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Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mechanism
Introduction: Engagement of the homotypic cell-to-cell adhesion molecule cadherin-11 on rheumatoid arthritis (RA) synovial fibroblasts with a chimeric molecule containing the cadherin-11 extracellular binding domain stimulated cytokine, chemokine, and matrix metalloproteinases (MMP) release, implicating cadherin-11 signaling in RA pathogenesis. The objective of this study was to determine if cadherin-11 extracellular domain fragments are found inside the joint and if a physiologic synovial fibroblast cleavage pathway releases those fragments. Methods: Cadherin-11 cleavage fragments were detected by western blot in cell media or lysates. Cleavage was interrupted using chemical inhibitors or short-interfering RNA (siRNA) gene silencing. The amount of cadherin-11 fragments in synovial fluid was measured by western blot and ELISA. Results: Soluble cadherin-11 extracellular fragments were detected in human synovial fluid at significantly higher levels in RA samples compared to osteoarthritis (OA) samples. A cadherin-11 N-terminal extracellular binding domain fragment was shed from synovial fibroblasts after ionomycin stimulation, followed by presenilin 1 (PSN1)-dependent regulated intramembrane proteolysis of the retained membrane-bound C-terminal fragments. In addition to ionomycin-induced calcium flux, tumor necrosis factor (TNF)-α also stimulated cleavage in both two- and three-dimensional fibroblast cultures. Although cadherin-11 extracellular domains were shed by a disintegrin and metalloproteinase (ADAM) 10 in several cell types, a novel ADAM- and metalloproteinase-independent activity mediated shedding in primary human fibroblasts. Conclusions: Cadherin-11 undergoes ectodomain shedding followed by regulated intramembrane proteolysis in synovial fibroblasts, triggered by a novel sheddase that generates extracelluar cadherin-11 fragments. Cadherin-11 fragments were enriched in RA synovial fluid, suggesting they may be a marker of synovial burden and may function to modify cadherin-11 interactions between synovial fibroblasts. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0647-9) contains supplementary material, which is available to authorized users
Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance
© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.This work was supported by NIH R01AI143723 (R.M. and D.F.W.), NIH R01AI152533 (M.R.L. and E.A.W.), 5F31AI129412 (L.F.), and the Bill & Melinda Gates Foundation (OPP1054480, E.A.W. and D.F.W.), LEAN program of the Leducq Foundation (U.O.), Arthritis Research UK 20522 (U.O.), Cancer Research UK A23900 (U.O.). N.C.P. was supported by a National Science Foundation Graduate Research Fellowship (DGE1745303). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). This publication includes data generated at the University of California, San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).info:eu-repo/semantics/publishedVersio
Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
<p>Abstract</p> <p>Background</p> <p>The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type.</p> <p>Results</p> <p>We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR).</p> <p>Conclusions</p> <p>Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.</p
Sex differences in post-acute neurological sequelae of SARS-CoV-2 and symptom resolution in adults after COVID-19 hospitalization: An international multicenter prospective observational study
Although it is known that COVID-19 can present with a range of neurological manifestations and in-hospital complications, sparse data exist if these initial neurological symptoms of COVID-19 are closely associated with post-acute neurological sequelae of SARS-CoV-2 (PANSC) and if female versus male sex impacts the symptom resolution. In this international, multicentre, prospective observational study across 407 sites from 15 countries (January/30th/2020-April/30th/2022), we report the prevalence and risk factors of PANSC among hospitalized adults and investigate the differences between males and females on neurological symptom resolution over time.
PANSC included altered consciousness/confusion, fatigue/malaise, anosmia, dysgeusia, and muscle aches/joint pain, which were collected at the index hospitalization and during the follow-up assessments. The analysis considered time to resolution of individual and all neurological symptoms. Resulting times were modeled by Weibull regression, assuming mixed-case interval censoring, with sex and age included as covariates. Model results were summarized as cumulative probability functions and age- and sex-adjusted median times to resolution.
We included 6,862 hospitalized adults with COVID-19, who had follow-up assessments. The median age of participants was 57 years (39.2% females). Males and females had similar baseline characteristics except that more males (vs. females) were admitted to Intensive Care Unit (30.5% vs. 20.3%) and received mechanical ventilation (17.2% vs. 11.8%).
Approximately 70% of patients had multiple neurological symptoms at the first follow-up (median=102 days). Fatigue (49.9%) and myalgia/arthralgia (45.2%) were the most prevalent symptoms of PANSC at the initial follow-up. Reported prevalence in females was generally higher (vs. males) for all symptoms. At 12 months, anosmia and dysgeusia were resolved in most patients, though fatigue, altered consciousness, and myalgia remained unresolved in >10% of the cohort. Females had a longer time to resolution (5.2 vs. 3.4 months) of neurological symptoms at follow-up for those with more than one neurological symptom.
In multivariable analysis, males were associated with a shorter time to resolution of symptoms (Hazard Ratio=1.53; 95% Confidence Interval =1.39–1.69). Intensive Care Unit admission was associated with a longer time to the resolution of symptoms (Hazard Ratio =0.68; 95% Confidence Interval=0.60–0.77). Post-discharge stroke was uncommon (0.3% in females; 0.5% in males).
Despite the methodological challenges of survey data, this international multicentre prospective cohort study demonstrates that PANSC following index hospitalization is high. Symptom prevalence was higher and took longer to resolve in females than in males. This supports that whilst males were sicker during acute illness, females were disproportionately affected by PANSC
Reduced Proliferation in the Adult Mouse Subventricular Zone Increases Survival of Olfactory Bulb Interneurons
Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/γ-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons
The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance
The James Webb Space Telescope (JWST) is a large, infrared space telescope
that has recently started its science program which will enable breakthroughs
in astrophysics and planetary science. Notably, JWST will provide the very
first observations of the earliest luminous objects in the Universe and start a
new era of exoplanet atmospheric characterization. This transformative science
is enabled by a 6.6 m telescope that is passively cooled with a 5-layer
sunshield. The primary mirror is comprised of 18 controllable, low areal
density hexagonal segments, that were aligned and phased relative to each other
in orbit using innovative image-based wavefront sensing and control algorithms.
This revolutionary telescope took more than two decades to develop with a
widely distributed team across engineering disciplines. We present an overview
of the telescope requirements, architecture, development, superb on-orbit
performance, and lessons learned. JWST successfully demonstrates a segmented
aperture space telescope and establishes a path to building even larger space
telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25
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Priorities for global research into children’s palliative care: results of an International Delphi Study
The Science Performance of JWST as Characterized in Commissioning
This paper characterizes the actual science performance of the James Webb
Space Telescope (JWST), as determined from the six month commissioning period.
We summarize the performance of the spacecraft, telescope, science instruments,
and ground system, with an emphasis on differences from pre-launch
expectations. Commissioning has made clear that JWST is fully capable of
achieving the discoveries for which it was built. Moreover, almost across the
board, the science performance of JWST is better than expected; in most cases,
JWST will go deeper faster than expected. The telescope and instrument suite
have demonstrated the sensitivity, stability, image quality, and spectral range
that are necessary to transform our understanding of the cosmos through
observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures;
https://iopscience.iop.org/article/10.1088/1538-3873/acb29
The James Webb Space Telescope Mission
Twenty-six years ago a small committee report, building on earlier studies,
expounded a compelling and poetic vision for the future of astronomy, calling
for an infrared-optimized space telescope with an aperture of at least .
With the support of their governments in the US, Europe, and Canada, 20,000
people realized that vision as the James Webb Space Telescope. A
generation of astronomers will celebrate their accomplishments for the life of
the mission, potentially as long as 20 years, and beyond. This report and the
scientific discoveries that follow are extended thank-you notes to the 20,000
team members. The telescope is working perfectly, with much better image
quality than expected. In this and accompanying papers, we give a brief
history, describe the observatory, outline its objectives and current observing
program, and discuss the inventions and people who made it possible. We cite
detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space
Telescope Overview, 29 pages, 4 figure
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