, accentuated with the elevation of the limb. Other symptoms are joint contractures, morphea-like lesions, inflammatory polyarthritis, myalgia, weight loss, asthenia and morning stiffness. Less frequently restrictive lung disease manifestations may be associated and pleural and pericardial effusion as well as renal involvement can also be present (1,5).THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Response of pruritic scrotal epidermolytic acanthomas to pimecrolimus 1% cream

Epidermolytic acanthomas (EA) are rare benign tumors of unclear etiology that present as flat, sometimes slightly keratotic, pale or whitish papules that are usually asymptomatic. Not uncommonly, their clinical appearance in the anogenital area might lead to misdiagnosis as other lesions that commonly develop at this site, such as condylomata acuminata. Though mainly asymptomatic, there are also reports of EA presenting with persistent genital pruritus. We describe the first reported case of pruritic scrotal EA successfully treated with topical pimecrolimus