UniMorph 4.0:Universal Morphology

The Universal Morphology (UniMorph) project is a collaborative effort providing broad-coverage instantiated normalized morphological inflection tables for hundreds of diverse world languages. The project comprises two major thrusts: a language-independent feature schema for rich morphological annotation and a type-level resource of annotated data in diverse languages realizing that schema. This paper presents the expansions and improvements made on several fronts over the last couple of years (since McCarthy et al. (2020)). Collaborative efforts by numerous linguists have added 67 new languages, including 30 endangered languages. We have implemented several improvements to the extraction pipeline to tackle some issues, e.g. missing gender and macron information. We have also amended the schema to use a hierarchical structure that is needed for morphological phenomena like multiple-argument agreement and case stacking, while adding some missing morphological features to make the schema more inclusive. In light of the last UniMorph release, we also augmented the database with morpheme segmentation for 16 languages. Lastly, this new release makes a push towards inclusion of derivational morphology in UniMorph by enriching the data and annotation schema with instances representing derivational processes from MorphyNet

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination

<div><p>Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG_35–55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (T_H1) and IL-17A-producing (T_H17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of T_H17 cells, they did not affect T_H1 activation, but enhanced T_H1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.</p></div

MSCs differentially affect the proliferation of effector CD4⁺ T cells <i>in vitro</i>.

<p>Naïve CD62L⁺CD4⁺ T cells were cultured in the absence or presence of MSCs at a T cell: MSC ratio of 4:1. CD4+ T cells were activated with plate-bound α-CD3 and soluble α-CD28 ± polarizing cytokines and neutralizing antibodies. After 72 hours, T cells were harvested, re-stimulated with cell stimulation cocktail for 5 hours, stained, and analyzed by flow cytometry. Shown are representative histograms of CFSE dilution, gated on CD4⁺ T cells, of undivided incomplete T_H17 cells (without IL-23/IL-1β) and complete T_H17 cells (with IL-23/IL-1β) <b>(A)</b>, and bar graphs of the undivided incomplete and complete T_H17 populations, activated CD4⁺ T cells, and T_H1 cells <b>(B)</b>, in the absence and presence of MSCs. Compiled bar graph data are from three separate experiments (n = 5/treatment group). Significance was measured by Student’s <i>t</i>-test, with *<i>p</i><0.05 and **<i>p</i><0.01.</p