Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β.

Mutations in human CLC-1 chloride channel are associated with the skeletal muscle disorder myotonia congenita. The disease-causing mutant A531V manifests enhanced proteasomal degradation of CLC-1. We recently found that CLC-1 degradation is mediated by cullin 4 ubiquitin ligase complex. It is currently unclear how quality control and protein degradation systems coordinate with each other to process the biosynthesis of CLC-1. Herein we aim to ascertain the molecular nature of the protein quality control system for CLC-1. We identified three CLC-1-interacting proteins that are well-known heat shock protein 90 (Hsp90)-associated co-chaperones: FK506-binding protein 8 (FKBP8), activator of Hsp90 ATPase homolog 1 (Aha1), and Hsp70/Hsp90 organizing protein (HOP). These co-chaperones promote both the protein level and the functional expression of CLC-1 wild-type and A531V mutant. CLC-1 biosynthesis is also facilitated by the molecular chaperones Hsc70 and Hsp90β. The protein stability of CLC-1 is notably increased by FKBP8 and the Hsp90β inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) that substantially suppresses cullin 4 expression. We further confirmed that cullin 4 may interact with Hsp90β and FKBP8. Our data are consistent with the idea that FKBP8 and Hsp90β play an essential role in the late phase of CLC-1 quality control by dynamically coordinating protein folding and degradation

Comparative outcomes of SARS-CoV-2 primary and reinfection in older adult patients

BackgroundThe outcomes of older adult people acquiring SARS-CoV-2 reinfection was unclear. This study aimed to compare the outcomes of older adult patients with COVID-19 reinfection and those with primary infection.MethodsThis retrospective cohort study used electronic medical records from the TriNetX Research Network. Older adult patients (aged ≥65 years) with COVID-19 between January 1, 2022, and December 31, 2022, were included in the study. The patients were subsequently categorized into reinfection or primary infection groups, according to whether they manifested two distinct COVID-19 episodes with an intervening period of more than 90 days. Propensity score matching was performed for covariate adjustment between the reinfection and primary infection groups. The primary outcome was a composite outcome, including emergency department visits, hospitalization, intensive care unit admission, mechanical ventilation use, and mortality, following primary infection and reinfection.ResultsAfter matching, 31,899 patients were identified in both the reinfection and primary infection groups. The risk of primary composite outcomes was 7.15% (n = 2,281) in the reinfection group and 7.53% (n = 2,403) in the primary infection group. No significant difference in the primary outcome was observed between groups (HR, 0.96; 95% CI, 0.91 to 1.02, p = 0.17). In addition, there was no significant differences between the reinfection and primary infection groups in terms of emergency department visit (HR, 1.03; 95% CI, 0.95 to 1.11, p = 0.49), all-cause hospitalization (HR, 0.94; 95% CI, 0.86 to 1.02, p = 0.14), intensive care unit admission (HR, 0.92; 95% CI, 0.67 to 1.28, p = 0.62), mechanical ventilation use (HR,1.35 95% CI, 0.69 to 2.64 p = 0.38), and all-cause mortality (HR, 0.94; 95% CI, 0.74 to 1.20, p = 0.62).ConclusionThere were no significant differences in clinical outcomes between older adult patients with COVID-19 reinfection and those with primary infection

A systematic review and meta-analysis comparing the efficacy and safety of ciprofol (HSK3486) versus propofol for anesthetic induction and non-ICU sedation

Background: Ciprofol (HSK3486) is a novel intravenous anesthetic agent that bears structural similarity to propofol and displays favorable pharmacodynamic characteristics such as rapid onset and offset. The meta-analysis aimed at comparing the efficacy and safety of ciprofol versus propofol in clinical practice.Methods: Medline, EMBASE, Google Scholar, Cochrane Library were searched from inception to April 2023. The primary outcome was success rate of sedation/anesthetic induction and differences in sedation/induction time. The secondary outcomes included risks of hemodynamic instability, respiratory complications, and pain on injection, as well as recovery profiles, satisfaction score, and top-up dose requirement.Results: Twelve RCTs (sedation: n = 6, anesthetic induction, n = 6, all conducted in China) involving 1,793 patients (age: 34–58 years) published from 2021 to 2023 were analyzed. Pooled results revealed no differences in success rate [risk ratio (RR) = 1, 95% confidence interval (CI): 0.99 to 1.01, I2 = 0%, 1,106 patients, p = 1] and time required for successful anesthetic induction/sedation [mean difference (MD) = 7.95 s, 95% CI: −1.09 to 16.99, I2 = 97%, 1,594 patients, p = 0.08]. The risks of top-up dose requirement (RR = 0.94, p = 0.48), cardiopulmonary complications [i.e., bradycardia (RR = 0.94, p = 0.67), tachycardia (RR = 0.83, p = 0.68), hypertension (RR = 1.28, p = 0.2), hypoxemia/pulmonary depression (RR = 0.78, p = 0.24)], and postoperative nausea/vomiting (RR = 0.85, p = 0.72), as well as discharge time (MD = 1.39 min, p = 0.14) and satisfaction score (standardized MD = 0.23, p = 0.16) did not differ significantly between the two groups. However, the ciprofol group had lower risks of hypotension (RR = 0.85, p = 0.02) and pain on injection (RR = 0.17, p < 0.00001) than the propofol group. The time to full alertness was statistically shorter in the propofol group (i.e., 0.66 min), but without clinical significance.Conclusion: Our results demonstrated similar efficacy between ciprofol and propofol for sedation and anesthetic induction, while ciprofol was associated with lower risks of hypotension and pain on injection. Future studies are warranted to evaluate the efficacy and safety of ciprofol in pediatric or the elderly populations.Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/), identifier (CRD42023421278)

Efficacy of the visual cognitive assessment test for mild cognitive impairment/mild dementia diagnosis: a meta-analysis

BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal ageing and dementia. The early identification of MCI is important for timely intervention. The visual cognitive assessment test (VCAT) is a brief language-neutral screening tool for detecting MCI/mild dementia. This meta-analysis evaluated the diagnostic efficacy of the VCAT for MCI/mild dementia.MethodsMedline, Embase, Google Scholar, and Cochrane Library were searched from their inception until August 2023 to identify studies using VCAT to diagnose MCI/mild dementia. The primary outcome was to assess the diagnostic accuracy of the VCAT for detecting MCI/mild dementia through area under the receiver operating characteristic curve (AU-ROC) analysis. The secondary outcome was to explore the correlation between VCAT scores and MCI/mild dementia presence by comparing scores among patients with and without MCI/mild dementia. Pooled sensitivity, specificity, and area under the curve (AUC) were calculated.ResultsFive studies with 1,446 older adults (mean age 64–68.3 years) were included. The percentage of participants with MCI/mild dementia versus controls ranged from 16.5% to 87% across studies. All studies were conducted in Asian populations, mostly Chinese, in Singapore and Malaysia. The pooled sensitivity was 80% [95% confidence interval (CI) 68%–88%] and the specificity was 75% (95% CI 68%–80%). The AU-ROCC was 0.77 (95% CI 0.73–0.81). Patients with MCI/mild dementia had lower VCAT scores than the controls (mean difference −6.85 points, p < 0.00001).ConclusionVCAT demonstrated acceptable diagnostic accuracy in distinguishing MCI/mild dementia in cognitively normal older adults. As a language-neutral and culturally unbiased tool, the VCAT shows promise in detecting MCI/mild dementia. Further studies in non-Asian populations are required.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42023453453

Extracellular Signal-regulated Kinase (ERK) Phosphorylates Histone Deacetylase 6 (HDAC6) at Serine 1035 to Stimulate Cell Migration

Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as α-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells. Yet, no connection between HDAC6 and ERK has been discovered. Here, for the first time, we reveal that ERK binds to and phosphorylates HDAC6 to promote cell migration via deacetylation of α-tubulin. We have identified two novel ERK-mediated phosphorylation sites: threonine 1031 and serine 1035 in HDAC6. Both sites were phosphorylated by ERK1 in vitro, whereas Ser-1035 was phosphorylated in response to the activation of EGFR-Ras-Raf-MEK-ERK signaling pathway in vivo. HDAC6-null mouse embryonic fibroblasts rescued by the nonphosphorylation mimicking mutant displayed significantly reduced cell migration compared with those rescued by the wild type. Consistently, the nonphosphorylation mimicking mutant exerted lower tubulin deacetylase activity in vivo compared with the wild type. These data indicate that ERK/HDAC6-mediated cell motility is through deacetylation of α-tubulin. Overall, our results suggest that HDAC6-mediated cell migration could be governed by EGFR-Ras-Raf-MEK-ERK signaling

Response of a CMS HGCAL silicon-pad electromagnetic calorimeter prototype to 20-300 GeV positrons

The Compact Muon Solenoid Collaboration is designing a new high-granularity endcap calorimeter, HGCAL, to be installed later this decade. As part of this development work, a prototype system was built, with an electromagnetic section consisting of 14 double-sided structures, providing 28 sampling layers. Each sampling layer has an hexagonal module, where a multipad large-area silicon sensor is glued between an electronics circuit board and a metal baseplate. The sensor pads of approximately 1 cm$^2$ are wire-bonded to the circuit board and are readout by custom integrated circuits. The prototype was extensively tested with beams at CERN's Super Proton Synchrotron in 2018. Based on the data collected with beams of positrons, with energies ranging from 20 to 300 GeV, measurements of the energy resolution and linearity, the position and angular resolutions, and the shower shapes are presented and compared to a detailed Geant4 simulation

Performance of the CMS High Granularity Calorimeter prototype to charged pion beams of 20−-300 GeV/c

The upgrade of the CMS experiment for the high luminosity operation of the LHC comprises the replacement of the current endcap calorimeter by a high granularity sampling calorimeter (HGCAL). The electromagnetic section of the HGCAL is based on silicon sensors interspersed between lead and copper (or copper tungsten) absorbers. The hadronic section uses layers of stainless steel as an absorbing medium and silicon sensors as an active medium in the regions of high radiation exposure, and scintillator tiles directly readout by silicon photomultipliers in the remaining regions. As part of the development of the detector and its readout electronic components, a section of a silicon-based HGCAL prototype detector along with a section of the CALICE AHCAL prototype was exposed to muons, electrons and charged pions in beam test experiments at the H2 beamline at the CERN SPS in October 2018. The AHCAL uses the same technology as foreseen for the HGCAL but with much finer longitudinal segmentation. The performance of the calorimeters in terms of energy response and resolution, longitudinal and transverse shower profiles is studied using negatively charged pions, and is compared to GEANT4 predictions. This is the first report summarizing results of hadronic showers measured by the HGCAL prototype using beam test data.Comment: To be submitted to JINS

Search for the decay of a Higgs boson in the ll gamma channel in proton-proton collisions at root s=13 TeV

A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.A search for a Higgs boson decaying into a pair of electrons or muons and a photon is described. Higgs boson decays to a Z boson and a photon (H Z , = e or ), or to two photons, one of which has an internal conversion into a muon pair (H (*) ) were considered. The analysis is performed using a data set recorded by the CMS experiment at the LHC from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No significant excess above the background prediction has been found. Limits are set on the cross section for a standard model Higgs boson decaying to opposite-sign electron or muon pairs and a photon. The observed limits on cross section times the corresponding branching fractions vary between 1.4 and 4.0 (6.1 and 11.4) times the standard model cross section for H (*) (H Z ) in the 120-130 GeV mass range of the system. The H (*) and H Z analyses are combined for m(H) =125GeV, obtaining an observed (expected) 95% confidence level upper limit of 3.9 (2.0) times the standard model cross section.Peer reviewe

Electron and photon reconstruction and identification with the CMS experiment at the CERN LHC

The performance is presented of the reconstruction and identification algorithms for electrons and photons with the CMS experiment at the LHC. The reported results are based on proton-proton collision data collected at a center-of-mass energy of 13 TeV and recorded in 2016-2018, corresponding to an integrated luminosity of 136 fb(-1). Results obtained from lead-lead collision data collected at root S-NN = 5.02 TeV are also presented. Innovative techniques are used to reconstruct the electron and photon signals in the detector and to optimize the energy resolution. Events with electrons and photons in the final state are used to measure the energy resolution and energy scale uncertainty in the recorded events. The measured energy resolution for electrons produced in Z boson decays in proton-proton collision data ranges from 2 to 5%, depending on electron pseudorapidity and energy loss through bremsstrahlung in the detector material. The energy scale in the same range of energies is measured with an uncertainty smaller than 0.1 (0.3)% in the barrel (endcap) region in proton-proton collisions and better than 1(3)% in the barrel (endcap) region in heavy ion collisions. The timing resolution for electrons from Z boson decays with the full 2016-2018 proton-proton collision data set is measured to be 200 ps.Peer reviewe