118 research outputs found
SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes
Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components and the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndromeâthe most common cause of deaf-blindness. Previously, SANS was shown to function only in the cytosol and primary cilia. Here, we have uncovered molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome in the nucleus. We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and human Usher syndrome. Thus, we provide the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome
Cerebrospinal Fluid NLRP3 is Increased After Severe Traumatic Brain Injury in Infants and Children
Background: Inflammasome-mediated neuroinflammation may cause secondary injury following traumatic brain injury (TBI) in children. The pattern recognition receptors NACHT domain-, Leucine-rich repeat-, and PYD-containing Protein 1 (NLRP1) and NLRP3 are essential components of their respective inflammasome complexes. We sought to investigate whether NLRP1 and/or NLRP3 abundance is altered in children with severe TBI.
Methods: Cerebrospinal fluid (CSF) from children (n = 34) with severe TBI (Glasgow coma scale score [GCS] â€8) who had externalized ventricular drains (EVD) placed for routine care was evaluated for NLRP1 and NLRP3 at 0-24, 25-48, 49-72, and >72 h post-TBI and was compared to infection-free controls that underwent lumbar puncture to rule out CNS infection (n = 8). Patient age, sex, initial GCS, mechanism of injury, treatment with therapeutic hypothermia, and 6-month Glasgow outcome score were collected.
Results: CSF NLRP1 was undetectable in controls and detected in 2 TBI patients at only 4 (15.50 [3.65-25.71] vs. 3.04 [1.52-8.87] ng/mL, respectively; p = 0.048). Controlling for initial GCS in multivariate analysis, peak NLRP3 >6.63 ng/mL was independently associated with poor outcome at 6 months.
Conclusions: In the first report of NLRP1 and NLRP3 in childhood neurotrauma, we found that CSF NLRP3 is elevated in children with severe TBI and independently associated with younger age and poor outcome. Future studies correlating NLRP3 with other markers of inflammation and response to therapy are warranted
Report of the Topical Group on Cosmic Frontier 5 Dark Energy and Cosmic Acceleration: Cosmic Dawn and Before for Snowmass 2021
This report summarizes the envisioned research activities as gathered from
the Snowmass 2021 CF5 working group concerning Dark Energy and Cosmic
Acceleration: Cosmic Dawn and Before. The scientific goals are to study
inflation and to search for new physics through precision measurements of relic
radiation from the early universe. The envisioned research activities for this
decade (2025-35) are constructing and operating major facilities and developing
critical enabling capabilities. The major facilities for this decade are the
CMB-S4 project, a new Stage-V spectroscopic survey facility, and existing
gravitational wave observatories. Enabling capabilities include aligning and
investing in theory, computation and model building, and investing in new
technologies needed for early universe studies in the following decade (2035+).Comment: contribution to Snowmass 202
Spectral Distortions of the CMB as a Probe of Inflation, Recombination, Structure Formation and Particle Physics
Following the pioneering observations with COBE in the early 1990s, studies
of the cosmic microwave background (CMB) have focused on temperature and
polarization anisotropies. CMB spectral distortions - tiny departures of the
CMB energy spectrum from that of a perfect blackbody - provide a second,
independent probe of fundamental physics, with a reach deep into the primordial
Universe. The theoretical foundation of spectral distortions has seen major
advances in recent years, which highlight the immense potential of this
emerging field. Spectral distortions probe a fundamental property of the
Universe - its thermal history - thereby providing additional insight into
processes within the cosmological standard model (CSM) as well as new physics
beyond. Spectral distortions are an important tool for understanding inflation
and the nature of dark matter. They shed new light on the physics of
recombination and reionization, both prominent stages in the evolution of our
Universe, and furnish critical information on baryonic feedback processes, in
addition to probing primordial correlation functions at scales inaccessible to
other tracers. In principle the range of signals is vast: many orders of
magnitude of discovery space could be explored by detailed observations of the
CMB energy spectrum. Several CSM signals are predicted and provide clear
experimental targets, some of which are already observable with present-day
technology. Confirmation of these signals would extend the reach of the CSM by
orders of magnitude in physical scale as the Universe evolves from the initial
stages to its present form. The absence of these signals would pose a huge
theoretical challenge, immediately pointing to new physics.Comment: Astro2020 Science White Paper, 5 pages text, 13 pages in total, 3
Figures, minor update to reference
Feebly Interacting Particles: FIPs 2022 workshop report
Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs
Feebly-interacting particles: FIPs 2022 Workshop Report
Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs
Prediction models for diagnosis and prognosis of covid-19: : systematic review and critical appraisal
Readersâ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity. Funding: LW, BVC, LH, and MDV acknowledge specific funding for this work from Internal Funds KU Leuven, KOOR, and the COVID-19 Fund. LW is a postdoctoral fellow of Research Foundation-Flanders (FWO) and receives support from ZonMw (grant 10430012010001). BVC received support from FWO (grant G0B4716N) and Internal Funds KU Leuven (grant C24/15/037). TPAD acknowledges financial support from the Netherlands Organisation for Health Research and Development (grant 91617050). VMTdJ was supported by the European Union Horizon 2020 Research and Innovation Programme under ReCoDID grant agreement 825746. KGMM and JAAD acknowledge financial support from Cochrane Collaboration (SMF 2018). KIES is funded by the National Institute for Health Research (NIHR) School for Primary Care Research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. GSC was supported by the NIHR Biomedical Research Centre, Oxford, and Cancer Research UK (programme grant C49297/A27294). JM was supported by the Cancer Research UK (programme grant C49297/A27294). PD was supported by the NIHR Biomedical Research Centre, Oxford. MOH is supported by the National Heart, Lung, and Blood Institute of the United States National Institutes of Health (grant R00 HL141678). ICCvDH and BCTvB received funding from Euregio Meuse-Rhine (grant Covid Data Platform (coDaP) interref EMR187). The funders played no role in study design, data collection, data analysis, data interpretation, or reporting.Peer reviewedPublisher PD
CMB-S4: Forecasting Constraints on Primordial Gravitational Waves
CMB-S4---the next-generation ground-based cosmic microwave background (CMB)
experiment---is set to significantly advance the sensitivity of CMB
measurements and enhance our understanding of the origin and evolution of the
Universe, from the highest energies at the dawn of time through the growth of
structure to the present day. Among the science cases pursued with CMB-S4, the
quest for detecting primordial gravitational waves is a central driver of the
experimental design. This work details the development of a forecasting
framework that includes a power-spectrum-based semi-analytic projection tool,
targeted explicitly towards optimizing constraints on the tensor-to-scalar
ratio, , in the presence of Galactic foregrounds and gravitational lensing
of the CMB. This framework is unique in its direct use of information from the
achieved performance of current Stage 2--3 CMB experiments to robustly forecast
the science reach of upcoming CMB-polarization endeavors. The methodology
allows for rapid iteration over experimental configurations and offers a
flexible way to optimize the design of future experiments given a desired
scientific goal. To form a closed-loop process, we couple this semi-analytic
tool with map-based validation studies, which allow for the injection of
additional complexity and verification of our forecasts with several
independent analysis methods. We document multiple rounds of forecasts for
CMB-S4 using this process and the resulting establishment of the current
reference design of the primordial gravitational-wave component of the Stage-4
experiment, optimized to achieve our science goals of detecting primordial
gravitational waves for at greater than , or, in the
absence of a detection, of reaching an upper limit of at CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note:
text overlap with arXiv:1907.0447
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