B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.UC is a chronic inflammatory bowel disease (IBD) characterized by relapsing episodes of inflammation of the colonic mucosa 1 . In healthy individuals, intestinal B cell responses are dominated by the homeostatic generation of IgA-producing plasma cells (PCs) that promote under exclusive licence to Springer Nature America, Inc. 2022Reprints and permissions information is available at www.nature.com/reprints.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

While the central common feature of the neurodegenerative diseases (NDs) is the accumulation of misfolded proteins, they share other pathogenic mechanisms. However, we miss an explanation for the onset of the NDs. The mechanisms through which genetic mutations, present from conception are expressed only after several decades of life are unknown. We aim to find clues on the complexity of the disease onset trigger of the different NDs expressed in the number of steps of factors related to a disease. We collected brain autopsies on diseased patients with NDs, and found a dynamic increase of the ND multimorbidity with the advance of age. Together with the observation that the NDs accumulate multiple misfolded proteins, and the same misfolded proteins are involved in more than one ND, motivated us to propose a model for a genealogical tree of the NDs. To collect the dynamic data needed to build the tree, we used a Big-data approach that searched automatically epidemiological datasets for age-stratified incidence of NDs. Based on meta-analysis of over 400 datasets, we developed an algorithm that checks whether a ND follows a multistep model, finds the number of steps necessary for the onset of each ND, finds the number of common steps with other NDs and the number of specific steps of each ND, and builds with these findings a parsimony tree of the genealogy of the NDs. The tree discloses three types of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5 to 6 steps; and the crown NDs with more than 7 steps. The tree provides a comprehensive understanding of the relationship across the different NDs, as well as a mathematical framework for dynamic adjustment of the genealogical tree of the NDs with the appearance of new epidemiological studies and the addition of new NDs to the model, thus setting the basis for the search for the identity and order of these steps. Understanding the complexity, or number of steps, of factors related to disease onset trigger is important prior deciding to study single factors for a multiple steps disease.