Exogenous hydrogen sulfide prevents SOD2 degradation to safeguard renal function in diabetic kidney disease.

Diabetic kidney disease (DKD) is a major contributor to chronic kidney disease. Hydrogen sulfide (H2S) serves as an endogenous gaseous signaling molecule capable of safeguarding renal function within the context of DKD. However, the underlying mechanisms need to be elucidated. This study was undertaken to unveil the mechanisms by which H2S counteracts against DKD. Utilizing mice and human renal tubular epithelial (HK-2) cells, we demonstrated a reduction in cystathionine-γ-lyase/H2S levels within renal tissues of db/db mice and in HK-2 cells subjected to hyperglycemic and hyperlipidemic environments. Notably, we observed that sodium hydrosulfide (NaHS) supplementation could serve as an exogenous source of H2S. Exogenous H2S exhibited the capacity to mitigate the accumulation of reactive oxygen species and attenuate the degradation of superoxide dismutase 2 (SOD2) by Lon protease homolog 1 induced by hyperglycemia and hyperlipidemia, thus affording cellular protection against mitochondrial apoptosis. Consequently, NaHS treatment led to decreased serum levels of blood urea nitrogen and serum creatinine, reflecting alleviated renal damage and thereby preserving renal function in db/db mice. Based on these findings, we propose that exogenous H2S exerts a protective role against DKD by inhibiting SOD2 degradation.

Human Biomonitoring of Environmental Chemicals among Elderly in Wuhan, China: Prioritizing Risks Using EPA's ToxCast Database.

In line with the "healthy aging" principle, we aim to assess the exposure map and health risks of environmental chemicals in the elderly. Blood samples from 918 elderly individuals in Wuhan, China, were analyzed using the combined gas/liquid-mass spectrometry technology to detect levels of 118 environmental chemicals. Cluster analysis identified exposure profiles, while risk indexes and bioanalytical equivalence percentages were calculated using EPA's ToxCast database. The detection rates for 87 compounds exceeded 70%. DEHP, DiBP, naphthalene, phenanthrene, DnBP, pyrene, anthracene, permethrin, fluoranthene, and PFOS showed the highest concentrations. Fat-soluble pollutants varied across lifestyles. In cluster 2, which was characterized by higher concentrations of fat-soluble substances, the proportion of smokers or drinkers was higher than that of nonsmokers or nondrinkers. Pesticides emerged as the most active environmental chemicals in peroxisome proliferator-activated receptor gamma antagonist, thyroid hormone receptor (TR) antagonist, TR agonist, and androgen receptor (AR) agonist activity assays. Additionally, PAEs and polycyclic aromatic hydrocarbons played significant roles as active contaminants for the corresponding targets of AR antagonists and estrogen receptor alpha. We proposed a list of priority pollutants linked to endocrine-disrupting toxic effects in the elderly, which may provide the groundwork for further research into environmental etiology.

Using three-dimensional modelling of the anterior sclera to investigate the scleral profile in myopic eyes.

PURPOSE: This study used three-dimensional (3D) modelling to investigate scleral profiles in myopic eyes and compare them with emmetropic eyes. METHODS: In this prospective observational study, the eyes of 151 participants were analysed using the corneoscleral profile module (CSP) of the Pentacam HR. Non-rotationally symmetrical ellipsoids were fitted to the anterior scleral sagittal height. Three radii were analysed, namely the nasal-temporal (Rx), superior-inferior (Ry) and anterior-posterior (Rz) orientations. Additionally, the area index (AI) and aspherical parameters (Qxy, Qxz and Qyz) of the anterior sclera-fitted ellipsoid (ASFE) were quantified. RESULTS: The findings showed an increase in Rx (-0.349 mm/D), Ry (-0.373 mm/D), Rz (-1.232 mm/D) and AI (-36.165 mm2 /D) with increasing myopia. From emmetropia to high myopia, the vertical and horizontal planes of the anterior sclera became increasingly prolate (emmetropia, Qxz: 0.02, Qyz: 0.01; low myopia, Qxz: -0.28, Qyz: -0.28; high myopia, Qxz: -0.41, Qyz: -0.43). There were no significant differences in the coronal plane across the three groups (H = 2.65, p = 0.27). The anterior scleral shape of high myopes in the horizontal and vertical planes was more prolate than that of emmetropes and low myopes (Qxz, high myopes vs. low myopes: p = 0.03, high myopes vs. emmetropes: p < 0.001; Qyz, high myopes vs. low myopes: p = 0.04, high myopes vs. emmetropes: p < 0.001). CONCLUSIONS: As the degree of myopia increased, non-uniform anterior scleral enlargement was observed. These findings provide a better understanding of the anterior segment with varying degrees of myopia.

Identifying the preoperative factors predicting the surgical difficulty of robotic distal pancreatectomy.

BACKGROUND: Few studies have evaluated the preoperative factors predicting the surgical difficulty of robotic distal pancreatectomy (RDP). This study aims to explore such factors and provide guidance on the selection of suitable patients to aid surgeons lacking extensive experience in RDP. METHODS: A retrospective study was conducted on consecutive patients who underwent RDP to identify preoperative factors predicting surgical difficulty. High surgical difficulty was defined by both operation time and intraoperative estimated blood loss exceeding their median, or by conversion to laparotomy. RESULTS: A total of 161 patients were ultimately enrolled, including 51 patients with high levels of surgical difficulty. Multivariate analysis revealed that male sex [OR (95% CI): 4.07 (1.77,9.40), p = 0.001], body mass index (BMI) ≥ 25 kg/m2 OR (95% CI): 2.27 (1.03,5.00), p = 0.042], tumors located at the neck of the pancreas [OR (95% CI): 4.15 (1.49,11.56), p = 0.006] and splenic artery type B [OR (95% CI): 3.28 (1.09,9.91), p = 0.035] were independent risk factors for surgical difficulty. Regarding postoperative complications, high surgical difficulty was associated with the risk of overall complications and pancreatic fistula (grade B/C) (49.0% vs. 22.7%, p < 0.001; 39.2% vs. 19.1%, p = 0.006). CONCLUSION: Male sex, body mass index ≥ 25 kg/m2, tumor located at the neck of the pancreas and splenic artery type B are associated with a high RDP difficulty level. These factors can be used preoperatively to assess the difficulty level of surgery, to help surgeons choose patients suitable for them and ensure surgical safety.

Ionization behavior of nanoporous polyamide membranes.

Escalating global water scarcity necessitates high-performance desalination membranes, for which fundamental understanding of structure-property-performance relationships is required. In this study, we comprehensively assess the ionization behavior of nanoporous polyamide selective layers in state-of-the-art nanofiltration (NF) membranes. In these films, residual carboxylic acids and amines influence permeability and selectivity by imparting hydrophilicity and ionizable moieties that can exclude coions. We utilize layered interfacial polymerization to prepare physically and chemically similar selective layers of controlled thickness. We then demonstrate location-dependent ionization of carboxyl groups in NF polyamide films. Specifically, only surface carboxyl groups ionize under neutral pH, whereas interior carboxyl ionization requires pH >9. Conversely, amine ionization behaves invariably across the film. First-principles simulations reveal that the low permittivity of nanoconfined water drives the anomalous carboxyl ionization behavior. Furthermore, we report that interior carboxyl ionization could improve the water-salt permselectivity of NF membranes over fourfold, suggesting that interior charge density could be an important tool to enhance the selectivity of polyamide membranes. Our findings highlight the influence of nanoconfinement on membrane transport properties and provide enhanced fundamental understanding of ionization that could enable novel membrane design.

Repeatability and Reproducibility of Corneoscleral Topography Measured With Scheimpflug Imaging in Keratoconus and Control Eyes.

OBJECTIVES: To determine and compare the repeatability and reproducibility of anterior scleral parameters measured by the corneoscleral profile (CSP) module of Pentacam in keratoconus (KC) and control eyes. METHODS: This is a prospective observational study. Thirty KC participants (30 eyes) and 24 control participants (24 eyes) were examined three times using the CSP. Sagittal height mean (SHM), sagittal height astigmatism (SHA), and mean bulbar slope (BSM) were measured in 12 mm and 16 mm chord lengths. The repeatability and reproducibility of these measurements were also assessed. Coefficients of variation (CoV), intraclass correlation coefficient (ICC), coefficient of repeatability (CoR1), and coefficient of reproducibility (CoR2) were adopted to assess the reliability. RESULTS: In the KC and control groups, SHM showed high repeatability and reproducibility (coefficients of variation [CoVs]≤0.96%, intraclass correlation coefficient [ICCs]≥0.97), and SHM of control eyes showed higher repeatability and reproducibility than that of KC eyes at 12 mm chord length (KC group, CoRs ranged from 35.56 µm to 43.52 µm, control group, ranged from 23.50 µm to 30.31 µm) and 16 mm chord length (KC group, CoRs ranged from 79.54 µm to 81.58 µm, control group, ranged from 48.25 µm to 66.10 µm). Mean bulbar slope also showed high repeatability and reproducibility (CoVs≤3.65%, CoRs≤2.64). Furthermore, the SHA of control eyes showed higher repeatability and reproducibility when compared with KC eyes (control group: CoVs≤29.95%, KC group: CoVs≥32.67%). CONCLUSIONS: Keratoconus and control eyes demonstrated high repeatability and reproducibility when using CSP measurements, which may prove helpful in fitting contact lenses.

Associated factors of health-promoting lifestyle of the elderly based on the theory of social ecosystem.

OBJECT: To explore the factors related to health-promoting lifestyles of the elderly based on social-ecosystem theory. DESIGN: A cross-sectional survey study was carried out to include 627 elderly people in communities in three cities of Hebei Province (Shijiazhuang, Tangshan, and Zhangjiakou) from October 2021 to January 2022 for questionnaire survey (601 validly returned cases). VENUE: Three cities of Hebei Province (Shijiazhuang, Tangshan, and Zhangjiakou). PARTICIPANTS: 627 elderly people. INTERVENTIONS: A cross-sectional survey study. MAIN MEASUREMENTS: The questionnaire survey was conducted by using the general demographic data, health promotion life scale, frailty scale, general self-efficacy scale, health engagement scale, General Self-Efficacy Scale, The family Adaptability, Partnership, Growth, Affection, and Resolve scale, and Perceived Social Support Scale. RESULTS: The total health promotion lifestyle score for the elderly was 100.20±16.21, which was at the lower limit of the good level, with the highest mean score for nutrition (2.71±0.51) and the lowest mean score for physical activity (2.25±0.56). Stepwise linear regression showed that exercise frequency (95% confidence interval (CI) 1.304-3.885), smoking status (95% CI -4.190 to -1.556), self-efficacy (95% CI 0.071-0.185), health management (95% CI 0.306-0.590), frailty (95% CI -3.327 to -1.162) in the microsystem, marital status (95% CI 0.677-3.660), children's attention to the elderly health (95% CI 4.866-11.305), family care in the mesosystem (95% CI 1.365-4.968), and pre-retirement occupation (95% CI 2.065-3.894), living area (95% CI 0.813-3.912), whether receive community-based chronic disease prevention and management services (95% CI 2.035-8.149), social support (95% CI 1.667-6.493) in the macrosystem were the main factors affecting health promotion of life in the elderly (P<0.05). Hierarchical regression analysis showed the microsystem accounted for 17.2%, the mesosystem accounted for 7.1%, and the macrosystem accounted for 11.4%. CONCLUSION: The health promotion lifestyle of the elderly in Hebei Province was at the lower limit of good level. Among them, exercise frequency, children's attention to the elderly health, and pre-retirement occupation played a major role in relation to the health-promoting lifestyle of the elderly. Hence, it needs the joint action of individuals, families, and society to promote the elderly to adopt the health promotion lifestyle and realize healthy aging.

Adaptation of Listeria monocytogenes to perturbation of c-di-AMP metabolism underpins its role in osmoadaptation and identifies a fosfomycin uptake system.

The human pathogen Listeria monocytogenes synthesizes and degrades c-di-AMP using the diadenylate cyclase CdaA and the phosphodiesterases PdeA and PgpH respectively. c-di-AMP is essential because it prevents the uncontrolled uptake of osmolytes. Here, we studied the phenotypes of cdaA, pdeA, pgpH and pdeA pgpH mutants with defects in c-di-AMP metabolism and characterized suppressor mutants restoring their growth defects. The characterization of the pdeA pgpH mutant revealed that the bacteria show growth defects in defined medium, a phenotype that is invariably suppressed by mutations in cdaA. The previously reported growth defect of the cdaA mutant in rich medium is suppressed by mutations that osmotically stabilize the c-di-AMP-free strain. We also found that the cdaA mutant has an increased sensitivity against isoleucine. The isoleucine-dependent growth inhibition of the cdaA mutant is suppressed by codY mutations that likely reduce the DNA-binding activity of encoded CodY variants. Moreover, the characterization of the cdaA suppressor mutants revealed that the Opp oligopeptide transport system is involved in the uptake of the antibiotic fosfomycin. In conclusion, the suppressor analysis corroborates a key function of c-di-AMP in controlling osmolyte homeostasis in L. monocytogenes.

COVID-19-inspired "artificial virus" to combat drug-resistant bacteria by membrane-intercalation- photothermal-photodynamic multistage effects.

COVID-19 threatens human life because of the super destructiveness produced from its coronal morphology and strong transmembrane infection based on spike glycoprotein. Inspired by the coronal morphology of COVID-19 and its means of infecting, we designed an "artificial virus" with coronal morphology based on the concept of "defeating superbacteria with superviruses" by self-assembling a transacting activator of transduction peptide with triple-shell porous graphitic carbon nitride (g-C3N4) embedded with cobalt nanoparticles to forcefully infect methicillin-resistant Staphylococcus aureus (MRSA). The results confirmed that this "artificial virus" had unique properties of crossing the bacterial cell membrane barrier, heating the internal bacterial microenvironment and triggering ROS outbreak, based on its coronal morphology, membrane penetration, temperature-rising and heat insulation, oxidase-like activity and excellent visible-light harvesting properties. It had a high sterilization efficiency of 99.99% at 20 min, which was 18.6 times that of g-C3N4, and the efficiency remained at 99.99% after 3 rounds of recycling and reuse. Additionally, it can rapidly inactivate bacteria in river water and accelerate wound healing.

Enhanced Ultrafast Broadband Reverse Saturable Absorption in Twistacenes with Enlarged π-Conjugated Central Bridge.

Optical nonlinearities of two all-carbon twistacenes, DPyA and DPyN, with the different π-conjugated central bridges were investigated. The nonlinear absorption properties of these compounds were measured using the femtosecond Z-scan with wavelengths between 650 and 900 nm. It has been found that the nonlinear absorption originated from two-photon absorption (TPA) and TPA-induced excited state absorption (ESA), wherein DPyA demonstrates higher performance than DPyN. The TPA cross section of DPyA (4300 GM) is nearly 4.3 times larger than that of DPyN at 650 nm. Moreover, the different central structures modulate the intensity of ESA at 532 nm, and DPyA exhibits an excellent ESA at 532 nm with multi-pulse excitation. Meanwhile, the result of data fitting and quantum chemistry calculation shows that the enhancement of nonlinear absorption in DPyA is due to the extended π- conjugated bridge and improved delocalization of π-electrons. These all-carbon twistacenes could yield potential applications in optical power limiting (OPL) technology.

The promoting effects of hsa_circ_0050102 in pancreatic cancer and the molecular mechanism by targeting miR-1182/NPSR1.

Pancreatic cancer is one of the most lethal tumors across the world with an overall 5-year survival rate of 9%, and great efforts have been devoted in early diagnosis and treatment in the past decades. Competing endogenous RNAs are novel and specific regulatory mechanisms of gene expression, and researches have indicated its important roles in tumor regulation. In this study, we explored the circ-0050102 expression in pancreatic cancer and its impacts on tumor malignant phenotypes and further investigated the correlations among circ-0050102, miR-1182 and NPSR1. Results of real-time quantitative PCR showed that circ-0050102 expressed higher in pancreatic cancers compared with that in adjacent normal tissues. In cell functional experiment, downregulation of circ-0050102 could suppress cell proliferation, migration and invasion ability, boost cell apoptosis and arrest cell cycle in both PANC-1 and CFPAC-1 cells. Furthermore, allogeneic transplantation in nude mice was performed and results showed that the inhibition of circ-0050102 could slow down tumor formation in vivo. Mechanism research suggested that circ-0050102 could downregulate miR-1182, while miR-1182 could not influence the expression of circ-0050102, and miR-1182 could directly target at NPSR1 and suppress it. Moreover, circ-0050102 could reverse the effects of si-NPSR1 on pancreatic cancer cells. In conclusion, we identified that circ-0050102 played an important role in promoting pancreatic cancer by regulating the miR-1182/NPSR1 pathway.

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H2 S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 µmol·kg-1 ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild-type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S-sulfhydration of Hrd1 were measured. Exogenous H2 S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H2 S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S-sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H2 S modified Hrd1 S-sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.

Manganese(III) porphyrin oligomers as high-relaxivity MRI contrast agents.

Manganese(III) porphyrins (MnIIIPs) as MRI contrast agents (CAs) have drawn particular attention due to their high longitudinal relaxivity (r1) and unique biodistribution. In this work, two MnIIIP-based oligomers, MnPD and MnPT, were designed to further improve the relaxivity with ease of synthesis. The two compounds were fully characterized and their nuclear magnetic relaxation dispersion (NMRD) profiles were acquired with a fast field cycling NMR relaxometer. Both of the compounds exhibited extended high molar r1 at high fields, higher than that of Gd-DTPA, the first clinical gadolinium(III)-based MRI CA. The r1 value of per manganese atom increased with the increasing number of MnIIIP building blocks, suggesting rotational correlation time (τR) played dominant role in the r1 dispersion. The toxicity of the two MnIIIPs and the imaging effectiveness were estimated in vitro and in vivo. With good biocompatibility, significant contrast enhancement, and complete excretion in 24 h, MnPD and MnPT are both promising for high field clinical applications. The applied strategy also potentially provided a facile approach for creation of more MnIIIP oligomer as efficient T1 MRI CAs.

Extended infusion of rituximab combined with steroids is effective in inducing remission and reducing relapse in adult minimal change disease.

BACKGROUND: Minimal change disease is a common cause of nephrotic syndrome in adults. Higher relapse rate put patients at risk of steroids toxicity due to long-term exposure. Rituximab has been suggested to maintain long time remission and withdraw steroids and other immunosuppressants with fewer adverse events. However, optimal dose and dosing interval have not been explored. METHODS: Twenty-five patients were enrolled from 2017-10 to 2020-03 in Nanfang Hospital in China. Clinical and biological data were extracted from medical records and laboratory databases. Therapy composed of 375mg/m2 rituximab once three weeks for 3 dose and corticosteroid was applied. Complete remission was defined as reduction of proteinuria to 0.3g/d. Remission rate, relapse rate, steroids used before and after rituximab therapy and adverse effects were documented at a mean time of 14.71 months. RESULTS: Twenty-two patients achieved complete remission for an average of 3.26 months and only 3 patients experienced one relapse respectively during the follow-up period. The mean remission maintenance time was 11.6 months, and was 5 months after steroids withdrawal. Steroids dose at last follow-up was 6.09mg/d, which was significantly reduced compared to 28.15mg/d before rituximab. Relapse rate before and after rituximab was 1.43 and 0.1, respectively. Only four minor adverse events were recorded. CONCLUSIONS: Therapy consisted of 375mg/m2 rituximab once three weeks for 3 dose combined with corticosteroid is effective in inducing remission in adult patients with minimal change disease. Both of the relapse rate and dose of steroids used are significantly decreased with fewer side effects.

Epidemiological characteristics and transmission dynamics of paediatric cases with coronavirus disease 2019 in Hubei province, China.

AIM: This study aimed to identify the epidemiological characteristics and transmission dynamics of paediatric cases. METHODS: Information on 1369 paediatric cases with COVID-19 from 8 December 2019 to 7 March 2020 in Hubei province was extracted from the National Infectious Disease Surveillance System. The analysis included epidemic curves, temporal-spatial distribution, clinical classification and interval times between onset and diagnosis. RESULTS: Among 1369 paediatric cases, the median age was 9 years and 58.2% of them were males. The proportion of severe and critical cases in children was lower than that in adults and the proportion of asymptomatic cases in children was five times greater than for adult cases. The first paediatric case was reported on 2 January 2020, and the daily number of new paediatric cases remained high from 1 February through to 22 February. The epidemiological curve of paediatric cases lagged behind that of adults by 19 days, and the first spike of the epidemic curve in senior high school students occurred 1 week earlier than in other paediatric groups. The proportion of clustered cases among children was about twice that for adults. The median of the interval in paediatric cases between onset and diagnosis, isolation and notification were 3, 0 and 3 days, respectively, and all of those were significantly shorter than in adults. CONCLUSIONS: The epidemic curve of child cases lagged behind that of adult cases by 19 days, and the major form of transmission observed was in clusters.

Epidemiological Characteristics and Incubation Period of 7015 Confirmed Cases With Coronavirus Disease 2019 Outside Hubei Province in China.

BACKGROUND: Disease caused by SARS-CoV-2 broke out in Wuhan in December 2019. We utilized confirmed cases outside Hubei Province to analyze epidemiologic characteristics and evaluate the effect of traffic restrictions implemented in Hubei beginning on 23 January 2020. METHODS: Information on 7015 confirmed cases from 19 January to 8 February 2020 in all provinces outside Hubei was collected from the national and local health commissions in China. Incubation period and interval times were calculated using dates of the following events: contact with an infected person, onset, first visit, and diagnosis. We evaluated changes in incubation period and interval times. RESULTS: The average age of all cases was 44.24 years. The median incubation period was 5 days and extended from 2 days on 23 January to 15 days on 8 February. The proportion of imported cases decreased from 85.71% to 33.19% after 23 January. In addition, lengths of intervals between onset and diagnosis, onset and first visit, and first visit and diagnosis decreased over time. CONCLUSIONS: Rapidly transmitting COVID-19 has a short incubation period. The onset mainly occurred among young to middle-aged adults. Traffic restrictions played an important role in the decreased number of imported cases outside Hubei.

Up-regulation of CDHR5 expression promotes malignant phenotype of pancreatic ductal adenocarcinoma.

CDHR5 has been reported to play key roles in carcinogenesis of various cancers, but its roles in pancreatic cancer have not been reported. The present study was designed to investigate its clinical value in pancreatic ductal adenocarcinoma (PDAC). Tissue microarray-based immunohistochemistry was performed to analyse the correlation between CDHR5 expression and clinical and pathological features of PDAC, as well as the CDHR5 expression during tumour progression. Cell function assays were performed to investigate CDHR5's effects on PDAC cells. Moreover, qRT-PCR was applied to investigate the expression of CDHR5 isoforms in PDAC cells. Expression of CDHR5 was higher on the membrane of PDAC cells. This high expression level was associated with shorter overall survival of PDAC patients and was identified as an independent prognostic factor for overall survival by multivariate Cox regression analysis. In addition, expression level of CDHR5 presented an increased trend in the occurrence and progression of PDAC. Cell experiment suggested that CDHR5 could notably promote invasion and migration of PDAC cells. Moreover, analysis of CDHR5 isoforms indicated CDHR5-L was the major isoform expressed in PDAC cell lines. CDHR5 appears to be a promising and novel prognostic factor for PDAC, and its promotion in PDAC metastasis might be ascribed to the isoform CDHR5-L.

Hydrogen sulphide ameliorating skeletal muscle atrophy in db/db mice via Muscle RING finger 1 S-sulfhydration.

Muscle atrophy occurs in many pathological states, including cancer, diabetes and sepsis, whose results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. Expression of Muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, was increased to induce the loss of muscle mass in diabetic condition. However, hydrogen sulphide (H2 S) plays a crucial role in the variety of physiological functions, including antihypertension, antiproliferation and antioxidant. In this study, db/db mice and C2C12 myoblasts treated by high glucose and palmitate and oleate were chose as animal and cellular models. We explored how exogenous H2 S attenuated the degradation of skeletal muscle via the modification of MuRF1 S-sulfhydration in db/db mice. Our results show cystathionine-r-lyase expression, and H2 S level in skeletal muscle of db/db mice was reduced. Simultaneously, exogenous H2 S could alleviate ROS production and reverse expression of ER stress protein markers. Exogenous H2 S could decrease the ubiquitination level of MYOM1 and MYH4 in db/db mice. In addition, exogenous H2 S reduced the interaction between MuRF1 with MYOM1 and MYH4 via MuRF1 S-sulfhydration. Based on these results, we establish that H2 S prevented the degradation of skeletal muscle via MuRF1 S-sulfhydration at the site of Cys44 in db/db mice.

c-di-AMP assists osmoadaptation by regulating the Listeria monocytogenes potassium transporters KimA and KtrCD.

Many bacteria and some archaea produce the second messenger cyclic diadenosine monophosphate (c-di-AMP). c-di-AMP controls the uptake of osmolytes in Firmicutes, including the human pathogen Listeria monocytogenes, making it essential for growth. c-di-AMP is known to directly regulate several potassium channels involved in osmolyte transport in species such as Bacillus subtilis and Streptococcus pneumoniae, but whether this same mechanism is involved in L. monocytogenes, or even whether similar ion channels were present, was not known. Here, we have identified and characterized the putative L. monocytogenes' potassium transporters KimA, KtrCD, and KdpABC. We demonstrate that Escherichia coli expressing KimA and KtrCD, but not KdpABC, transport potassium into the cell, and both KimA and KtrCD are inhibited by c-di-AMP in vivo For KimA, c-di-AMP-dependent regulation requires the C-terminal domain. In vitro assays demonstrated that the dinucleotide binds to the cytoplasmic regulatory subunit KtrC and to the KdpD sensor kinase of the KdpDE two-component system, which in Staphylococcus aureus regulates the corresponding KdpABC transporter. Finally, we also show that S. aureus contains a homolog of KimA, which mediates potassium transport. Thus, the c-di-AMP-dependent control of systems involved in potassium homeostasis seems to be conserved in phylogenetically related bacteria. Surprisingly, the growth of an L. monocytogenes mutant lacking the c-di-AMP-synthesizing enzyme cdaA is only weakly inhibited by potassium. Thus, the physiological impact of the c-di-AMP-dependent control of potassium uptake seems to be less pronounced in L. monocytogenes than in other Firmicutes.

The genomic profile of parathyroid carcinoma based on whole-genome sequencing.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole-genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. Inactivating CDC73 mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer-related mutations identified in more than one case were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild-type CDC73 samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P = .006) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer-predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild-type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow-up and therapy for PC patients.