Enantioselective Arylation of Sulfenamides to Access Sulfilimines Enabled by Palladium Catalysis.

Sulfur-containing functional groups have garnered considerable attention owing to their frequent occurrence in ligands, pharmaceuticals and insecticides. However, enantioselective synthesis of sulfilimines, particularly diaryl sulfilimines remains a challenging and long-standing goal. Herein we report a highly enantio- and chemoselective cross-coupling of sulfenamides with aryl electrophiles to construct diverse S(IV) stereocenters by Pd catalysis. Bisphosphine ligands bearing sulfinamide groups were crucial for attaining high reactivity and selectivity. This strategy offers a general, modular and divergent platform for rapid synthesis of chiral sulfilimines and sulfoximines that are otherwise difficult to access. Furthermore, the origins of the high chemoselectivity and enantioselectivity were extensively investigated using density functional theory calculations.

Avoiding threats, but not acquiring benefits, explains the effect of future time perspective on promoting health behavior.

Promoting health behavior among the public is always a pressing issue. The present research systematically investigated the association between future time perspective and adherence to health behavior including dietary habits, physical activities, and substance use in a Chinese college student sample (N = 519). Results showed that individuals with stronger future time perspective were more likely to adhere to health behavior. Moreover, building upon the health belief model and the protection motivation theory, the present research further explored the underlying mechanisms. Results revealed that it is perceived threats of not carrying out health behavior, but not perceived benefits of carrying out health behavior, that asymmetrically explained the association between stronger future time perspective and greater adherence to health behavior. These findings contribute to both the future time perspective literature and the health behavior literature.

Spatial position is a key determinant of N-glycan functionality of the scavenger receptor cysteine-rich domain of human hepsin.

The scavenger receptor cysteine-rich (SRCR) domain is a key constituent in diverse proteins. N-glycosylation is important in protein expression and function. In the SRCR domain of different proteins, N-glycosylation sites and functionality vary substantially. In this study, we examined the importance of N-glycosylation site positions in the SRCR domain of hepsin, a type II transmembrane serine protease involved in many pathophysiological processes. We analysed hepsin mutants with alternative N-glycosylation sites in the SRCR and protease domains using three-dimensional modelling, site-directed mutagenesis, HepG2 cell expression, immunostaining, and western blotting. We found that the N-glycan function in the SRCR domain in promoting hepsin expression and activation on the cell surface cannot be replaced by alternatively created N-glycans in the protease domain. Within the SRCR domain, the presence of an N-glycan in a confined surface area was essential for calnexin-assisted protein folding, endoplasmic reticulum (ER) exiting, and zymogen activation of hepsin on the cell surface. Hepsin mutants with alternative N-glycosylation sites on the opposite side of the SRCR domain were trapped by ER chaperones, resulting in the activation of the unfolded protein response in HepG2 cells. These results indicate that the spatial N-glycan positioning in the SRCR domain is a key determinant in the interaction with calnexin and subsequent cell surface expression of hepsin. These findings may help to understand the conservation and functionality of N-glycosylation sites in the SRCR domains of different proteins.

A world together: Global citizen identification as a basis for prosociality in the face of COVID-19.

How do global citizens respond to a global health emergency? The present research examined the association between global citizen identification and prosociality using two cross-national datasets-the World Values Survey (Study 1, N = 93,338 from 60 countries and regions) and data collected in 11 countries at the start of the COVID-19 pandemic (Study 2, N = 5,427). Results showed that individuals who identified more strongly as global citizens reported greater prosociality both generally (Study 1) and more specifically in the COVID-19 global health emergency (Study 2). Notably, global citizen identification was a stronger predictor of prosociality in response to COVID-19 than national identification (Study 2). Moreover, analyses revealed that shared ingroup identity accounted for the positive association between global citizen identification and prosociality (Study 2). Overall, these findings highlight global citizenship as a unique and promising direction in promoting prosociality and solidarity, especially in the fight against COVID-19.

Renal Corin Is Essential for Normal Blood Pressure and Sodium Homeostasis.

Atrial natriuretic peptide (ANP)-mediated natriuresis is known as a cardiac endocrine function in sodium and body fluid homeostasis. Corin is a protease essential for ANP activation. Here, we studied the role of renal corin in regulating salt excretion and blood pressure. We created corin conditional knockout (cKO), in which the Corin gene was selectively disrupted in the kidney (kcKO) or heart (hcKO). We examined the blood pressure, urinary Na+ and Cl- excretion, and cardiac hypertrophy in wild-type, corin global KO, kcKO, and hcKO mice fed normal- and high-salt diets. We found that on a normal-salt diet (0.3% NaCl), corin kcKO and hcKO mice had increased blood pressure, indicating that both renal and cardiac corin is necessary for normal blood pressure in mice. On a high-salt diet (4% NaCl), reduced urinary Na+ and Cl- excretion, increased body weight, salt-exacerbated hypertension, and cardiac hypertrophy were observed in corin kcKO mice. In contrast, impaired urinary Na+ and Cl- excretion and salt-exacerbated hypertension were not observed in corin hcKO mice. These results indicated that renal corin function is important in enhancing natriuresis upon high salt intakes and that this function cannot be compensated by the cardiac corin function in mice.

Transmembrane serine protease TMPRSS2 implicated in SARS-CoV-2 infection is autoactivated intracellularly and requires N-glycosylation for regulation.

Transmembrane protease serine 2 (TMPRSS2) is a membrane-bound protease expressed in many human epithelial tissues, including the airway and lung. TMPRSS2-mediated cleavage of viral spike protein is a key mechanism in severe acute respiratory syndrome coronavirus 2 activation and host cell entry. To date, the cellular mechanisms that regulate TMPRSS2 activity and cell surface expression are not fully characterized. In this study, we examined two major post-translational events, zymogen activation and N-glycosylation, in human TMPRSS2. In experiments with human embryonic kidney 293, bronchial epithelial 16HBE, and lung alveolar epithelial A549 cells, we found that TMPRSS2 was activated via intracellular autocatalysis and that this process was blocked in the presence of hepatocyte growth factor activator inhibitors 1 and 2. By glycosidase digestion and site-directed mutagenesis, we showed that human TMPRSS2 was N-glycosylated. N-glycosylation at an evolutionarily conserved site in the scavenger receptor cysteine-rich domain was required for calnexin-assisted protein folding in the endoplasmic reticulum and subsequent intracellular trafficking, zymogen activation, and cell surface expression. Moreover, we showed that TMPRSS2 cleaved severe acute respiratory syndrome coronavirus 2 spike protein intracellularly in human embryonic kidney 293 cells. These results provide new insights into the cellular mechanism in regulating TMPRSS2 biosynthesis and function. Our findings should help to understand the role of TMPRSS2 in major respiratory viral diseases.

Meaning in life as a mediator of dark triad with confidence in treatment and subjective evaluation of treatment outcome among male drug abstainers.

Background: Although the roles of personality in predicting substance abuse have been widely documented, few studies have investigated the relationships the dark triad (DT) personalities had with confidence in treatment (CIT) and subjective evaluation of treatment outcome (SETO) in drug abstainers. Objective: This study examined the relationship between DT and treatment-relevant variables, and the potential effect of meaning in life (MIL) in these links. Methods: Participants were male inpatients who started substance abuse treatment between June and December 2018 in Henan Province, China. The inclusion criteria were the diagnosis of substance use disorders. The exclusion criteria were illiteracy, comorbidity with psychopathology disorders, intellectual disability, and refusal of consent. A total of 236 men (aged 21-62 years, M = 45.30, SD = 7.72) were randomly selected and reported their DT, MIL, CIT, and SETO. Results: Results showed that DT was negatively correlated with MIL, CIT, and SETO. MIL was positively correlated with CIT and SETO. The dark triad is associated with CIT both directly and indirectly via MIL. DT is indirectly correlated with SETO via MIL. Higher levels of DT in drug abstainers can reduce CIT and SETO by decreasing individual's MIL. Conclusion: This study provides insights into the links between the DT and treatment-relevant variables, which can potentially impact the effectiveness of current substance abuse treatment programs.

Differential Eating Behavior Patterns among the Dark Triad.

There is little extant empirical literature examining the associations between Dark Triad (DT: Machiavellianism, narcissism, and psychopathy) and eating behaviors. The current study (n = 361) investigated the associations between Dark Triad and restrained eating, uncontrolled eating, and emotional eating in a sample drawn from the general population. The results from the study indicate that (a) despite expected sex differences in narcissism and primary psychopathy, no sex differences were found in Machiavellianism, secondary psychopathy, and eating behaviors; (b) among women, Machiavellianism was a protective factor against uncontrolled eating behaviors; (c) the sex of the participant moderated the narcissism-uncontrolled eating behaviors and narcissism-emotional eating behaviors relationships, with the negative correlation being stronger for men than that for women; (d) secondary psychopathy, rather than primary psychopathy, was associated with higher uncontrolled eating behaviors in both sexes, and associated with higher emotional eating behaviors for men only. The implication of these findings are interpreted and discussed.

CD320 expression and apical membrane targeting in renal and intestinal epithelial cells.

Vitamin B12 is an essential nutrient acquired via dietary intake. Receptor-mediated endocytosis is a key mechanism in vitamin B12 absorption, cellular uptake, and reabsorption. CD320 is a type I transmembrane protein responsible for cellular uptake of vitamin B12 in peripheral tissues. In this study, we examined segmental distribution and cellular expression of CD320 in mouse kidneys and intestines. We show that CD320 is expressed on the luminal surface in the small intestine and in proximal tubules in the kidney, suggesting that, in addition to its role in vitamin B12 uptake in peripheral tissues, CD320 may participate in vitamin B12 absorption in the small intestine and reabsorption in the kidney. Moreover, we show that an amino acid motif, DSSDE, in the second low-density lipoprotein receptor class A domain of CD320 is a key apical membrane targeting signal in both renal and intestinal epithelial cells. Mutations or deletion of this motif abolish the specific apical membrane expression of CD320 in polarized Madin-Darby canine kidney cells and human colon cancer-derived Caco-2 cells. In short-hairpin RNA-based gene knockdown experiments, we show that the apical membrane targeting of CD320 is mediated by a Rab11a-dependent mechanism. These results extend our knowledge regarding the cell biology of CD320 and its role in vitamin B12 metabolism.

Hepsin: a multifunctional transmembrane serine protease in pathobiology.

Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

A conserved LDL-receptor motif regulates corin and CD320 membrane targeting in polarized renal epithelial cells.

Selective protein distribution on distinct plasma membranes is important for epithelial cell function. To date, how proteins are directed to specific epithelial cell surface is not fully understood. Here we report a conserved DSSDE motif in LDL-receptor (LDLR) modules of corin (a transmembrane serine protease) and CD320 (a receptor for vitamin B12 uptake), which regulates apical membrane targeting in renal epithelial cells. Altering this motif prevents specific apical corin and CD320 expression in polarized Madin-Darby canine kidney (MDCK) cells. Mechanistic studies indicate that this DSSDE motif participates in a Rab11a-dependent mechanism that specifies apical sorting. In MDCK cells, inhibition of Rab11a, but not Rab11b, expression leads to corin and CD320 expression on both apical and basolateral membranes. Together, our results reveal a novel molecular recognition mechanism that regulates LDLR module-containing proteins in their specific apical expression in polarized renal epithelial cells.

Function and regulation of corin in physiology and disease.

Atrial natriuretic peptide (ANP) is of major importance in the maintenance of electrolyte balance and normal blood pressure. Reduced plasma ANP levels are associated with the increased risk of cardiovascular disease. Corin is a type II transmembrane serine protease that converts the ANP precursor to mature ANP. Corin deficiency prevents ANP generation and alters electrolyte and body fluid homeostasis. Corin is synthesized as a zymogen that is proteolytically activated on the cell surface. Factors that disrupt corin folding, intracellular trafficking, cell surface expression, and zymogen activation are expected to impair corin function. To date, CORIN variants that reduce corin activity have been identified in hypertensive patients. In addition to the heart, corin expression has been detected in non-cardiac tissues, where corin and ANP participate in diverse physiological processes. In this review, we summarize the current knowledge in corin biosynthesis and post-translational modifications. We also discuss tissue-specific corin expression and function in physiology and disease.

Intracellular autoactivation of TMPRSS11A, an airway epithelial transmembrane serine protease.

Type II transmembrane serine proteases (TTSPs) are a group of enzymes participating in diverse biological processes. Some members of the TTSP family are implicated in viral infection. TMPRSS11A is a TTSP expressed on the surface of airway epithelial cells, which has been shown to cleave and activate spike proteins of the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome coronaviruses (CoVs). In this study, we examined the mechanism underlying the activation cleavage of TMPRSS11A that converts the one-chain zymogen to a two-chain enzyme. By expression in human embryonic kidney 293, esophageal EC9706, and lung epithelial A549 and 16HBE cells, Western blotting, and site-directed mutagenesis, we found that the activation cleavage of human TMPRSS11A was mediated by autocatalysis. Moreover, we found that TMPRSS11A activation cleavage occurred before the protein reached the cell surface, as indicated by studies with trypsin digestion to remove cell surface proteins, treatment with cell organelle-disturbing agents to block intracellular protein trafficking, and analysis of a soluble form of TMPRSS11A without the transmembrane domain. We also showed that TMPRSS11A was able to cleave the SARS-CoV-2 spike protein. These results reveal an intracellular autocleavage mechanism in TMPRSS11A zymogen activation, which differs from the extracellular zymogen activation reported in other TTSPs. These findings provide new insights into the diverse mechanisms in regulating TTSP activation.

N-glycan in the scavenger receptor cysteine-rich domain of hepsin promotes intracellular trafficking and cell surface expression.

The group A scavenger receptor cysteine-rich (SRCR) domain is a conserved module present in numerous proteins involved in diverse biological processes. Hepsin, a hepatic protease implicated in many cancers, consists of a cytoplasmic tail, a transmembrane domain and an extracellular regions with a group A SRCR domain and a serine protease domain. Like in many SRCR-containing proteins, the SRCR domain in hepsin has an N-glycosylation site, but its functional significance is unknown. In this study, we confirmed N-glycosylation at Asn112 in hepsin by glycosidase digestion and site-directed mutagenesis in human hepatoma cells. In Western blotting, fluorogenic substrate assay, flow cytometry, and protein-chase experiments, we found that Asn112 to Gln (N112Q) mutation inhibited hepsin intracellular trafficking, cell surface expression, and zymogen activation. By immunofluorescent staining, we found that the N112Q mutant was more abundant than wild-type hepsin in the endoplasmic reticulum (ER). Further co-immunoprecipitation studies indicated increased binding of the N112Q mutant to calnexin and binding-immunoglobulin protein (BiP), two ER chaperones. Our results indicate that the N-glycan in the SRCR domain of hepsin promotes intracellular trafficking and cell surface expression, possibly by a calnexin-dependent mechanism in facilitating ER exiting.

Autoactivation and calpain-1-mediated shedding of hepsin in human hepatoma cells.

Hepsin is a transmembrane serine protease implicated in many biological processes, including hepatocyte growth, urinary protein secretion, auditory nerve development, and cancer metastasis. Zymogen activation is critical for hepsin function. To date, how hepsin is activated and regulated in cells remains an enigma. In this study, we conducted site-directed mutagenesis, cell expression, plasma membrane protein labeling, trypsin digestion, Western blotting, and flow cytometry experiments in human hepatoma HepG2 cells, where hepsin was originally discovered, and SMMC-7721 cells. Our results show that hepsin is activated by autocatalysis on the cell surface but not intracellularly. Moreover, we show that hepsin undergoes ectodomain shedding. In the conditioned medium from HepG2 and SMMC-7721 cells, we detected a soluble fragment comprising nearly the entire extracellular region of hepsin. By testing protease inhibitors, gene knockdown, and site-directed mutagenesis, we identified calpain-1 as a primary protease that acted extracellularly to cleave Tyr52 in the juxtamembrane space of hepsin. These results provide new insights into the biochemical and cellular mechanisms that regulate hepsin expression and activity.

Study of intra-abdominal hypertension prevalence and awareness level among experienced ICU medical staff.

BACKGROUND: Intra-abdominal hypertension (IAH) is a disease with high morbidity and mortality among critically ill patients. The study's objectives were to explore the prevalence of IAH and physicians' awareness of the 2013 World Society of Abdominal Compartment Syndrome (WSACS) guidelines in Chinese intensive care units (ICUs). METHODS: A cross-sectional study of four ICUs in Southwestern China was conducted from June 17 to August 2, 2014. Adult patients admitted to the ICU for more than 24 h, with bladder catheter but without obvious intravesical pressure (IVP) measurement contraindications, were recruited. Intensivists with more than 5 years of ICU working experience were also recruited. Epidemiological information, potential IAH risk factors, IVP measurements and questionnaire results were recorded. RESULTS: Forty-one patients were selected. Fifteen (36.59 %) had IVP ≥ 12 mmHg. SOFA (Sequential Organ Failure Assessment) hepatic and neurological sub-scores were utilized as independent predictors for IAH via logistic backward analysis. Thirty-seven intensivists participated in the survey (response rate: 80.43 %). The average score of each center was less than 35 points. All physicians believed the IAH prevalence in their departments was no more than 20.00 %. A significant negative correlation was observed between the intensivists' awareness of the 2013 WSACS guidelines and the IAH prevalence in each center (r = -0.975, P = 0.025). CONCLUSIONS: The prevalence and independent predictors of IAH among the surveyed population are similar to the reports in the literature. Intensivists generally have a low awareness of the 2013 WSACS guidelines. A systematic guideline training program is vital for improving the efficiency of the diagnosis and treatment of IAH.

The effect of different types of abdominal binders on intra-abdominal pressure.

OBJECTIVES: To investigate the effect of non-elastic/elastic abdominal binders on intra-vesical pressure (IVP), physiological functions, and clinical outcomes in laparotomy patients at the perioperative stage.  METHODS: This prospective study was conducted from May to October 2014 at the Trauma Surgery Department, Daping Hospital, Chongqing, China. Laparotomy patients were randomly divided into non-elastic abdominal binder group (28 patients), and elastic abdominal binder group (29 patients). Binders were applied for 14 days following the operation, or until discharge. Demographic information, Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation  II (APACHE-II) scores (prior to the operation, on the first day after operation, the day IVP measurement was stopped, and one day before discharge), and outcomes were recorded. The IVP was measured before the operation to postoperative day 7. RESULTS: There were no significant differences in the demographic information, outcomes, SOFA or APACHE-II scores between the 2 groups. Initial out-of-bed mobilization occurred earlier in the elastic binder group (3.2 ± 2.0 versus 5.0 ± 3.7 days, p=0.028). A greater increase in IVP was observed in the non-elastic binder group than in the elastic binder group (2.9 ± 1.1 versus 1.1 ± 0.7 mm Hg, p=0.000). CONCLUSION: Elastic binders have relatively little effect on IVP and are more helpful at promoting postoperative recovery than non-elastic binders. Therefore, elastic binders are more suitable for clinical use.

"One-stop hybrid procedure" in the treatment of vascular injury of lower extremity.

As a new surgical technique, "one-stop hybrid procedure" is rarely applied in trauma patients. This paper aims to explore its role in vascular injury of the lower extremity. Vascular intervention combined with open surgery was performed to treat three cases of vessel injuries of the lower extremity in our hybrid operating room. One patient with stab injury to the left femoral vein was treated by temporary artery blocking after excluding arterial injury by angiography, followed by blocking surgery and debridement and repair of the injured vein. The other two patients with drug addiction history, who were found to have pricking injuries to the femoral artery combined with local infection, were successfully treated by endovascular techniques and open debridement. One-stop hybrid procedure in treating vascular injury patients could simplify the operation procedure, reduce operative risk, and achieve good curative effect.

Prevalence and diagnosis rate of intra-abdominal hypertension in critically ill adult patients: A single-center cross-sectional study.

PURPOSE: To investigate the prevalence and diagnosis rate of intra-abdominal hypertension (IAH) in a mixed-population intensive care unit (ICU), and to investigate the knowledge of ICU staff regarding the guidelines published by the World Society of Abdominal Compartment Syndrome (WSACS) in 2013. METHODS: A one-day cross-sectional study based on the WSACS 2013 guidelines was conducted in the general ICU of a tertiary teaching hospital in Chongqing, China. The included patients were divided into intravesical pressure (IVP) measured group and IVP unmeasured group. The epidemiologic data were recorded, and potential IAH risk factors (RFs) were collected based on the guidelines. IVP measurements were conducted by investigators every 4 h and the result was compared to that measured by the ICU staff to evaluate the diagnosis rate. Besides, a questionnaire was used to investigate the understanding of the guidelines among ICU staff. RESULTS: Thirty-two patients were included, 14 in the IVP measured group and 18 in the IVP unmeasured group. The prevalence of IAH during the survey was 15.63% (5/32), 35.71% (5/14) in IVP measured group. Only one case of IAH had been diagnosed by the ICU physician and the diagnosis rate was as low as 20.00%. Logistic regression analysis showed that sequential organ failure assessment (SOFA) score was an independent RF for IAH (OR: 1.532, 95% CI: 1.029-2.282, p=0.036. Fourteen doctors and 5 nurses were investigated and the response rate was 67.86%. The average scores of the doctors and nurses were 27.14±20.16 and 16.00±8.94 respectively. None of them had studied the WSACS 2013 guidelines thoroughly. CONCLUSION: Patients with a higher SOFA score has a higher incidence of IAH. The IAH prevalence in 14 ICU patients with indwelling catheter was 35.71%. Strengthening the wide and rational use of WSACS guideline is important to improve the diagnosis of IAH.

Cultural adaptation in measuring common client characteristics with an urban Mainland Chinese sample.

OBJECTIVES: This study aimed to develop a culturally adapted version of the Systematic Treatment Selection-Innerlife (STS) in China. METHODS: A total of 300 nonclinical participants collected from Mainland China and 240 nonclinical US participants were drawn from archival data. A Chinese version of the STS was developed, using translation and back-translation procedures. After confirmatory factor analysis (CFA) of the original STS sub scales failed on both samples, exploratory factor analysis (EFA) was then used to access whether a simple structure would emerge on these STS treatment items. Parallel analysis and minimum average partial were used to determine the number of factor to retain. RESULTS: Three cross-cultural factors were found in this study, Internalized Distress, Externalized Distress and interpersonal relations. CONCLUSIONS: This supported that regardless of whether one is in presumably different cultural contexts of the USA or China, psychological distress is expressed in a few basic channels of internalized distress, externalized distress, and interpersonal relations, from which different manifestations in different culture were also discussed.