Opposing roles of RUBCN isoforms in autophagy and memory B cell generation.

RUBCN (also known as Rubicon) was originally identified as a negative regulator of autophagy, a process by which cells degrade and recycle damaged components or organelles and that requires the activity of the class III PI3K VPS34 and the mTORC1 protein complex. Here, we characterized the role of a shorter isoform, RUBCN100, as an autophagy-promoting factor in B cells. RUBCN100 was translated from alternative translation initiation sites and lacked the RUN domain of the longer, previously characterized RUBCN130 isoform. Specific deficiency of RUBCN130 in B cells enhanced autophagy, which promoted memory B cell generation. In contrast to RUBCN130, which is localized in late endosomes and lysosomes and suppresses the enzymatic activity of VPS34, an effect thought to mediated by its RUN domain, RUBCN100 was preferentially located in early endosomes and enhanced VPS34 activity, presumably because of the absence of the RUN domain. Furthermore, RUBCN100, but not RUBCN130, enhanced autophagy and suppressed mTORC1 activation. Our findings reveal that the opposing roles of two RUBCN isoforms are critical for autophagy regulation and memory B cell differentiation.

Photochromic Polyoxoniobates with Photoinduced "D-f-A" Electron Transfer Mechanism.

Compounds with redox activities have appealing applications in catalytic, electronic and magnetic properties, but the redox inert of polyoxoniobates (PONbs) significantly limits their applications for a long time. In this work, we are able to integrate organophosphate and lanthanide cluster into PONb to create the first family of inorganic-organic hybrid organophosphate-Ln-PONb composite clusters. These novel species not only present the first family of redox active PONbs that can be reduced to form long-lived "heteropoly blues" under ambient conditions, but also a new photochromic system. More importantly, the analyses of the electronic configurations and photochromic properties for a series of designed proof-of-concept PONbs models allow us to discover a D-f-A electron transfer mechanism, that is, photoinduced electron is transferred from a photosensitive organophosphate electron donor (D) to the NbV electron acceptor (A) through the unoccupied 4 f-orbitals of Ln (f). This work paves the way for developing diverse PONb-based redox materials and expanding the possibility of the applications of PONbs in the redox chemistry.

A Three-Dimensional (3D) Indium-Containing Polyoxoniobate Framework Based on {In5Nb71}n Helical Pillars.

A rare 3D Indium-containing polyoxoniobate framework {H9[Cu(en)2(H2O)2][Cu(en)2]12[In(en)]5[Nb23-O65(OH)3(H2O)2]{Nb24O67(OH)2(H2O)3]2}·68H2O(1), based on the In-containing polyoxoniobate cluster, {[In(en)]5[Nb23O65(OH)3(H2O)2][Nb24O67(OH)2(H2O)3]2}35- ({In5Nb71}) and [Cu(en)2]2+ linkers has been successfully synthesized. The nest-like cluster {In5Nb71} is constructed from one brand-new V-shaped {Nb23O70}, two triangle-shaped {Nb24O72} and five [In(en)]3+. The [In(en)] fragments link {Nb24O72} and {Nb23O70} units into unique {In5Nb71}n helical pillars. The copper-amine complexes connect the {In5Nb71}n helical pillars into a three-dimensional (3D) inorganic-organic hybrid In-Cu-containing framework. This material also exhibits good ionic conductivity and vapor adsorption capacity properties.

A novel and effective approach to generate germline-like monoclonal antibodies by integration of phage and mammalian cell display platforms.

Phage display technology allows for rapid selection of antibodies from the large repertoire of human antibody fragments displayed on phages. However, antibody fragments should be converted to IgG for biological characterizations and affinity of antibodies obtained from phage display library is frequently not sufficient for efficient use in clinical settings. Here, we describe a new approach that combines phage and mammalian cell display, enabling simultaneous affinity screening of full-length IgG antibodies. Using this strategy, we successfully obtained a novel germline-like anti-TIM-3 monoclonal antibody named m101, which was revealed to be a potent anti-TIM-3 therapeutic monoclonal antibody via in vitro and in vivo experiments, indicating its effectiveness and power. Thus, this platform can help develop new monoclonal antibody therapeutics with high affinity and low immunogenicity.

Circulating Blood miR-155 and miR-21 Promote the Development of Acute Pancreatitis and Can Be Used to Assess the Risk Stratification of Pancreatitis.

To explore the role of circulating blood miR-155 and miR-21 in promoting acute pancreatitis (AP) and evaluating the risk stratification of pancreatitis. In this experiment, 70 patients with AP treated in our hospital from October 2019 to December 2020 were included in the research group (RG), and the blood of 52 healthy cases was collected and they were included in the control group (CG). The expression of miR-155 and miR-21 in circulating blood was observed in the two groups. The diagnostic efficacy of miR-155 and miR-21 in AP was observed. The risk factors of patients with AP were observed. The expression of serum gastrointestinal hormones was observed in the two groups. The GAS and VIP in RG were higher than those in CG, while MTL and CCK were lower than those in CG. Moreover, the detection level of mild, moderate, severe, and critical patients was also significantly different (P < 0.05). The expression of miR-155 and miR-21 in circulating blood of RG was significantly lower than that of CG (P < 0.05), and the area under the miR-155 curve was 0.775 and the area under the miR-21 curve was 0.832. Alcoholism, GAS, VIP, MTL, CCK, miR-155, and miR-21 were the risk factors of patients. miR-155 and miR-21 show low expression in the serum of patients. The lower the expression, the more serious the disease. They are closely related to the development of AP. miR-155 and miR-21 have good diagnostic efficacy by ROC analysis, and they are expected to become effective indicators for the diagnosis and treatment of AP in the future.

3d-4f Heterometallic cluster incorporated polyoxoniobates with magnetic properties.

A series of 3d-4f heterometallic cluster incorporated polyoxoniobates (PONbs) with different magnetic properties were first made and characterized. This work not only provides a promising strategy to make new heterometallic cluster incorporated PONbs but also demonstrates an ideal model to probe how transition-metal ions influence the magnetic property of PONbs.

Proton conductive polyoxoniobate frameworks constructed from nanoscale {Nb68O200} cages.

Nanoscale {Nb68O200} cages have been successfully employed as flexible and stable secondary building units to combine with bridging copper-amine complexes to construct two proton conductive polyoxoniobate frameworks, demonstrating a promising strategy for making new porous materials.

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection.

Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections.IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

Osteoprotegerin is an independent risk factor for coronary calcification in patients with hypertension and is associated with angiotensin Ⅱ / 西安交通大学学报(医学版)

Objective: To evaluate the relationship between plasma osteoprotegerin (OPG) level and coronary artery calcification in patients with hypertension and the relationship between OPG and angiotensin Ⅱ (AngⅡ). Methods: A total of 348 patients with hypertension were enrolled in this study. Coronary calcification was determined by 64-row coronary CT. Patients with hypertension were divided into coronary calcification group and non-coronary calcification group according to their coronary calcification score. We compared the clinical and laboratory indications of the two groups. The odds ratio (OR) value of risk factors for coronary calcification and the correlation coefficient between OPG and AngⅡ levels were calculated. Results: The OPG and AngⅡ levels in patients with coronary calcification were higher than those in patients without coronary calcification (P0.05). Conclusion: OPG is an independent risk factor for coronary artery calcification in patients with hypertension and is related to the severity of coronary artery calcification. In hypertensive patients with coronary artery calcification, OPG and AngⅡ levels are positively correlated.

Expression of macrophage migration inhibitory factor in experimental autoimmune myocarditis and the mechanism of resveratrol's therapeutic effect / 西安交通大学学报(医学版)

Objective To explore the expression of macrophage migration inhibitory factor(MIF)in rat hearts with experimental autoimmune myocarditis(EAM)and the possible mechanism of resveratrol's therapeutic effect.Methods Experimental myocarditis model was established by using porcine myocardial immunoglobulin. Twenty-four male 6-week-old Lewis rats were randomly divided into control group(Con),EAM model group(MC) and resveratrol treatment group(MC+ Res).All the rats were detected and compared in the cardiac function according to echocardiographic analysis,and the expression of MIF was detected by Western blot.The degree of myocardial injury was detected by HE staining and the degree of macrophage infiltration in the myocardium was detected by immunohistochemistry.Results In control group,there was no significant inflammatory infiltration or myocardial injury in the myocardium.Heavy local infiltration of macrophages,and dissolved and fractured myocardial fibers were observed in model group.Resveratrol significantly decreased macrophage density and myocardial injury in the heart(P＜ 0.05).Compared with those in control group,LVEDs were significantly increased(P＜0.01)while LVEF and LVFS were markedly decreased in model group(P＜0.01).Compared with model group,LVEDs were significantly decreased(P＜0.05)while LVEF and LVFS were markedly increased in resveratrol group(P＜0.05).The protein expression of MIF was markedly increased in rats of model group(P＜0.01),but was decreased in resveratrol group compared with model groups(P＜ 0.05).Conclusion Increased expression of MIF may be involved in the pathogenesis of EAM.The therapeutic effect of resveratrol on EAM may be associated with down-regulated MIF expression and decreased macrophage infiltration.

The Extracts of Astragalus membranaceus Inhibit Melanogenesis through the ERK Signaling Pathway.

Melanin is a normal production protecting skin from environment-causing damage. Plants produce some agents in response to their environment. These agents could be applied in cosmetic production. Some Chinese herbals have immunomodulatory activities and modulate the symptoms of several diseases. Melanogenesis represents a complex group of conditions that are thought to be mediated through a complex network of regulatory processes. Previously, some studies found that the extracts of Astragalus membranaceus (PG2) regulated immunity and supported hematopoiesis. Herein, we want to determine the molecular mechanisms by which PG2 inhibits melanogenesis in B16F10 melanoma cells. The cellular melanin contents and expression of melanogenesis-related protein, including microphthalmia associated transcription factor (MITF) and tyrosinase were significantly reduced after PG2 treatment. Moreover, PG2 increased phosphorylation of ERK, without affecting phosphorylation of p38. These results suggested that PG2 as a new target in reducing hyperpigmentation through the ERK signal pathway. PG2 has potential for cosmetic usage in the future.

The inhibition of indoleamine 2, 3-dioxygenase 1 by connexin 43.

Upregulation of connexin 43 (Cx43) showed potential in enhancing immune surveillance that was suppressed in the tumor microenvironment. The expression of indoleamine 2, 3-dioxygenase (IDO) is one of the crucial factors contributing to tumor immune tolerance by depletion of tryptophan and IDO-mediated tryptophan metabolites. Here, we aim to investigate the role of Cx43 in IDO production in murine tumor by using Cx43 inducers. Resveratrol (trans-3, 5, 4 '-trihydroxystilbene) is a natural plant-derived polyphenol possessing positive effect against cancer. Salmonella enterica serovar choleraesuis (S.C.) was proved to target and inhibit tumor growth. Both of them regulated Cx43 expression in tumor cells and led to either chemosensitizing or immune-activating. In this study, the correlation between Cx43 and IDO were determined by the treatment of resveratrol and S.C. Our data showed an increase in Cx43 while IDO protein and IDO-mediated inhibited effects on T cell decreased after tumor cells are given with resveratrol and S.C. TREATMENTS: All of which could be inhibited once the expression of Cx43 was blocked. Cx43 involved in IDO regulation might be useful in developing IDO-targeted cancer immune therapy.