Efficacy and safety of PD-1/PD-L1 inhibitor-based immune combination therapy versus sorafenib in the treatment of advanced hepatocellular carcinoma: a meta-analysis.

Objective: To systematically evaluate the safety and efficacy of PD-1/PD-L1 inhibitor-based immunotherapy (hereafter referred to as "combination immunotherapy") compared with that of sorafenib in the treatment of hepatocellular carcinoma (HCC). Methods: Databases such as PubMed, Embase, and the Cochrane Library were searched from the date of their establishment to September 2023 to identify randomized controlled trials (RCTs) of combination immunotherapy versus sorafenib for the treatment of advanced HCC. Two reviewers independently evaluated the quality of the included studies, extracted the data, and cross-checked the information. The meta-analysis was performed using RevMan 5.3 software. Results: A total of 5 RCTs were included. The results of the meta-analysis showed the following: (1) Effectiveness. Compared to sorafenib, combination immunotherapy significantly improved overall survival (OS, HR = 0.69, 95% CI: 0.58 ~ 0.82, p < 0.01) and progression-free survival (PFS, HR = 0.62, 95% CI: 0.50 ~ 0.78, p < 0.001) in patients with advanced HCC. (2) Safety. Both groups had comparatively high incidences of adverse events (AEs), but the difference in any treatment-related adverse events was not significant between the two arms (OR = 0.98, 95% CI: 0.95 ~ 1.02, p = 0.34). The difference in the incidence of grade 1-2 adverse reactions was statistically significant (OR = 0.66, 95% CI = 0.49-0.90, p = 0.001). There were no differences in grade 3/4 TRAEs or grade 5 TRAEs (OR = 1.46, 95% CI = 0.78 ~ 2.71, p = 0.24; OR = 1.08, 95% CI = 0.73 ~ 1.58, p = 0.71). Conclusion: Combined immunotherapy can significantly prolong the OS and PFS of patients with advanced HCC without increasing the incidence of adverse effects in terms of safety, but the incidence of AEs in different systems is different.

Pathways linking workplace violence and suicidal ideation/non-suicidal self-injury among nurse staff: the mediating role of loneliness and depressive symptoms.

BACKGROUND: Nurses face disproportionately high rates of suicidal ideation and non-suicidal self-injury (NSSI). The role of workplace violence, loneliness, and depressive symptoms in exacerbating these issues is poorly understood. This study aims to explore these relationships to inform interventions for improving nurses' mental health. METHODS: A cross-sectional study involving 1,774 Chinese nurse staff selected through convenient sampling methods was conducted. Workplace violence, depressive symptoms, and loneliness were assessed using the Chinese versions of the Workplace Violence Scale (WVS), the 9-item Patient Health Questionnaire (PHQ-9), and a three-item loneliness scale, respectively. Participants completed self-report questionnaires anonymously to ensure adherence to ethical standards. Statistical analysis utilized structural equation modeling (SEM) to examine the intricate relationships among variables, thereby elucidating the impact of workplace violence, loneliness, and depressive symptoms on nurses' suicidal ideation/NSSI outcomes. RESULTS: Nurse staff 165 (7.8%) were reported different level of suicidal ideation and 139 (7.8%) participants were reported different level of NSSI. And the final model of workplace violence on suicidal ideation shown a good model fit index (CMIN/DF = 3.482 NFI = 0.969 CFI = 0.977 TLI = 0.955 RFI = 0.938, RMSEA = 0.037 SRMR = 0.035). The pathway of workplace violence to loneliness (ß = 0.163, P < 0.001), the indirect effect of workplace violence on suicidal ideation via loneliness and depressive symptoms were 0.100 (95%CI = 0.085, 0.121), the indirect effect of loneliness on suicidal ideation via depressive symptoms were 0.128 (95%CI = 0.100, 0.158). Similarly, the final model of workplace violence on NSSI shown a good model fit index (CMIN/DF = 3.482 NFI = 0.967 CFI = 0.976 TLI = 0.953 RFI = 0.935, RMSEA = 0.037 SRMR = 0.034), the pathways of workplace violence to NSSI (ß = 0.115, P < 0.001), the indirect effect of workplace violence on NSSI via loneliness and depressive symptoms were 0.075 (95%CI = 0.055, 0.096), the indirect effect of loneliness on NSSI via depressive symptoms were 0.102 (95%CI = 0.076, 0.130). CONCLUSION: Our study unveils the role of workplace violence in nurses' suicidal ideation and NSSI, mediated by loneliness and depressive symptoms. Interventions targeting workplace violence are crucial for nurses' well-being, potentially reducing loneliness and depressive symptoms and lowering the risk of suicidal ideation and NSSI. However, further research is needed to explore additional mediators and pathways, employing longitudinal designs to establish causality and develop tailored interventions for nurses affected by workplace violence.

Expression Profiles and Bioinformatic Analysis of Circular RNAs in Db/Db Mice with Cardiac Fibrosis.

Introduction: Cardiac fibrosis is one of the important causes of heart failure and death in diabetic cardiomyopathy (DCM) patients. Circular RNAs (circRNAs) are covalently closed RNA molecules in eukaryotes and have high stability. Their role in myocardial fibrosis with diabetic cardiomyopathy (DCM) remain to be fully elucidated. This study aimed to understand the expression profiles of circRNAs in myocardial fibrosis with DCM, exploring the possible biomarkers and therapeutic targets for DCM. Methods: At 21 weeks of age, db/db mice established the type 2 DCM model measured by echocardiography, and the cardiac tissue was extracted for Hematoxylin-eosin, Masson's trichrome staining, and transmission electron microscopy. Subsequently, the expression profile of circRNAs in myocardial fibrosis of db/db mice was constructed using microarray hybridization and verified by real-time quantitative polymerase chain reaction. A circRNA-microRNA-messenger RNA coexpression network was constructed, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were done. Results: Compared with normal control mice, db/db mice had 77 upregulated circRNAs and 135 downregulated circRNAs in their chromosomes (fold change ≥1.5, P ≤ 0.05). Moreover, the enrichment analysis of circRNA host genes showed that these differentially expressed circRNAs were mainly involved in mitogen-activated protein kinase signaling pathways. CircPHF20L1, circCLASP1, and circSLC8A1 were the key circRNAs. Moreover, circCLASP1/miR-182-5p/Wnt7a, circSLC8A1/miR-29b-1-5p/Col12a1, and most especially circPHF20L1/miR-29a-3p/Col6a2 might be three novel axes in the development of myocardial fibrosis in DCM. Conclusion: The findings will provide some novel circRNAs and molecular pathways for the prevention or clinical treatment of DCM through intervention with specific circRNAs.

Psychosocial characteristics pattern correlated with suicidal ideation and non-suicidal self-injury among nurse staff: a latent profile analysis.

BACKGROUND: Nurses frequently endure elevated levels of psychosocial stress, which often correlates with an increased suicide risk. This study aimed to investigate the impact of latent psychosocial characteristic patterns on suicidal ideation and non-suicidal self-injury among nursing staff. METHOD: Participants were recruited from the Dehong districts of Yunnan province, China, between July 11th and July 26th, 2022. Subgroups were identified using variables linked to suicidal ideation and non-suicidal self-injury, including perceived cognitive deficits, anxiety symptoms, depressive symptoms, resilience, social support, childhood trauma, loneliness, and sleep quality. Measurement tools included the Perceived Deficit Questionnaire-5-item (PDQ-5), Generalized Anxiety Disorder-7 items (GAD-7), Patient Health Questionnaire (PHQ-9), Connor-Davidson Resilience Scale-10 items (CD-RISC10), Multidimensional Scale of Perceived Social Support (MSPSS), Childhood Trauma Questionnaire-Short Form (CTQ-SF), Three-Item Loneliness Scale, and a single-item sleep quality scale. RESULTS: Latent profile analysis (LPA) revealed four distinct psychosocial characteristic patterns: "class 1," "class 2," "class 3," and "class 4." Compared to class 2, individuals in class 1 had a sixfold increased risk of suicidal ideation (OR = 6.59, 95%CI = 4.42-9.81) and a fivefold increased risk of non-suicidal self-injury (OR = 5.13, 95%CI = 3.38-7.78). Similarly, class 4 individuals had twice the risk of suicidal ideation (OR = 2.13, 95%CI = 1.25-3.62) and non-suicidal self-injury (OR = 2.13, 95%CI = 1.25-3.65) compared to class 2. Conversely, class 3 individuals had a lower risk of suicidal ideation (OR = 0.21, 95%CI = 0.11-0.42) and non-suicidal self-injury (OR = 0.15, 95%CI = 0.07-0.36) than class 2. Additionally, divorced/other marital status individuals had a higher risk of suicidal ideation (OR = 2.34, 95%CI = 1.02-5.35) and non-suicidal self-injury (OR = 2.58, 95%CI = 1.01-6.65) compared to married individuals, while unmarried individuals had a lower risk of suicidal ideation (OR = 0.58, 95%CI = 0.37-0.91). CONCLUSIONS: The study identified eight important psychosocial factors divided into four latent pattern classes. Individuals in "class 1" and "class 4" were more likely to have a higher risk of suicidal ideation and non-suicidal self-injury, while those in "class 3" were more likely to have a lower risk of both outcomes. It is suggested that further research should focus on "class 1" and "class 4" for targeted intervention.

LncRNA and mRNA expression characteristic and bioinformatic analysis in myocardium of diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM) is becoming a very well-known clinical entity and leads to increased heart failure in diabetic patients. Long non-coding RNAs (LncRNAs) play an important role in the pathogenesis of DCM. In the present study, the expression profiles of lncRNAs and mRNAs were illuminated in myocardium from DCM mice, with purpose of exploring probable pathological processes of DCM involved by differentially expressed genes in order to provide a new direction for the future researches of DCM. RESULTS: The results showed that a total of 93 differentially expressed lncRNA transcripts and 881 mRNA transcripts were aberrantly expressed in db/db mice compared with the controls. The top 6 differentially expressed lncRNAs like up-regulated Hmga1b, Gm8909, Gm50252 and down-regulated Msantd4, 4933413J09Rik, Gm41414 have not yet been reported in DCM. The lncRNAs-mRNAs co-expression network analysis showed that LncRNA 2610507I01Rik, 2310015A16Rik, Gm10503, A930015D03Rik and Gm48483 were the most relevant to differentially expressed mRNAs. CONCLUSION: Our results showed that db/db DCM mice exist differentially expressed lncRNAs and mRNAs in hearts. These differentially expressed lncRNAs may be involved in the pathological process of cardiomyocyte apoptosis and fibrosis in DCM.

Impact of workplace violence against psychological health among nurse staff from Yunnan-Myanmar Chinese border region: propensity score matching analysis.

BACKGROUND: Owing to different social background factor in Yunnan-Myanmar Chinese border region, stressful working environment may lead to extra psychological burden among nurse staff in China. However, the prevalence of workplace violence and its effect on psychological characteristics among nurse staff are still unclear. This study aims to explore the effect of workplace violence against psychological health among nurse staff from Yunnan-Myanmar Chinese border region. METHODS: A cross-sectional survey was conducted among 18 local governmental hospitals in Dehong districts. Participants were 1,774 nurses. Psychosocial characteristics were screened by sleep quality, the 9-item Patient Health Questionnaire for depressive symptoms, the generalized anxiety disorder-7 for anxiety symptoms, the Connor Davidson Resilience Scale - 10 item for resilience, the multidimensional scale of perceived social support for social support, the Chinese version of Work place Violence Scale for workplace violence. Propensity score matching and multivariate linear regression were applied to analyze the data. RESULTS: The nurse staff with workplace violence have a higher risk of bad sleep quality (b = -0.883, 95%CI = [-1.171, -0.595]), anxiety symptoms (b = 2.531, 95%CI = [2.031, 3.031]) and depressive symptoms (b = 3.227, 95%CI = [2.635, 3.819]), loneliness (b = 0.683, 95%CI = [0.503, 0.863]), perceived cognitive deficits (b = 1.629, 95%CI = [1.131, 2.127]), poor resilience (b = -2.012, 95%CI = [-2.963, -1.061]), and poor social support (b = -5.659, 95%CI = [-7.307, -4.011]). CONCLUSIONS: Preventing workplace violence can improve mental health outcomes significantly among nurse staff, including loneliness, perceived cognitive deficits, anxiety symptoms, depressive symptoms, sleep quality, resilience and social support.

MALAT1/miR-185-5p mediated high glucose-induced oxidative stress, mitochondrial injury and cardiomyocyte apoptosis via the RhoA/ROCK pathway.

To explore the underlying mechanism of lncRNA MALAT1 in the pathogenesis of diabetic cardiomyopathy (DCM). DCM models were confirmed in db/db mice. MiRNAs in myocardium were detected by miRNA sequencing. The interactions of miR-185-5p with MALAT1 and RhoA were validated by dual-luciferase reporter assays. Primary neonatal cardiomyocytes were cultured with 5.5 or 30 mmol/L D-glucose (HG) in the presence or absence of MALAT1-shRNA and fasudil, a ROCK inhibitor. MALAT1 and miR-185-5p expression were determined by real-time quantitative PCR. The apoptotic cardiomyocytes were evaluated using flow cytometry and TUNEL staining. SOD activity and MDA contents were measured. The ROCK activity, phosphorylation of Drp1S616 , mitofusin 2 and apoptosis-related proteins were analysed by Western blotting. Mitochondrial membrane potential was examined by JC-1. MALAT1 was significantly up-regulated while miR-185-5p was down-regulated in myocardium of db/db mice and HG-induced cardiomyocytes. MALAT1 regulated RhoA/ROCK pathway via sponging miR-185-5p in cardiomyocytes in HG. Knockdown of MALAT1 and fasudil all inhibited HG-induced oxidative stress, and alleviated imbalance of mitochondrial dynamics and mitochondrial dysfunction, accompanied by reduced cardiomyocyte apoptosis. MALAT1 activated the RhoA/ROCK pathway via sponging miR-185-5p and mediated HG-induced oxidative stress, mitochondrial damage and apoptosis of cardiomyocytes in mice.

Atorvastatin ameliorated myocardial fibrosis in db/db mice by inhibiting oxidative stress and modulating macrophage polarization.

BACKGROUND: People with diabetes mellitus (DM) suffer from multiple chronic complications due to sustained hyperglycemia, especially diabetic cardiomyopathy (DCM). Oxidative stress and inflammatory cells play crucial roles in the occurrence and progression of myocardial remodeling. Macrophages polarize to two distinct phenotypes: M1 and M2, and such plasticity in phenotypes provide macrophages various biological functions. AIM: To investigate the effect of atorvastatin on cardiac function of DCM in db/db mice and its underlying mechanisms. METHODS: DCM mouse models were established and randomly divided into DM, atorvastatin, and metformin groups. C57BL/6 mice were used as the control. Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson staining was used to examine the morphology and collagen fibers in myocardial tissues. The expression of transforming growth factor-ß1 (TGF-ß1), tumor necrosis factor-α (TNF-α), interleukin-1 ß (IL-1ß),M1 macrophages (iNOS+), and M2 macrophages (CD206+) were demonstrated by immunohistochemistry and immunofluorescence staining. The levels of TGF-ß1, IL-1ß, and TNF-α were detected by ELISA and real-time quantitative polymerase chain reaction. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) ac-tivities were also measured. RESULTS: Treatment with atorvastatin alleviated cardiac dysfunction and decreased db/db mice. The broken myocardial fibers and deposition of collagen in the myocardial interstitium were relieved especially by atorvastatin treatment. Atorvastatin also reduced the levels of serum lactate dehydrogenase, creatine kinase isoenzyme, and troponin; lowered the levels of TGF-ß1, TNF-α and IL-1ß in serum and myocardium; decreased the concentration of MDA and increased SOD activity in myocardium of db/db mice; inhibited M1 macrophages; and promoted M2 macrophages. CONCLUSION: Administration of atorvastatin attenuates myocardial fibrosis in db/db mice, which may be associated with the antioxidative stress and anti-inflammatory effects of atorvastatin on diabetic myocardium through modulating macrophage polarization.

Empagliflozin ameliorates diabetic cardiomyopathy probably via activating AMPK/PGC-1α and inhibiting the RhoA/ROCK pathway.

BACKGROUND: Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear. AIM: To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism. METHODS: Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels. RESULTS: In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 µM) or fasudil (FA) (a ROCK inhibitor, 100 µM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes. CONCLUSION: Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.

A Genome-Wide Analysis of StTGA Genes Reveals the Critical Role in Enhanced Bacterial Wilt Tolerance in Potato During Ralstonia solanacearum Infection.

TGA is one of the members of TGACG sequence-specific binding protein family, which plays a crucial role in the regulated course of hormone synthesis as a stress-responsive transcription factor (TF). Little is known, however, about its implication in response to bacterial wilt disease in potato (Solanum tuberosum) caused by Ralstonia solanacearum. Here, we performed an in silico identification and analysis of the members of the TGA family based on the whole genome data of potato. In total, 42 StTGAs were predicted to be distributed on four chromosomes in potato genome. Phylogenetic analysis showed that the proteins of StTGAs could be divided into six sub-families. We found that many of these genes have more than one exon according to the conserved motif and gene structure analysis. The heat map inferred that StTGAs are generally expressed in different tissues which are at different stages of development. Genomic collinear analysis showed that there are homologous relationships among potato, tomato, pepper, Arabidopsis, and tobacco TGA genes. Cis-element in silico analysis predicted that there may be many cis-acting elements related to abiotic and biotic stress upstream of StTGA promoter including plant hormone response elements. A representative member StTGA39 was selected to investigate the potential function of the StTGA genes for further analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) assays indicated that the expression of the StTGAs was significantly induced by R. solanacearum infection and upregulated by exogenous salicylic acid (SA), abscisic acid (ABA), gibberellin 3 (GA3), and methyl jasmonate (MeJA). The results of yeast one-hybrid (Y1H) assay showed that StTGA39 regulates S. tuberosum BRI1-associated receptor kinase 1 (StBAK1) expression. Thus, our study provides a theoretical basis for further research of the molecular mechanism of the StTGA gene of potato tolerance to bacterial wilt.

Water quality assessment based on Nemerow pollution index method: A case study of Heilongtan reservoir in central Sichuan province, China.

In this paper, three monitoring sections were set up in Heilongtan Reservoir, and water samples were collected in 2019, 2020, and 2021 for the determination of physical and chemical properties such as permanganate index, chemical oxygen demand, and biochemical oxygen demand (BOD5). The water quality was evaluated by the single factor pollution index method and the Nemerow pollution index method, and the temporal and spatial changes of water quality were analyzed.The single factor pollution index method determines the water quality category by identifying the single worst indicator of water quality, based on the classified water quality category. The Nemerow pollution index method emphasizes the most polluting factor while also taking into account the contribution of other factors in the assessment system, and determines the water quality category through the comprehensive pollution index. The results of the study indicate that the monitoring indicators of the monitoring sections have reached the Category III water quality standard and above in the "Surface Water Environmental Quality Standard" during the three years 2019 to 2021. The Heilongtan Reservoir's water quality in 2019, 2020, and 2021 is of Category I standard, according to the results of the evaluation of water quality using the single factor pollution index technique. According to the Nemerow pollution index method's results for evaluating water quality, the water quality pollution index for the three monitoring sections as a whole ranges from 0.36 to 0.51 in three years. The three monitoring sections' water quality-Dongfeng Canal, Longmiao, and Sixin Village-has not changed significantly during that time, remaining clean. In terms of temporal and spatial rates of change, the temporal rate of change (T) and spatial rate of change (S) over the three years were less than 20%, and the changes in water quality at each monitoring site were not significant.

Synthesis and fluorescent properties of europium(III) complexes based on novel coumarin derivatives.

Four novel coumarin fluorescence small-molecules were successfully prepared and validated by proton nuclear magnetic resonance (1 H-NMR), carbon-13 (13 C)-NMR, and mass spectrometry (MS). Their corresponding europium(III) complexes were synthesized and characterized. The ligand can emit green fluorescence in solutions, and the best concentration was 40 µmol/L. The emission peak of ligand has a red-shift with the increase of concentration and solvent polarity. And the effect of various substituents in ligand was ordered using fluorescence intensity as standard: -NO2 > -Cl > -OCH3 > -OH. The order of fluorescence quantum yield is in line with the order of fluorescence intensity. The title europium complexes exhibit red fluorescence of europium ion (Eu3+ ) with good thermal stability. The effect of various substituents in ligand on the fluorescence intensity of title europium complexes was also consistent with the earlier results. This suggests that the prepared coumarins fluorescence small-molecules and their corresponding europium complexes have potential application prospects in the field of optical materials.

The cssR gene of Corynebacterium glutamicum plays a negative regulatory role in stress responses.

BACKGROUND: CssR, the product of the Corynebacterium glutamicum ncgl1578 gene cotranscribed with ncgl1579, is a TetR (tetracycline regulator) family repressor. Although many TetR-type regulators in C. glutamicum have been extensively described, members of the TetR family involved in the stress response remain unidentified. RESULTS: In this study, we found that CssR regulated the transcription of its own gene and the ncgl1576-ncgl1577 operon. The ncgl1576-ncgl1577 operon, which is located upstream of cssR in the orientation opposite that of the cssR operon, encodes an ATP-binding cassette (ABC), some of which are involved in the export of a wide range of antimicrobial compounds. The cssR-deletion (ΔcssR) mutant displayed increased resistance to various stresses. An imperfect palindromic motif (5'-TAA(G)TGN13CA(G)TTA-3'; 25 bp) located at the intergenic region between cssR and ncgl1577 was identified as the sole binding site for CssR. Expression of cssR and ncgl1577 was induced by antibiotics and heavy metals but not H2O2 or diamide, and the DNA-binding activity of CssR was impaired by antibiotics and heavy metals but not H2O2. Antibiotics and heavy metals caused CssR dissociation from target gene promoters, thus derepressing their transcription. Oxidant treatment neither altered the conformation of CssR nor modified its cysteine residues, indicating that the cysteine residues in CssR have no redox activity. In the ΔcssR mutant strain, genes involved in redox homeostasis also showed increased transcription levels, and the NADPH/NADP+ ratio was higher than that of the parental strain. CONCLUSION: The stress response mechanism of CssR in C. glutamicum is realized via ligand-induced conformational changes of the protein, not via cysteine oxidation-based thiol modification. Moreover, the crucial role of CssR in the stress response was demonstrated by negatively controlling the expression of the ncgl1576-ncgl1577 operon, its structural gene, and/or redox homeostasis-related genes.

Exploration of hosts and transmission traits for SARS-CoV-2 based on the k-mer natural vector.

A severe respiratory pneumonia COVID-19 has raged all over the world, and a coronavirus named SARS-CoV-2 is blamed for this global pandemic. Despite intensive research into the origins of the COVID-19 pandemic, the evolutionary history of its agent SARS-CoV-2 remains unclear, which is vital to control the pandemic and prevent another round of outbreak. Coronaviruses are highly recombinogenic, which are not well handled with alignment-based method. In addition, deletions have been found in the genomes of several SARS-CoV-2, which cannot be resolved with current phylogenetic methods. Therefore, the k-mer natural vector is proposed to explore hosts and transmission traits for SARS-CoV-2 using strict phylogenetic reconstruction. SARS-CoV-2 clustering with bat-origin coronaviruses strongly suggests bats to be the natural reservoir of SARS-CoV-2. By building bat-to-human transmission route, pangolin is identified as an intermediate host, and civet is predicted as a possible candidate. We speculate that SARS-CoV-2 undergoes cross-species recombination between bat and pangolin coronaviruses. This study also demonstrates transmission mode and features of SARS-CoV-2 in the COVID-19 pandemic when it broke out early around the world.

Tf2O/DMSO-Promoted P-O and P-S Bond Formation: A Scalable Synthesis of Multifarious Organophosphinates and Thiophosphates.

A Tf2O/DMSO-based system for the dehydrogenative coupling of a wide range of alcohols, phenols, thiols, and thiophenols with diverse phosphorus reagents has been developed. This metal- and strong-oxidant-free strategy provides a facile approach to a great variety of organophosphinates and thiophosphates. The simple reaction system, good functional-group tolerance, and broad substrate scope enable the application of this method to the modification of natural products and the direct synthesis of bioactive molecules and flame retardants.

Psychological Stress Up-Regulates CD147 Expression Through Beta-Arrestin1/ERK to Promote Proliferation and Invasiveness of Glioma Cells.

Psychological stress is closely related to the occurrence and prognosis of various malignant tumors, but the underlying mechanisms are not well studied. CD147 has been reported to be expressed in glioma and other malignant tumors. CD147 not only participates in lactic acid transport, but it also plays an important role in the invasion and metastasis of malignant tumor cells by stimulating the production of numerous matrix metalloproteinases (MMPs) and vascular endothelial growth factor by fibroblasts, and could also act as an autocrine factor stimulating MMPs production in metastatic tumor cells. Here, we found that silencing CD147 in chronically stressed nude mice not only inhibited the proliferation of xenografts but also decreased matrix metalloproteinase-2, 9 expression and lactic acid content in tumor tissues. Furthermore, norepinephrine (NE) was significantly increased in the serum of nude mice in glioma stress model. To determine the underlying cellular mechanism, we added exogenous NE into LN229 and U87 cells to simulate the stress environment in vitro. The invasiveness of the glioma cells was subsequently examined using a Matrigel invasion assay. We demonstrated that knockdown of CD147 inhibited glioma invasiveness and metastasis with norepinephrine stimulation. Luciferase reporter gene experiments further demonstrated that the expression of CD147 is up-regulated primarily by norepinephrine via the ß-Adrenalin receptor (ßAR)-ß-arrestin1-ERK1/2-Sp1 pathway. High expression of CD147 promoted the secretion of MMP-2 and the increment of lactic acid, which accelerated the augmented invasion and metastasis of glioma induced by psychological stress. Taken together, these results suggest that psychological stress promotes glioma proliferation and invasiveness by up-regulating CD147 expression. Thus, CD147 might be a potential target site in the treatment of glioma progression induced by chronic psychological stress.

Morphometric Trajectory Analysis for Occipital Condyle Screws.

OBJECTIVES: Occipitocervical fusion (OCF) is an effective treatment for instability of occipitocervical junction (OCJ). The occipital condyle screw serves as a novel surgical technique for occipitocervical fixation. However, the intraoperative procedures for the occipital condyle screw technique have relied on surgeons' experience, so the pool of surgeons who are able to perform this surgery safely is limited. The present study aims to evaluate the feasibility and safety of the occipital condyle screw technique using human cadavers and to provide image anatomy for clinical application basis. METHODS: The scientific study comprised 10 fresh-frozen cadaveric specimens from the anatomy department of Qingdao University. Placement of the occipital condyle screws (3.5 mm diameter and 20.0 mm length) was performed in the 10 fresh-frozen cadaveric specimens with intact occipitocervical junctions, respectively. Occipitocervical CT was performed for all specimens and the DICOM data was obtained. Occipitocervical CT three-dimensional (3D) reconstruction was performed for the cadavers. Morphometric analysis was performed on the bilateral occipitocervical junction of 10 cadaveric specimens based on the 3D reconstruction CT images. Detailed morphometric measurements of the 20 occipital condyles screws were conducted including the average length of the screw trajectory, inside and upper tilting angles of screws, distance to the hypoglossal canal, and to the medial wall of occipital condyle. RESULTS: Placement of the occipital condyle screws into the 20 occipital condyles of the 10 cadaveric specimens was performed successfully and the trajectory of implantation was satisfactory according to 3D CT reconstruction images, respectively. There was no obvious injury to the spinal cord, nerve root, and vertebral artery. The length of the bilateral screw trajectory was, respectively, 20.96 ± 0.91 mm (left) and 20.59 ± 0.77 mm (right) (t = 1.306, P > 0.05). The upper tilting angle of bilateral screws was, respectively, 11.24° ± 0.74° (left) and 11.11° ± 0.64° (right) (t = 0.681, P > 0.05). The inside tilting angle of bilateral screws was, respectively, 31.00° ± 1.32° (left) and 30.85° ± 1.27° (right) (t = 0.307, P > 0.05). The screw's distance to the bilateral hypoglossal canal was, respectively, 4.84 ± 0.54 mm (left) and 4.70 ± 0.54 mm (right) (t = 0.685, P > 0.05). The screw's distance to the medial wall of the bilateral occipital condyle was, respectively, 5.13 ± 0.77 mm (left) and 5.04 ± 0.71 mm (right) (t = 0.384, P > 0.05). CONCLUSION: The occipital condyle screw technique can serve as a feasible and safe treatment for instability of the occipitocervical junction with meticulous preoperative planning of the screw entry point and direction based on individual differences. Morphometric trajectory analysis is also an effective way to evaluate the surgical procedure.

Thioredoxin and protein-disulfide isomerase selectivity for redox regulation of proteins in Corynebacterium glutamicum.

Thioredoxins (Trxs) and protein-disulfide isomerases (PDIs) are believed to play a pivotal role in ensuring the proper folding of proteins, facilitating appropriate functioning of proteins, and maintaining intracellular redox homeostasis in bacteria. Two thioredoxins (Trxs) and three thiol-disulfide isomerases (PDIs) have been annotated in Corynebacterium glutamicum. However, nothing is known about their functional diversity in the redox regulation of proteins. Thus, we here analyzed the Trx- and PDI-dependent redox shifts of ribonucleotide reductase (RNR), insulin, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), and several thiol-dependent peroxidases by measuring enzyme activity and thiol status in vitro. We found that the two Trxs and the three PDIs had activities in the cleavage of the disulfidebond, whereas the PDIs had a lower efficiency than the two Trxs. Trx2 could activate thiol-dependent peroxidases with an efficiency comparable with that of Trx1, but the PDIs were inefficient. The redox-active Cys-X-X-Cys motif harbored in both Trxs and PDIs was essential to supply efficiently the donor of reducing equivalents for protein disulfides. In addition, stress-responsive extracytoplasmic function (ECF)-sigma factor H (SigH)-dependent Trxs and PDIs expressions were observed. These results contributed importantly to our overall understanding of reducing functionality of the Trx and PDI systems, and also highlighted the complexity and plasticity of the intracellular redox network.

CarR, a MarR-family regulator from Corynebacterium glutamicum, modulated antibiotic and aromatic compound resistance.

MarR (multiple antibiotic resistance regulator) proteins are a family of transcriptional regulators that is prevalent in Corynebacterium glutamicum. Understanding the physiological and biochemical function of MarR homologs in C. glutamicum has focused on cysteine oxidation-based redox-sensing and substrate metabolism-involving regulators. In this study, we characterized the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator CarR (C. glutamicum antibiotic-responding regulator). We demonstrate that CarR negatively regulates the expression of the carR (ncgl2886)-uspA (ncgl2887) operon and the adjacent, oppositely oriented gene ncgl2885, encoding the hypothetical deacylase DecE. We also show that CarR directly activates transcription of the ncgl2882-ncgl2884 operon, encoding the peptidoglycan synthesis operon (PSO) located upstream of carR in the opposite orientation. The addition of stress-associated ligands such as penicillin and streptomycin induced carR, uspA, decE, and PSO expression in vivo, as well as attenuated binding of CarR to operator DNA in vitro. Importantly, stress response-induced up-regulation of carR, uspA, and PSO gene expression correlated with cell resistance to ß-lactam antibiotics and aromatic compounds. Six highly conserved residues in CarR were found to strongly influence its ligand binding and transcriptional regulatory properties. Collectively, the results indicate that the ligand binding of CarR induces its dissociation from the carR-uspA promoter to derepress carR and uspA transcription. Ligand-free CarR also activates PSO expression, which in turn contributes to C. glutamicum stress resistance. The outcomes indicate that the stress response mechanism of CarR in C. glutamicum occurs via ligand-induced conformational changes to the protein, not via cysteine oxidation-based thiol modifications.

OsmC in Corynebacterium glutamicum was a thiol-dependent organic hydroperoxide reductase.

Bacterial antioxidants play a vital role in the detoxification of exogenous peroxides. Several antioxidant defenses including low-molecular-weight thiols (LMWTs) and protective enzymes were developed to help the bacterium withstand the adverse stress. Although osmotically induced bacterial protein C (OsmC), classified as the organic hydroperoxide reductase (Ohr)/OsmC superfamily, has been demonstrated in some mycobacterial species, including M. tuberculosis and M. smegmatis, its physiological and biochemical functions in C. glutamicum remained elusive. Here we found the lack of C. glutamicum osmC gene resulted in decreased cell viability and increased intracellular reactive oxygen species accumulation under organic hydroperoxides (OHPs) stress conditions. The osmC expression was induced in the multiple antibiotic resistance regulator MarR-dependent manner by OHPs, and not by other oxidants or osmotic stress. Peroxide reductase activity showed that OsmC had a narrow range of substrates-only degrading OHPs, and detoxified OHPs mainly by linking the alkyl hydroperoxide reductase (AhpD) system (AhpD/dihydrolipoamide dehydrogenase (Lpd)/dihydrolipoamide acyltransferase (SucB)). Site-directed mutagenesis confirmed Cys48 was the peroxidatic cysteine, while Cys114 was the resolving Cys residue that formed an intramolecular disulfide bond with oxidized Cys48. Therefore, C. glutamicum OsmC was a thiol-dependent OHP reductase and played important role of protection against OHPs together with Ohr.