Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function

Advanced Scanning Probe Microscopy for Materials Research

Scanning probe microscopy (SPM) encompasses a set of advanced techniques for mapping the structure and properties of the surfaces of materials from the atomic to micro scales. The most widely used SPM technique is atomic force microscopy (AFM), in which forces exerted between the tip of a needle probe and the sample surface can be measured with extremely high precision. By recording these forces as the tip raster’s across the surface, an image of the sample surface topography is obtained. Beyond the surface topography, several SPM techniques can provide quantitative information about the properties of a material’s surface. These include scanning Kelvin probe force microscopy (KPFM) for surface potential measurements, scanning capacitance microscopy (SCM) for surface capacitance mapping, conductive and tunneling AFM (C-AFM and TUNA) for imaging the electrical conductance of a surface, as well as several techniques for imaging the mechanical properties of a surface. These advanced SPM techniques provide tools for direct structure-property correlations in materials at the nanoscale and are powerful capabilities for materials research, especially when co-located with other surface analytical techniques. Each of these advanced SPM techniques is available for materials research in the Boise State University Surface Science Laboratory

Corrosion Initiation and Propagation on Carburized Martensitic Stainless Steel Surfaces Studied via Advanced Scanning Probe Microscopy

Historically, high carbon steels have been used in mechanical applications because their high surface hardness contributes to excellent wear performance. However, in aggressive environments, current bearing steels exhibit insufficient corrosion resistance. Martensitic stainless steels are attractive for bearing applications due to their high corrosion resistance and ability to be surface hardened via carburizing heat treatments. Here three different carburizing heat treatments were applied to UNS S42670: a high-temperature temper (HTT), a low-temperature temper (LTT), and carbo-nitriding (CN). Magnetic force microscopy showed differences in magnetic domains between the matrix and carbides, while scanning Kelvin probe force microscopy (SKPFM) revealed a 90–200 mV Volta potential difference between the two phases. Corrosion progression was monitored on the nanoscale via SKPFM and in situ atomic force microscopy (AFM), revealing different corrosion modes among heat treatments that predicted bulk corrosion behavior in electrochemical testing. HTT outperforms LTT and CN in wear testing and thus is recommended for non-corrosive aerospace applications, whereas CN is recommended for corrosion-prone applications as it exhibits exceptional corrosion resistance. The results reported here support the use of scanning probe microscopy for predicting bulk corrosion behavior by measuring nanoscale surface differences in properties between carbides and the surrounding matrix

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function