Junctophilin-2 Protects Cardiomyocytes against Palmitate-induced Injury

Cardiac lipotoxicity may induce cardiomyocyte apoptosis, eventually leading to myocardial dysfunction and heart failure. This study investigated whether and how junctophilin-2 (JPH2) plays a role in palmitate-induced apoptosis in cardiomyocytes. Here, we found palmitate incubation reduced JPH2 protein levels, increased cytosolic Ca2+ and induced apoptosis in cardiomyocytes. JPH2 over-expression prevented the increased cytosolic Ca2+ and apoptosis in palmitate-stimulated cardiomyocytes. JPH2 over-expression also attenuated palmitate-induced CCAAT-enhancer-binding protein homologous protein (CHOP) expression and CHOP deletion alleviated palmitate-induced apoptosis. Furthermore, blocking Ca2+ release from ryanodine receptor-2 (RyR2) prevented palmitate-stimulated CHOP induction and apoptosis. Additionally, JPH2 silencing elevated cytosolic Ca2+, induced CHOP expression and apoptosis in cardiomyocytes; these effects of JPH2 silencing were inhibited by blocking Ca2+ release from RyR2. In summary, we demonstrate that JPH2 attenuates palmitate-induced apoptosis by reducing Ca2+ release from RyR2 and preventing CHOP expression in cardiomyocytes. Thus, targeting JPH2 may represent a new therapeutic strategy to treat cardiac lipotoxicity

Iterative Methods at Lower Precision

Since numbers in the computer are represented with a fixed number of bits, loss of accuracy during calculation is unavoidable. At high precision where more bits (e.g. 64) are allocated to each number, round-off errors are typically small. On the other hand, calculating at lower precision, such as half (16 bits), has the advantage of being much faster. This research focuses on experimenting with arithmetic at different precision levels for large-scale inverse problems, which are represented by linear systems with ill-conditioned matrices. We modified the Conjugate Gradient Method for Least Squares (CGLS) and the Chebyshev Semi-Iterative Method (CS) with Tikhonov regularization to do arithmetic at lower precision using the MATLAB chop function, and we ran experiments on applications from image processing and compared their performance at different precision levels. We concluded that CGLS is a more stable algorithm, but overflows easily due to the computation of inner products, while CS is less likely to overflow but it has more erratic convergence behavior. When the noise level is high, CS outperforms CGLS by being able to run more iterations before overflow occurs; when the noise level is close to zero, CS appears to be more susceptible to accumulation of round-off errors

Mga Modulates Bmpr1a Activity by Antagonizing Bs69 in Zebrafish

MAX giant associated protein (MGA) is a dual transcriptional factor containing both T-box and bHLHzip DNA binding domains. In vitro studies have shown that MGA functions as a transcriptional repressor or activator to regulate transcription of promotors containing either E-box or T-box binding sites. BS69 (ZMYND11), a multidomain-containing (i.e., PHD, BROMO, PWWP, and MYND) protein, has been shown to selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3), modulates RNA Polymerase II elongation, and functions as RNA splicing regulator. Mutations in MGA or BS69 have been linked to multiple cancers or neural developmental disorders. Here, by TALEN and CRISPR/Cas9-mediated loss of gene function assays, we show that zebrafish Mga and Bs69 are required to maintain proper Bmp signaling during early embryogenesis. We found that Mga protein localized in the cytoplasm modulates Bmpr1a activity by physical association with Zmynd11/Bs69. The Mynd domain of Bs69 specifically binds the kinase domain of Bmpr1a and interferes with its phosphorylation and activation of Smad1/5/8. Mga acts to antagonize Bs69 and facilitate the Bmp signaling pathway by disrupting the Bs69-Bmpr1a association. Functionally, Bmp signaling under control of Mga and Bs69 is required for properly specifying the ventral tailfin cell fate.</p

The impact of ESG performance on firms’ technological innovation: evidence from China

Technological innovation is crucial for creating sustainable corporate value and shaping competitive advantage in the market. ESG, as an indicator of corporate value practices, plays a significant role in enterprise technological innovation. However, there is little empirical evidence to support this claim. This study analyzes the relationship between ESG performance and technological innovation in Chinese A-share listed enterprises from 2011 to 2021. The statistical data shows that strong ESG performance has a significant positive impact on corporate technological innovation. ESG performance can promote corporate technological innovation through external mechanisms, such as enhancing corporate network location and increasing institutional shareholding. Additionally, internal mechanisms, such as reducing labor costs and easing financing constraints, can also promote corporate technological innovation. The impact of ESG performance on corporations exhibits heterogeneity, with ESG performance promoting innovation more strongly among labor-intensive firms, non-state-owned firms, highly competitive industries, and mature firms. Based on the study results, it is recommended that enterprises actively practice ESG development concepts, optimize their equity structure, strengthen information communication with stakeholders, and alleviate problems such as information asymmetry to improve their technological innovation. The government should focus on enterprise characteristics, improve ESG development policies, and promote enterprise innovation through ESG performance

Numerical calculation of strong-field laser-atom interaction: An approach with perfect reflection-free radiation boundary conditions

The time-dependent, single-particle Schrodinger equation with a finite-range potential is solved numerically on a three-dimensional spherical domain. In order to correctly account for outgoing waves, perfect reflection-free radiation boundary conditions are used on the surface of a sphere. These are computationally most effective if the particle wavefunction is expanded in the set of spherical harmonics and computations are performed in the Kramers-Henneberger accelerated frame. The method allows one to solve the full ionization dynamics in intense laser fields within a small region of atomic dimensions

The Cassiopeia Filament: A Blown Spur of the Local Arm

We present wide-field and high-sensitivity CO(1-0) molecular line observations toward the Cassiopeia region, using the 13.7m millimeter telescope of the Purple Mountain Observatory (PMO). The CO observations reveal a large-scale highly filamentary molecular cloud within the Galactic region of 132\fdg0\,$\geq$\,$l$\,$\geq$\,122\fdg0 and -1\fdg0\,$\leq$\,$b$\,$\leq$\,3\fdg0 and the velocity range from approximately +1 to +4 km/s. The measured length of the large-scale filament, referred to as the Cassiopeia Filament, is about 390 pc. The observed properties of the Cassiopeia Filament, such as length, column density, and velocity gradient, are consistent with those synthetic large-scale filaments in the inter-arm regions. Based on its observed properties and location on the Galactic plane, we suggest that the Cassiopeia Filament is a spur of the Local arm, which is formed due to the galactic shear. The western end of the Cassiopeia Filament shows a giant arc-like molecular gas shell, which is extending in the velocity range from roughly -1 to +7 km/s. Finger-like structures, with systematic velocity gradients, are detected in the shell. The CO kinematics suggest that the large shell is expanding at a velocity of ~6.5 km/s. Both the shell and finger-like structures outline a giant bubble with a radius of ~16 pc, which is likely produced by stellar wind from the progenitor star of a supernova remnant. The observed spectral linewidths suggest that the whole Cassiopeia Filament was quiescent initially until its west part was blown by stellar wind and became supersonically turbulent.Comment: 46 pages, 19 figures, to be published by the A

Prognostic and therapeutic significance of microbial cell-free DNA in plasma of people with acutely decompensated cirrhosis

BACKGROUND AND AIMS: Although the effect of bacterial infection on cirrhosis has been well-described, the effect of non-hepatotropic virus (NHV) infection is unknown. This study evaluated the genome fragments of circulating microorganisms using metagenomic next-generation sequencing (mNGS) in cirrhosis patients with acute decompensation (AD), focusing on NHVs and related the findings to clinical outcomes. METHODS: Plasma mNGS was performed in 129 cirrhosis patients with AD in study cohort. Ten healthy volunteers and 20, 39, and 81 patients with stable cirrhosis, severe sepsis and hematological malignancies, respectively, were enrolled as controls. Validation assays for human cytomegalovirus (CMV) reactivation in a validation cohort (n = 58) were performed and exploratory treatment instituted. RESULTS: In study cohort, 188 microorganisms were detected in 74.4% (96/129) patients, including viruses (58.0%), bacteria (34.1%), fungi (7.4%) and chlamydia (0.5%). Patients with AD had an NHV signature, and CMV was the most frequent NHV, which correlated with the clinical effect of empirical antibiotic treatment, progression to acute-on-chronic liver failure (ACLF), and 90-day mortality. The NHV signature in ACLF patients was similar to patients with sepsis and hematological malignancies. The treatable NHV, CMV was detected in 24.1% (14/58) patients in the validation cohort. Of the 14 cases with detectable CMV by mNGS, 9 were further validated by DNA RT-PCR or pp65 antigenemia testing. Three patients with CMV reactivation received ganciclovir therapy in exploratory manner with clinical resolutions. CONCLUSIONS: The results of this study suggests that NHVs may have a pathogenic role in complicating the course of AD. Further validation is needed to define whether this should be incorporated in the routine management of AD patients. IMPACT AND IMPLICATIONS: ●Cirrhosis patients with acute decompensation have a non-hepatotropic virus (NHV) signature, which is similar to that in sepsis and hematological malignancies patients. ●The detected viral signature had clinical correlates, including clinical efficacy of empirical antibiotic treatment, progression to acute-on-chronic liver failure and short-term mortality. ●The treatable NHV, CMV reactivation may be involved in the clinical outcomes of decompensated cirrhosis. ●Routine screening for NHVs, especially CMV, may be useful for the management of patients with acutely decompensated cirrhosis

Three Capsular Polysaccharide Synthesis-Related Glucosyltransferases, GT-1, GT-2 and WcaJ, Are Associated With Virulence and Phage Sensitivity of Klebsiella pneumoniae

Klebsiella pneumoniae (K. pneumoniae) spp. are important nosocomial and community-acquired opportunistic pathogens, which cause various infections. We observed that K. pneumoniae strain K7 abruptly mutates to rough-type phage-resistant phenotype upon treatment with phage GH-K3. In the present study, the rough-type phage-resistant mutant named K7RR showed much lower virulence than K7. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis indicated that WcaJ and two undefined glycosyltransferases (GTs)- named GT-1, GT-2- were found to be down-regulated drastically in K7RR as compared to K7 strain. GT-1, GT-2, and wcaJ are all located in the gene cluster of capsular polysaccharide (CPS). Upon deletion, even of single component, of GT-1, GT-2, and wcaJ resulted clearly in significant decline of CPS synthesis with concomitant development of GH-K3 resistance and decline of virulence of K. pneumoniae, indicating that all these three GTs are more likely involved in maintenance of phage sensitivity and bacterial virulence. Additionally, K7RR and GT-deficient strains were found sensitive to endocytosis of macrophages. Mitogen-activated protein kinase (MAPK) signaling pathway of macrophages was significantly activated by K7RR and GT-deficient strains comparing with that of K7. Interestingly, in the presence of macromolecular CPS residues (&gt;250 KD), K7(ΔGT-1) and K7(ΔwcaJ) could still be bounded by GH-K3, though with a modest adsorption efficiency, and showed minor virulence, suggesting that the CPS residues accumulated upon deletion of GT-1 or wcaJ did retain phage binding sites as well maintain mild virulence. In brief, our study defines, for the first time, the potential roles of GT-1, GT-2, and WcaJ in K. pneumoniae in bacterial virulence and generation of rough-type mutation under the pressure of bacteriophage