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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Rabbit Anatomy: A Brief Photographic Atlas and Dissection Guide - Part I: Muscular System

https://tigerprints.clemson.edu/rabbit/1000/thumbnail.jp

Rabbit Anatomy: A Brief Photographic Atlas

This anatomical atlas of a rabbit used for Anatomy and Physiology I & II was created under a Round Twelve Transformation Grant. The atlas is divided into two parts: a muscular atlas and a cardiovascular atlas.https://oer.galileo.usg.edu/biology-textbooks/1028/thumbnail.jp

Rabbit Anatomy: A Brief Photographic Atlas and Dissection Guide - Part II: Cardiovascular System

https://tigerprints.clemson.edu/rabbit/1001/thumbnail.jp

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

Search for high-mass exclusive diphoton production with tagged protons in proton-proton collisions at s= \sqrt{s} = 13 TeV

A search is presented for high-mass exclusive diphoton production via photon-photon fusion in proton-proton collisions at $\sqrt{s} =$ 13 TeV in events where both protons survive the interaction. The analysis utilizes data corresponding to an integrated luminosity of 103 fb$^{-1}$ collected in 2016--2018 with the central CMS detector and the CMS and TOTEM precision proton spectrometer (PPS). Events that have two photons with high transverse momenta ($p_{\mathrm{T}}^{\gamma} >$ 100 GeV), back-to-back in azimuth, and with a large diphoton invariant mass ($m_{\gamma\gamma} >$ 350 GeV) are selected. To remove the dominant inclusive diphoton backgrounds, the kinematic properties of the protons detected in PPS are required to match those of the central diphoton system. Only events having opposite-side forward protons detected with a fractional momentum loss between 0.035 and 0.15 (0.18) for the detectors on the negative (positive) side of CMS are considered. One exclusive diphoton candidate is observed for an expected background of 1.1 events. Limits at 95% confidence level are derived for the four-photon anomalous coupling parameters $|\zeta_1|$ 100 GeV), back-to-back in azimuth, and with a large diphoton invariant mass ($m_{\gamma\gamma} \gt$ 350 GeV) are selected. To remove the dominant inclusive diphoton backgrounds, the kinematic properties of the protons detected in PPS are required to match those of the central diphoton system. Only events having opposite-side forward protons detected with a fractional momentum loss between 0.035 and 0.15 (0.18) for the detectors on the negative (positive) side of CMS are considered. One exclusive diphoton candidate is observed for an expected background of 1.1 events. Limits at 95% confidence level are derived for the four-photon anomalous coupling parameters $\lvert\zeta_1\rvert \lt$ 0.073 TeV$^{-4}$ and $\lvert\zeta_2\rvert \lt$ 0.15 TeV$^{-4}$, using an effective field theory. Additionally, upper limits are placed on the production of axion-like particles with coupling strength to photons $f^{-1}$ that varies from 0.03 TeV$^{-1}$ to 1 TeV$^{-1}$ over the mass range from 500 to 2000 GeV

First search for exclusive diphoton production at high mass with tagged protons in proton-proton collisions at s=\sqrt{s} = 13 TeV

A search for exclusive two-photon production via photon exchange in proton-proton collisions, pp $\to$ p$\gamma\gamma$p with intact protons, is presented. The data correspond to an integrated luminosity of 9.4 fb$^{-1}$ collected in 2016 using the CMS and TOTEM detectors at a center-of-mass energy of 13 TeV at the LHC. Events are selected with a diphoton invariant mass above 350 GeV and with both protons intact in the final state, to reduce backgrounds from strong interactions. The events of interest are those where the invariant mass and rapidity calculated from the momentum losses of the forward-moving protons matches the mass and rapidity of the central, two-photon system. No events are found that satisfy this condition. Interpreting this result in an effective dimension-8 extension of the standard model, the first limits are set on the two anomalous four-photon coupling parameters. If the other parameter is constrained to its standard model value, the limits at 95% CL are $\lvert\zeta_1\rvert$ $\lt$ 2.9 $\times$ 10$^{-13}$ GeV$^{-4}$ and $\lvert\zeta_2\rvert$ $\lt$ 6.0 $\times$ 10$^{-13}$ GeV$^{-4}$