Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

The Potential Role of Virus Infection in the Progression of Thyroid Cancer.

Multiple factors have engaged in the progression of thyroid cancer (TC). Recent studies have shown that viral infection can be a critical factor in the pathogenesis of TC. Viruses, such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may play an essential role in the occurrence, development, and even prognosis in TC. This review mainly explored the potential role of viral infection in the progress of TC. The possible mechanisms could be recognizing the host cell, binding to the receptors, affecting oncogenes levels, releasing viral products to shape a beneficial environment, interacting with immune cells to induce immune evasion, and altering the pituitary-thyroid axis. Thus, comprehensive knowledge may provide insights into finding molecular targets for diagnosing and treating virus-related TC.

Multifunctional Lipidated Protein Carrier with a Built-In Adjuvant as a Universal Vaccine Platform Potently Elevates Immunogenicity of Weak Antigens.

Weak antigens represented by MUC1 are poorly immunogenic, which greatly constrains the development of relevant vaccines. Herein, we developed a multifunctional lipidated protein as a carrier, in which the TLR1/2 agonist Pam3CSK4 was conjugated to the N-terminus of MUC1-loaded carrier protein BSA through pyridoxal 5'-phosphate-mediated transamination reaction. The resulting Pam3CSK4-BSA-MUC1 conjugate was subsequently incorporated into liposomes, which biomimics the membrane structure of tumor cells. The results indicated that this lipidated protein carrier significantly enhanced antigen uptake by APCs and obviously augmented the retention of the vaccine at the injection site. Compared with the BSA-MUC1 and BSA-MUC1 + Pam3CSK4 groups, Pam3CSK4-BSA-MUC1 evoked 22- and 11-fold increases in MUC1-specific IgG titers. Importantly, Pam3CSK4-BSA-MUC1 elicited robust cellular immunity and significantly inhibited tumor growth. This is the first time that lipidated protein was constructed to enhance antigen immunogenicity, and this universal carrier platform exhibits promise for utilization in various vaccines, holding the potential for further clinical application.

Association between calf circumference and cardiac metabolic risk factors in middle-aged and elderly women.

Aims: To assess the correlation between calf circumference and cardiac metabolic risk factors such as hypertension, abnormal blood glucose and dyslipidaemia among middle-aged and elderly women. Methods: The cross-sectional study population consisted of 476 female participants aged 40-80 years, including 304 perimenopausal and 172 postmenopausal women. Calf circumference, body mass index (BMI), blood pressure, blood glucose and blood lipids were measured. Logistic regression analysis was used to evaluate the study aims. Results: Calf circumference was lower in postmenopausal than perimenopausal women, and postmenopausal women had the highest rates of hypertension, abnormal blood glucose and abnormal blood lipids. Pearson correlation coefficients showed that calf circumference was positively correlated with triglycerides (TGs), BMI, fasting plasma glucose (FPG),2-h plasma glucose, glycated haemoglobin (HbA1C), systolic blood pressure and diastolic blood pressure; and negatively correlated with high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC). The group with the lowest quantile of calf circumference had higher rates of hypertension (odds ratio (OR)2.14,95% confidence interval (CI)1.67-2.74),dysglycaemia (OR1.40,95%CI1.03-1.90) and dyslipidaemia (OR2.14,95%CI 1.86-2.46). Conclusion: In perimenopausal women, measurements of calf circumference can be used to predict the presence of cardiac metabolic risk factors, which can be detected by observing blood pressure, blood glucose, and blood lipids.

pH-Sensitive and Biodegradable Mn3(PO4)2·3H2O Nanoparticles as an Adjuvant of Protein-Based Bivalent COVID-19 Vaccine to Induce Potent and Broad-Spectrum Immunity.

Developing a novel and potent adjuvant with great biocompatibility for immune response augmentation is of great significance to enhance vaccine efficacy. In this work, we prepared a long-term stable, pH-sensitive, and biodegradable Mn3(PO4)2·3H2O nanoparticle (nano-MnP) by simply mixing MnCl2/NaH2PO4/Na2HPO4 solution for the first time and employed it as an immune stimulant in the bivalent COVID-19 protein vaccine comprised of wild-type S1 (S1-WT) and Omicron S1 (S1-Omicron) proteins as antigens to elicit a broad-spectrum immunity. The biological experiments indicated that the nano-MnP could effectively activate antigen-presenting cells through the cGAS-STING pathway. Compared with the conventional Alum-adjuvanted group, the nano-MnP-adjuvanted bivalent vaccine elicited approximately 7- and 8-fold increases in IgG antibody titers and antigen-specific IFN-γ secreting T cells, respectively. Importantly, antisera of the nano-MnP-adjuvanted group could effectively cross-neutralize the SARS-CoV-2 and its five variants of concern (VOCs) including Alpha, Beta, Gamma, Delta, and Omicron, demonstrating that this bivalent vaccine based on S1-WT and S1-Omicron proteins is an effective vaccine design strategy to induce broad-spectrum immune responses. Collectively, this nano-MnP material may provide a novel and efficient adjuvant platform for various prophylactic and therapeutic vaccines and provide insights for the development of the next-generation manganese adjuvant.

Self-Adjuvanting Protein Vaccine Conjugated with a Novel Synthetic TLR4 Agonist on Virus-Like Liposome Induces Potent Immunity against SARS-CoV-2.

Exploring potent adjuvants and new vaccine strategies is crucial for the development of protein vaccines. In this work, we synthesized a new TLR4 agonist, structurally simplified lipid A analogue GAP112, as a potent built-in adjuvant to improve the immunogenicity of SARS-CoV-2 spike RBD protein. The new TLR4 agonist GAP112 was site-selectively conjugated on the N-terminus of RBD to construct an adjuvant-protein conjugate vaccine in a liposomal formulation. It is the first time that a TLR4 agonist is site-specifically and quantitatively conjugated to a protein antigen. Compared with an unconjugated mixture of GAP112/RBD, a two-dose immunization of the GAP112-RBD conjugate vaccine strongly activated innate immune cells, elicited a 223-fold increase in RBD-specific antibodies, and markedly enhanced T-cell responses. Antibodies induced by GAP112-RBD also effectively cross-neutralized SARS-CoV-2 variants (Delta/B.1.617.2 and Omicron/B.1.1.529). This conjugate strategy provides an effective method to greatly enhance the immunogenicity of antigen in protein vaccines against SARS-CoV-2 and other diseases.

Impact of local steroid application on dysphagia after anterior cervical spine surgery: a meta-analysis.

INTRODUCTION: Dysphagia is one of the most common complications of anterior cervical spine surgery. Local steroid was widely used to reduce the postoperative swallowing pain. However, the effect of local steroid application on dysphagia after anterior cervical spine surgery was still uncertain. MATERIALS AND METHODS: We searched Medline (PubMed), Embase and the Cochrane Library on July 27, 2021 for studies investigating the effect of local steroid application on dysphagia after anterior cervical spine surgery from their date of inception to 2021. The relative risk or weighted mean difference with 95% confidence interval was recorded as a summary statistic consist of postoperative dysphagia, swallowing VAS scores, SWAL-QOL scores, PSTSI, and steroid related complications. RESULTS: This meta-analysis included 7 RCT studies involving 254 patients in the steroid group and 232 patients in the placebo group. Results showed local steroid group had less patients with dysphagia, lower swallowing VAS scores and less severe of prevertebral soft-tissue edema on the fourth day after surgery. No significant difference in non-fusion rate between the two groups was observed. And all included studies had no serious steroid related complications reported. CONCLUSIONS: The use of local steroid in anterior cervical spine surgery could reduce the early postoperative dysphagia without serious steroid related complication. However, the safety of local steroid application still need further studies with larger samples.

Immunogenicity of mucosal COVID-19 vaccine candidates based on the highly attenuated vesicular stomatitis virus vector (VSVMT) in golden syrian hamster

COVID-19 is caused by coronavirus SARS-CoV-2. Current systemic vaccines generally provide limited protection against viral replication and shedding within the airway. Recombinant VSV (rVSV) is an effective vector which inducing potent and comprehensive immunities. Currently, there are two clinical trials investigating COVID-19 vaccines based on VSV vectors. These vaccines were developed with spike protein of WA1 which administrated intramuscularly. Although intranasal route is ideal for activating mucosal immunity with VSV vector, safety is of concern. Thus, a highly attenuated rVSV with three amino acids mutations in matrix protein (VSVMT) was developed to construct safe mucosal vaccines against multiple SARS-CoV-2 variants of concern. It demonstrated that spike protein mutant lacking 21 amino acids in its cytoplasmic domain could rescue rVSV efficiently. VSVMT indicated improved safeness compared with wild-type VSV as the vector encoding SARS-CoV-2 spike protein. With a single-dosed intranasal inoculation of rVSVΔGMT-SΔ21, potent SARS-CoV-2 specific neutralization antibodies could be stimulated in animals, particularly in term of mucosal and cellular immunity. Strikingly, the chimeric VSV encoding SΔ21 of Delta-variant can induce more potent immune responses compared with those encoding SΔ21 of Omicron- or WA1-strain. VSVMT is a promising platform to develop a mucosal vaccine for countering COVID-19.

Roles and crosstalks of macrophages in diabetic nephropathy.

Diabetic nephropathy (DN) is the most common chronic kidney disease. Accumulation of glucose and metabolites activates resident macrophages in kidneys. Resident macrophages play diverse roles on diabetic kidney injuries by releasing cytokines/chemokines, recruiting peripheral monocytes/macrophages, enhancing renal cell injuries (podocytes, mesangial cells, endothelial cells and tubular epithelial cells), and macrophage-myofibroblast transition. The differentiation and cross-talks of macrophages ultimately result renal inflammation and fibrosis in DN. Emerging evidence shows that targeting macrophages by suppressing macrophage activation/transition, and macrophages-cell interactions may be a promising approach to attenuate DN. In the review, we summarized the diverse roles of macrophages and the cross-talks to other cells in DN, and highlighted the therapeutic potentials by targeting macrophages.

Plasma SIRT3 as a Biomarker of Severity and Prognosis After Acute Intracerebral Hemorrhage: A Prospective Cohort Study.

Objective: SIRT3 may act as a brain-protective factor. We measured the plasma SIRT3 levels of patients with intracerebral hemorrhage (ICH) and further determined the relationship between plasma SIRT3 and clinical outcome plus severity of ICH. Methods: In this prospective cohort study, we quantified plasma SIRT3 levels in 105 ICH patients and 72 healthy controls. Glasgow Coma Scale (GCS) score and hematoma volume were used to assess severity. Poor prognosis was defined as a Glasgow Outcome Scale (GOS) score of 1-3 at 90 days after ICH. Results: Plasma SIRT3 levels were markedly lower in patients than in controls (median, 10.19 versus 13.17 ng/mL; P<0.001). Among all patients, plasma SIRT3 levels were independently correlated with hematoma volume (beta, -0.098; 95% confidence interval, -0.158--0.039; t, -3.282; P=0.001) and GCS score (beta, 0.465; 95% confidence interval, 0.107-0.823; t, 2.576; P=0.011). A total of 46 cases had a poor prognosis at post-stroke 90 days. The plasma levels of SIRT3 significantly decreased in patients with a poor prognosis, compared with those with a good prognosis (median, 6.1 versus 11.2 ng/mL; P<0.001). Plasma SIRT3 was an independent predictor for 90-day poor prognosis of patients (odds ratio, 0.837; 95% confidence interval, 0.708-0.990; P=0.038). Plasma SIRT3 levels distinguished the development of poor prognosis with area under receiver operating characteristic curve at 0.801 (95% confidence interval, 0.711-0.872) and plasma SIRT3 levels ≤7.38 ng/mL predicted poor prognosis with 63.04% sensitivity and 93.22% specificity. Conclusion: Declined plasma SIRT3 levels are highly associated with hemorrhagic severity and poor 90-day outcome, thus suggesting that plasma SIRT3 may serve as a potential prognostic biomarker for ICH.

Long-term passaging of replication competent pseudo-typed SARS-CoV-2 reveals the antiviral breadth of monoclonal and bispecific antibody cocktails

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.

Clinical features and risk factors of severely and critically ill patients with COVID-19.

BACKGROUND: As of June 1, 2020, over 370000 coronavirus disease 2019 (COVID-19) deaths have been reported to the World Health Organization. However, the risk factors for patients with moderate-to-severe or severe-to-critical COVID-19 remain unclear. AIM: To explore the characteristics and predictive markers of severely and critically ill patients with COVID-19. METHODS: A retrospective study was conducted at the B11 Zhongfaxincheng campus and E1-3 Guanggu campus of Tongji Hospital affiliated with Huazhong University of Science and Technology in Wuhan. Patients with COVID-19 admitted from 1st February 2020 to 8th March 2020 were enrolled and categorized into 3 groups: The moderate group, severe group and critically ill group. Epidemiological data, demographic data, clinical symptoms and outcomes, complications, laboratory tests and radiographic examinations were collected retrospectively from the hospital information system and then compared between groups. RESULTS: A total of 126 patients were enrolled. There were 59 in the moderate group, 49 in the severe group, and 18 in the critically ill group. Multivariate logistic regression analysis showed that age [odd ratio (OR) = 1.055, 95% (confidence interval) CI: 1.099-1.104], elevated neutrophil-to-lymphocyte ratios (OR = 4.019, 95%CI: 1.045-15.467) and elevated high-sensitivity cardiac troponin I (OR = 10.126, 95%CI: 1.088 -94.247) were high-risk factors. CONCLUSION: The following indicators can help clinicians identify patients with severe COVID-19 at an early stage: age, an elevated neutrophil-to-lymphocyte ratio and high sensitivity cardiac troponin I.

Efficient Neutralization of SARS-CoV-2 Omicron and Other VOCs by a Broad Spectrum Antibody 8G3

Numerous mutations in the spike protein of SARS-CoV-2 B.1.1.529 Omicron variant pose a crisis for antibody-based immunotherapies. The efficacy of emergency use authorized (EUA) antibodies that developed in early SARS-CoV-2 pandemic seems to be in flounder. We tested the Omicron neutralization efficacy of an early B cell antibody repertoire as well as several EUA antibodies in pseudovirus and authentic virus systems. More than half of the antibodies in the repertoire that showed good activity against WA1/2020 previously had completely lost neutralizing activity against Omicron, while antibody 8G3 displayed non-regressive activity. EUA antibodies Etesevimab, Casirivimab, Imdevimab and Bamlanivimab were entirely desensitized by Omicron. Only Sotrovimab targeting the non-ACE2 overlap epitope showed a dramatic decrease activity. Antibody 8G3 efficiently neutralized Omicron in pseudovirus and authentic virus systems. The in vivo results showed that Omicron virus was less virulent than the WA1/2020 strain, but still caused deterioration of health and even death in mice. Treatment with 8G3 quickly cleared virus load of mice. Antibody 8G3 also showed excellent activity against other variants of concern (VOCs), especially more efficient against authentic Delta plus virus. Collectively, our results suggest that neutralizing antibodies with breadth remains broad neutralizing activity in tackling SARS-CoV-2 infection despite the universal evasion from EUA antibodies by Omicron variant.

Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Emerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants that were resistant to the therapeutic antibodies currently in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.

Deletion of Smad3 protects against C-reactive protein-induced renal fibrosis and inflammation in obstructive nephropathy.

Introduction and Aims: Elevated plasma levels of C-reactive protein (CRP) are closely associated with progressive renal injury in patients with chronic kidney disease (CKD). Here, we tested a hypothesis that CRP may promote renal fibrosis and inflammation via a TGF-ß/Smad3-dependent mechanism. Methods: Role and mechanisms of TGF-ß/Smad3 in CRP-induced renal fibrosis and inflammation were examined in a mouse model of unilateral ureteral obstruction (UUO) induced in CRP Tg/Smad3 KO mice and in a rat tubular epithelial cell line in which Smad3 gene is stably knocked down (S3KD-NRK52E). Results: We found that mice overexpressing the human CRP gene were largely promoted renal inflammation and fibrosis as evidenced by increasing IL-1ß, TNF-α, MCP-1 expression, F4/80+ macrophages infiltration, and marked accumulation of α-smooth muscle actin (α-SMA), collagen I and fibronectin in the UUO kidney, which were blunted when Smad3 gene was deleted in CRPtg-Smad3KO. Mechanistically, we found that the protection of renal inflammation and fibrosis in the UUO kidney of CRPtg-Smad3KO mice was associated with the inactivation of CD32-NF-κB and TGF-ß/Smad3 signaling. Conclusion: In conclusion, Smad3 deficiency protects against CRP-mediated renal inflammation and fibrosis in the UUO kidney by inactivating CD32-NF-κB and TGF-ß/Smad3 signaling.

Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with ACE2 interface, which gives 2G1 ability to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar IC50 in vitro. In SARS-CoV-2 and Beta- and Delta-variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 could be potentially capable of dealing with emerging SARS-CoV-2 variants in future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

Serum Hypoxia-Inducible Factor 1alpha Levels Correlate with Outcomes After Intracerebral Hemorrhage.

BACKGROUND: Serum hypoxia-inducible factor 1alpha (HIF-1α) is a key regulator in hypoxic and ischemic brain injury. We determined the relationship between serum HIF-1α levels and long-term prognosis plus severity of intracerebral hemorrhage (ICH). METHODS: A total of 97 ICH cases and 97 healthy controls were enrolled. Glasgow Coma Scale (GCS) score and hematoma volume were used to assess hemorrhagic severity. Glasgow Outcome Scale (GOS) score of 1-3 at post-stroke 90 days was defined as a poor outcome. RESULTS: Serum HIF-1α levels of ICH patients were significantly higher than those of healthy controls (median, 218.8 vs 105.4 pg/mL; P<0.001) and were substantially correlated with GCS score (r=-0.485, P<0.001), hematoma volume (r=0.357, P<0.001) and GOS score (r=-0.436, P<0.001). Serum HIF-1α levels >239.4 pg/mL discriminated patients at risk of 90-day poor outcome with sensitivity of 65.9% and specificity of 79.3% (area under the receiver operating characteristic curve, 0.725; 95% confidence interval, 0.625-0.811; P<0.001). Moreover, serum HIF-1α levels >239.4 pg/mL were independently associated with a poor 90-day outcome (odds ratio, 5.133; 95% confidence interval, 1.117-23.593; P=0.036). CONCLUSION: Serum HIF-1α, in close correlation with hemorrhagic severity and poor 90-day outcome, may serve as a potential prognostic biomarker for ICH.

Ni17 W3 -W Interconnected Hybrid Prepared by Atmosphere- and Thermal-Induced Phase Separation for Efficient Electrocatalysis of Alkaline Hydrogen Evolution.

The development of efficient and stable noble-metal-free electrocatalysts for hydrogen evolution reaction (HER) in alkaline media is still a challenge. Herein, a hybrid material formed by the interconnection of Ni17 W3 intermetallic compound with metallic W is demonstrated for HER. The Ni17 W3 -W hybrid is prepared by the atmosphere- and thermal-induced phase-separation strategy from a single-phase precursor (NiWO4 ), which gives Ni17 W3 -W hybrid abundant and tight interfaces. The theoretical calculation manifests that Ni17 W3 shows more optimized energetics for adsorbed H atom, while W has lower energy barrier for water dissociation, and the synergistic effect between them is believed to facilitate the HER kinetics. Moreover, Ni17 W3 presents a proper adsorption strength for both adsorbed OH and H, and thus Ni17 W3 may also act as a high HER catalyst by itself. As a result, the Ni17 W3 -W hybrid demonstrates high activity and durability for HER in liquid alkaline electrolyte; the electrolyzer assembled by Ni17 W3 -W hybrid and Ni-Fe-layered double hydroxide (LDH) as, respectively, the cathode and anode electrocatalysts presents superior performance to Pt/C-IrO2 benchmark. In addition, the Ni17 W3 -W hybrid also works well in the water electrolyzer based on solid hydroxide exchange membrane. The present work provides a promising pathway to the design of high-performance electrocatalysts.

Amorphous Ni-Fe-Mo Suboxides Coupled with Ni Network as Porous Nanoplate Array on Nickel Foam: A Highly Efficient and Durable Bifunctional Electrode for Overall Water Splitting.

It is a great challenge to fabricate electrode with simultaneous high activity for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Herein, a high-performance bifunctional electrode formed by vertically depositing a porous nanoplate array on the surface of nickel foam is provided, where the nanoplate is made up by the interconnection of trinary Ni-Fe-Mo suboxides and Ni nanoparticles. The amorphous Ni-Fe-Mo suboxide and its in situ transformed amorphous Ni-Fe-Mo (oxy)hydroxide acts as the main active species for HER and OER, respectively. The conductive network built by Ni nanoparticles provides rapid electron transfer to active sites. Moreover, the hydrophilic and aerophobic electrode surface together with the hierarchical pore structure facilitate mass transfer. The corresponding water electrolyzer demonstrates low cell voltage (1.50 V @ 10 mA cm-2 and 1.63 V @ 100 mA cm-2) with high durability at 500 mA cm-2 for at least 100 h in 1 m KOH.

Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy.

BACKGROUND: Transforming growth factor (TGF)-ß/Smad3 signaling is highly activated in kidneys of patients with type 2 diabetic nephropathy (T2DN), however, the precise role of Smad3 in the pathogenesis of diabetic nephropathy remains unclear. METHODS: Smad3 knockout (KO)-db/db mice were generated by intercrossing of male and female double-heterozygous Smad3+/- db/m mice. Renal functions including urinary albumin excretion and serum creatinine were determined. Renal histological injury including renal fibrosis and inflammation were examined by periodic acid Schiff (PAS), periodic acid-silver methenamine (PASM), and immunohistochemistry (IHC) staining. RESULTS: Smad3 knockout (KO)-db/db mice were protected from the development of diabetic kidney injury, characterized by the normal levels of urinary albumin excretion and serum creatinine without any evidence for renal fibrosis and inflammation. In contrast, Smad3 wild-type (WT) db/db and Smad3+/- db/db mice developed progressively decline in renal function over the 12 to 32-week time course, including increased microalbuminuria and elevated levels of serum creatinine. Pathologically, Smad3 WT db/db and Smad3+/- db/db mice exhibited a marked deposition of collagen-I (colI), collagen-IV(col-IV), and an increased infiltration of F4/80+ macrophages in kidney. Mechanistically, Smad3 deficiency decreased the lncRNA Erbb4-IR transcription, while increased miR-29b transcription and therefore protected the kidney from progressive renal injury in db/db mice. CONCLUSION: Results from this study imply that Smad3 may represent as a novel and effective therapeutic target for T2DN.