Postprocedural Anticoagulation After Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction: A Multicenter, Randomized, Double-Blind Trial.

BACKGROUND: Postprocedural anticoagulation (PPA) is frequently administered after primary percutaneous coronary intervention in ST-segment-elevation myocardial infarction, although no conclusive data support this practice. METHODS: The RIGHT trial (Comparison of Anticoagulation Prolongation vs no Anticoagulation in STEMI Patients After Primary PCI) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled, superiority trial conducted at 53 centers in China. Patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomly assigned by center to receive low-dose PPA or matching placebo for at least 48 hours. Before trial initiation, each center selected 1 of 3 PPA regimens (40 mg of enoxaparin once daily subcutaneously; 10 U·kg·h of unfractionated heparin intravenously, adjusted to maintain activated clotting time between 150 and 220 seconds; or 0.2 mg·kg·h of bivalirudin intravenously). The primary efficacy objective was to demonstrate superiority of PPA to reduce the primary efficacy end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, stent thrombosis (definite), or urgent revascularization (any vessel) within 30 days. The key secondary objective was to evaluate the effect of each specific anticoagulation regimen (enoxaparin, unfractionated heparin, or bivalirudin) on the primary efficacy end point. The primary safety end point was Bleeding Academic Research Consortium 3 to 5 bleeding at 30 days. RESULTS: Between January 10, 2019, and September 18, 2021, a total of 2989 patients were randomized. The primary efficacy end point occurred in 37 patients (2.5%) in both the PPA and placebo groups (hazard ratio, 1.00 [95% CI, 0.63 to 1.57]). The incidence of Bleeding Academic Research Consortium 3 to 5 bleeding did not differ between the PPA and placebo groups (8 [0.5%] vs 11 [0.7%] patients; hazard ratio, 0.74 [95% CI, 0.30 to 1.83]). CONCLUSIONS: Routine PPA after primary percutaneous coronary intervention was safe but did not reduce 30-day ischemic events. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03664180.

Metabolomic landscape of macrophage discloses an anabolic signature of dengue virus infection and antibody-dependent enhancement of viral infection.

Dengue virus (DENV) infection causes dengue fever, the most prevalent arthropod-transmitted viral disease worldwide. Viruses are acellular parasites and obligately rely on host cell machinery for reproduction. Previous studies have indicated metabolomic changes in endothelial cell models and sera of animal models and patients with dengue fever. To probe the immunometabolic mechanism of DENV infection, here, we report the metabolomic landscape of a human macrophage cell model of DENV infection and its antibody-dependent enhancement. DENV infection of THP-1-derived macrophages caused 202 metabolic variants, of which amino acids occupied 23.7%, fatty acids 21.78%, carbohydrates 10.4%, organic acids 13.37%, and carnitines 10.4%. These metabolomic changes indicated an overall anabolic signature, which was characterized by the global exhaustion of amino acids, increases of cellular fatty acids, carbohydrates and pentoses, but decreases of acylcarnitine. Significant activation of metabolic pathways of glycolysis, pentose phosphate, amino acid metabolism, and tricarboxylic acid cycle collectively support the overall anabolism to meet metabolic demands of DENV replication and immune activation by viral infection. Totally 88 of 202 metabolic variants were significantly changed by DENV infection, 36 of which met the statistical standard (P<0.05, VIP>1.5) of differentially expressed metabolites, which were the predominantly decreased variants of acylcarnitine and the increased variants of fatty acids and carbohydrates. Remarkably, 11 differentially expressed metabolites were significantly distinct between DENV only infection and antibody-dependent enhancement of viral infection. Our data suggested that the anabolic activation by DENV infection integrates the viral replication and anti-viral immune activation.

Epitope delimitation: A new method for defining epitopes of human IgG-reactive antigenic peptides based on rabbit-recognized epitope motifs.

The use of precise epitope peptides as antigens is essential for accurate serological diagnosis of viral-infected individuals, but now it remains an unsolvable problem for mapping precise B cell epitopes (BCEs) recognized by human serum. To address this challenge, we propose a novel epitope delimitation (ED) method to uncover BCEs in the delineated human IgG-reactive (HR) antigenic peptides (APs). Specifically, the method based on the rationale of similarities in humoral immune responses between mammalian species consists of a pair of elements: experimentally delineated HR-AP and rabbit-recognized (RR) BCE motif and corresponding pair of sequence alignment analysis. As a result of using the ED approach, after decoding four RR-epitomes of human papillomavirus types 16/18-E6 and E7 proteins utilizing rabbit serum against each recombinant protein and sequence alignment analysis of HR-APs and RR-BCEs, 19 fine BCEs in 17 of 22 known HR-APs were defined based on each corresponding RR-BCE motifs, including the type-specificity of each delimited BCE in homologous proteins. The test with 22 known 16/20mer HR-APs demonstrated that the ED method is effective and efficient, indicating that it can be used as an alternative method to the conventional identification of fine BCEs using overlapping 8mer peptides.

Plant biomass extracted eco-friendly natural surfactant enhanced bio-electrokinetic remediation of crude oil contaminated soil.

The current work investigates bioremediation (BIO) and electrokinetic (EK) remediation of crude oil hydrocarbons utilizing the biomass-electrokinetic (BIO-EK) approaches. The use of natural surfactants derived from plant biomass may improve remediation capacity by enhancing the solubility of organic pollutants. Sapindus mukorossi, a natural surfactant producer, was extracted from plant biomass in this study. The crude oil biodegradation efficiency was reported to be 98 %. In nature, FTIR confirms that plant biomass is lipopeptide. GCMS revealed that the crude oil (C7 - C23) was efficiently bio-degraded from lower to higher molecular weight. The application of natural surfactants in electokinetic remediation increased the plant biomass degradation of crude oil polluted soil by 98% compared to electrokinetic 55% in 2 days. Natural surfactant improves hydrocarbon solubilization and accelerates hydrocarbon electro migration to the anodic compartment, as confirmed by the presence of greater total organic content than the electrokinetic. This study proves that BIO-EK compared with a natural surfactant derived from plant biomass may be utilized to improve in situ bioremediation of crude oil polluted soils.

Development and Internal Validation of a Nomogram for Predicting Postoperative Cardiac Events in Elderly Hip Fracture Patients.

Purpose: Postoperative cardiac events (PCEs) are among the main adverse events after hip fracture surgery in the elderly. Existing cardiac risk assessment tools have some limitations and are not specifically designed for elderly patients undergoing hip fracture surgery. This study aimed to develop and internally validate a nomogram for prediction of PCEs in these patients. Patients and Methods: We performed a retrospective study of 992 patients aged ≥65 years undergoing hip fracture surgery in our hospital from July 2015 to December 2021. Patients' demographics and clinical data were collected. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to select predictors, and multivariate logistic regression was employed to construct a nomogram. Internal validation was performed by bootstrapping. The discriminatory ability of the model was determined by the area under the receiver operating characteristic curve (AUC). The calibration and clinical utility of the model were assessed. The predictive power and clinical benefit of the nomogram were compared with the Revised Cardiac Risk Index (RCRI). Results: The nomogram was constructed including seven variables: general anesthesia, the American Society of Anesthesiologists (ASA) classification, history of heart failure, history of severe arrhythmia, history of coronary artery disease, preoperative platelet count, and serum creatinine. The nomogram had an excellent predictive ability (AUC = 0.875, 95% confidence interval [CI]: 0.828-0.918). Satisfactory calibration was shown by calibration plots and the Hosmer-Lemeshow goodness-of-fit test (P = 0.520). Clinical usefulness was confirmed by decision curve analysis and clinical impact curve. The predictive power and clinical utility of the nomogram were superior to RCRI. Conclusion: We developed an easy-to-use nomogram for prediction of PCEs in elderly hip fracture patients. This prediction model could effectively identify patients at high risk of PCEs and may be useful for perioperative management optimization.

Chemically sprayed CdO: Cr thin films for formaldehyde gas detection and optoelectronic applications.

Chromium (Cr) doped CdO films are chemically sprayed and are characterized by their optical, electrical, structural, and microstructural characteristics. The thickness of the films is determined by spectroscopic ellipsometry. The cubic crystal structure with a superior growth along (111) plane of the spray-deposited films is confirmed from the powder X-ray diffraction (XRD) analysis. XRD studies also suggested that some of the Cd2+ ions were substituted by Cr3+ ions, and the solubility of Cr in CdO is minimal, to be around ∼0.75 wt%. The analysis by atomic force microscopy shows uniform distribution of grains throughout the surface, whose roughness is varied from 33 to 13.9 nm concerning Cr-doping concentration. The microstructures from the field emission scanning electron microscope reveal a smooth surface. The elemental composition is examined using an energy dispersive spectroscope. The micro-Raman studies carried out in room temperature endorse the presence of metal oxide (Cd-O) bond vibrations. Transmittance spectra are obtained using UV-vis-NIR spectrophotometer, and the band gap values are estimated from the absorption coefficient. The films show high optical transmittance (>75%) in vis-NIR region. A maximum optical band gap of 2.35 eV is obtained from 1.0 wt% Cr-doping. The electrical measurement (Hall analysis) confirmed the degeneracy nature and n-type semi-conductivity. The carrier density, carrier mobility, and dc-conductivity are increased for higher Cr-dopant percentage. High mobility (85 cm2V-1s-1) is observed for 0.75 wt% Cr-doping. The 0.75 wt% Cr-doping show a remarkable response to formaldehyde gas (74.39%).

[Value of serum procalcitonin and acute physiology and chronic health evaluation II score on predicting the prognosis of sepsis in elderly patients].

OBJECTIVE: To explore the value of serum procalcitonin (PCT) and acute physiology and chronic health evaluation II (APACHE II) score on predicting prognosis of elderly patients with sepsis. METHODS: A retrospective cohort study, patients with sepsis who admitted to the department of emergency and the department of geriatric medicine of Peking University Third Hospital from March 2020 to June 2021 were enrolled. Patients' demographics, routine laboratory examinations, APACHE II score that within 24 hours of admission were obtained from their electronic medical records. The prognosis during the hospitalization and one year after discharge were collected, retrospectively. Univariate and multivariate analysis of prognostic factors were performed. And Kaplan-Meier survival curves were used to examine overall survival. RESULTS: A total of 116 elderly patients met inclusion criteria, 55 were alive and 61 were died. On univariate analysis, clinical variables such as lactic acid [Lac, hazard ratio (HR) = 1.16, 95% confidence interval (95%CI) was 1.07-1.26, P < 0.001], PCT (HR = 1.02, 95%CI was 1.01-1.04, P < 0.001), alanine aminotransferase (ALT, HR = 1.00,95%CI was 1.00-1.00, P = 0.143), aspartate aminotransferase (AST, HR = 1.00, 95%CI was 1.00-1.01, P = 0.014), lactate dehydrogenase (LDH, HR = 1.00, 95%CI was 1.00-1.00, P < 0.001), hydroxybutyrate dehydrogenase (HBDH, HR = 1.00, 95%CI was 1.00-1.00, P = 0.001), creatine kinase (CK, HR = 1.00, 95%CI was 1.00-1.00, P = 0.002), MB isoenzyme of creatine kinase (CK-MB, HR = 1.01, 95%CI was 1.01-1.02, P < 0.001), Na (HR = 1.02, 95%CI was 0.99-1.05, P = 0.183), blood urea nitrogen (BUN, HR = 1.02, 95%CI was 0.99-1.05, P = 0.139), fibrinogen (FIB, HR = 0.85, 95%CI was 0.71-1.02, P = 0.078), neutrophil ratio (NEU%, HR = 0.99, 95%CI was 0.97-1.00, P = 0.114), platelet count (PLT, HR = 1.00, 95%CI was 0.99-1.00, P = 0.108) and total bile acid (TBA, HR = 1.01, 95%CI was 1.00-1.02, P = 0.096) shown to be associated with poor prognosis. On multivariable analysis, level of PCT was an important factor influencing the outcome of sepsis (HR = 1.03, 95%CI was 1.01-1.05, P = 0.002). Kaplan-Meier survival curve showed that there was no significant difference with respect to the overall survival between the two groups, with patients of PCT ≤ 0.25 µg/L and PCT > 0.25 µg/L (P = 0.220). It also showed that the overall survival rate in patients with high APACHE II score (> 27 points) was significantly lower than that in patients with low APACHE II score (≤ 27 points, P = 0.015). CONCLUSIONS: Serum PCT level is valuable prognostic factors of elderly patients with sepsis, and higher APACHE II score (> 27 points) indicates a poor prognosis.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Controllable Majorana vortex states in iron-based superconducting nanowires.

To reveal the non-Abelian braiding statistics of Majorana zero modes (MZMs), it is crucial to design a Majorana platform, in which MZMs can be easily manipulated in a broad topological nontrivial parameter space. This is also an essential step to confirm their existence. In this study, we propose an iron-based superconducting nanowire system with Majorana vortex states to satisfy desirable conditions. This system has a radius-induced topological phase transition, giving a lower bound for the nanowire radius. In the topological phase, the iron-based superconducting nanowires have only one pair of MZMs over a wide range of radii, chemical potential and external magnetic fields. The wave function of MZMs has a sizable distribution at the side edge of the nanowires. This property enables the control of the interaction of MZMs in neighboring vortex nanowires and paves the way for Majorana fusion and braiding.

Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial.

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

Celebrex Adjuvant Therapy on Coronavirus Disease 2019: An Experimental Study.

Background: The pandemic of coronavirus disease 2019 (COVID-19) resulted in grave morbidity and mortality worldwide. There is currently no effective drug to cure COVID-19. Based on analyses of available data, we deduced that excessive prostaglandin E2 (PGE2) produced by cyclooxygenase-2 was a key pathological event of COVID-19. Methods: A prospective clinical study was conducted in one hospital for COVID-19 treatment with Celebrex to suppress the excessive PGE2 production. A total of 44 COVID-19 cases were enrolled, 37 cases in the experimental group received Celebrex as adjuvant (full dose: 0.2 g, bid; half dose: 0.2 g, qd) for 7-14 days, and the dosage and duration was adjusted for individuals, while seven cases in the control group received the standard therapy. The clinical outcomes were evaluated by measuring the urine PGE2 levels, lab tests, CT scans, vital signs, and other clinical data. The urine PGE2 levels were measured by mass spectrometry. The study was registered and can be accessed at http://www.chictr.org.cn/showproj.aspx?proj=50474. Results: The concentrations of PGE2 in urine samples of COVID-19 patients were significantly higher than those of PGE2 in urine samples of healthy individuals (mean value: 170 ng/ml vs 18.8 ng/ml, p < 0.01) and positively correlated with the progression of COVID-19. Among those 37 experimental cases, there were 10 cases with age over 60 years (27%, 10/37) and 13 cases (35%, 13/37) with preexisting conditions including cancer, atherosclerosis, and diabetes. Twenty-five cases had full dose, 11 cases with half dose of Celebrex, and one case with ibuprofen. The remission rates in midterm were 100%, 82%, and 57% of the full dose, half dose, and control group, respectively, and the discharged rate was 100% at the endpoint with Celebrex treatment. Celebrex significantly reduced the PGE2 levels and promoted recovery of ordinary and severe COVID-19. Furthermore, more complications, severity, and death rate were widely observed and reported in the COVID-19 group of elders and with comorbidities; however, this phenomenon did not appear in this particular Celebrex adjunctive treatment study. Conclusion: This clinical study indicates that Celebrex adjuvant treatment promotes the recovery of all types of COVID-19 and further reduces the mortality rate of elderly and those with comorbidities.

Preparation and Characterization of Anti-GPC3 Nanobody Against Hepatocellular Carcinoma.

BACKGROUND: Glypican-3 (GPC3) is a newly identified target molecule for the early diagnosis of hepatocellular carcinoma (HCC), while targeted inhibition of GPC3 signaling may help to control the proliferation and metastasis of HCC cells. The purpose of this study was to prepare the anti-GPC3 nanobody and to investigate the affinity of the anti-GPC3 nanobodies in vitro and the anticancer effects on hepatocellular carcinoma in vivo. METHODS: To screen for unknown anti-GPC3 antibodies, we constructed an antibody phage display library. After three rounds of panning, positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA). Further, the nanobody fusion protein was expressed in E. coli BL21 cells and purified by affinity chromatography. Competitive ELISA and flow cytometry were conducted to confirm the affinity of the anti-GPC3 nanobodies in vitro. The antitumor effects of VHHGPC3 were assessed in vivo. RESULTS: The results showed that the nanobody VHHGPC3 had specific high-affinity binding to His-GPC3 antigen. Moreover, VHHGPC3 exhibited specific binding to commercial human GPC3 and recognized the surface GPC3 protein of the hepatoma cell line HepG2. Importantly, in vivo study showed that GPC3 nanobody suppresses the growth of HepG2 and improves the survival rate of tumor mice. DISCUSSION: In summary, our new anti-GPC3 nanobody suggests a strong application potential for targeted therapy of liver cancer.

Scalable Majorana vortex modes in iron-based superconductors.

The iron-based superconductor FeTe x Se1-x is one of the material candidates hosting Majorana vortex modes residing in the vortex cores. It has been observed by recent scanning tunneling spectroscopy measurement that the fraction of vortex cores having zero-bias peaks decreases with increasing magnetic field on the surface of FeTe x Se1-x . The hybridization of two Majorana vortex modes cannot simply explain this phenomenon. We construct a three-dimensional tight-binding model simulating the physics of over a hundred Majorana vortex modes in FeTe x Se1-x . Our simulation shows that the Majorana hybridization and disordered vortex distribution can explain the decreasing fraction of the zero-bias peaks observed in the experiment; the statistics of the energy peaks off zero energy in our Majorana simulation are in agreement with the experiment. These agreements lead to an important indication of scalable Majorana vortex modes in FeTe x Se1-x . Thus, FeTe x Se1-x can be one promising platform having scalable Majorana qubits for quantum computing.

The clinical significance of myeloid-derived suppressor cells in dengue fever patients.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play immunosuppressive roles in cancers and some infectious diseases; however, their role in dengue fever (DF) remains unknown. This study evaluated the clinical significance of MDSCs in DF patients. METHODS: This study comprised 178 non-severe DF patients, 20 non-dengue fever (NDF) controls, and 30 healthy donors. The DF patients were divided into the following five groups based on the fever duration from its onset to the day of sample collection: fever duration of 1-2, 3-4, 5-6, 7-8, and > 9 days. Among these DF patients, 14 were monitored for eight days, and their peripheral blood samples were collected every two days. The mononuclear cells were isolated and analyzed using flow cytometry. The correlation between the MDSCs and clinical and immunological indicators of the DF patients was evaluated using Spearman analysis. RESULTS: The count of the peripheral blood MDSCs, especially monocytic MDSCs, of the 178 DF patients were dramatically higher than those of the NDF and healthy controls, and remarkably decreased with the fever duration. Moreover, the MDSC count correlated with some indicators, including the dengue viral load (rho = 0.367, p < .001), body temperature (rho = 0.263, p = .005), prothrombin time (rho = 0.475, p < .001), CD4+ T cell number (rho = - 0.317, p < .001), CD8+ T cell number (rho = - 0.361, p < .001), "programmed cell death protein 1" (PD-1) (rho = - 0.347, p < .001), "T cell immunoglobulin domain and mucin domain-3" (Tim3) (rho = - 0.258, p = .001), interferon-α (IFN-α) (rho = 0.43, p < .001), and "regulated upon activation normal T-cell expressed and secreted" (RANTES) (rho = 0.278, p = .019). Furthermore, the level of arginase-1, but not nitric oxide, was higher in the DF patients than in the healthy controls and was closely related to the number of MDSCs (rho = 0.265, p = .024). CONCLUSIONS: Our study reveals a significant correlation between MDSCs and DF clinical indicators, posing MDSCs as potential target cells for DF treatment.

Convalescent patient-derived monoclonal antibodies targeting different epitopes of E protein confer protection against Zika virus in a neonatal mouse model.

The Zika virus (ZIKV) outbreak and its link to microcephaly triggered a public health concern. To examine antibody response in a patient infected with ZIKV, we used single-cell PCR to clone 31 heavy and light chain-paired monoclonal antibodies (mAbs) that bind to ZIKV envelope (E) proteins isolated from memory B cells of a ZIKV-infected patient. Three mAbs (7B3, 1C11, and 6A6) that showed the most potent and broad neutralization activities against the African, Asian, and American strains were selected for further analysis. mAb 7B3 showed an IC50 value of 11.6 ng/mL against the circulating American strain GZ02. Epitope mapping revealed that mAbs 7B3 and 1C11 targeted residue K394 of the lateral ridge (LR) epitope of the EDIII domain, but 7B3 has a broader LR epitope footprint and recognizes residues T335, G337, E370, and N371 as well. mAb 6A6 recognized residues D67, K118, and K251 of the EDII domain. Interestingly, although the patient was seronegative for DENV infection, mAb 1C11, originating from the VH3-23 and VK1-5 germline pair, neutralized both ZIKV and DENV1. Administration of the mAbs 7B3, 1C11, and 6A6 protected neonatal SCID mice infected with a lethal dose of ZIKV. This study provides potential therapeutic antibody candidates and insights into the antibody response after ZIKV infection.

Structural Basis for Neutralization and Protection by a Zika Virus-Specific Human Antibody.

We previously reported a human monoclonal antibody, ZK2B10, capable of protection against Zika virus (ZIKV) infection and microcephaly in developing mouse embryos. Here, we report the structural features and mechanism of action of ZK2B10. The crystal structure at a resolution of 2.32 Å revealed that the epitope is located on the lateral ridge of DIII of the envelope glycoprotein. Cryo-EM structure with mature ZIKV showed that the antibody binds to DIIIs around the icosahedral 2-fold, 3-fold, and 5-fold axes, a distinct feature compared to those reported for DIII-specific antibodies. The binding of ZK2B10 to ZIKV has no detectable effect on viral attachment to target cells or on conformational changes of the E glycoprotein in the acidic environment, suggesting that ZK2B10 functions at steps between the formation of the fusion intermediate and membrane fusion. These results provide structural and mechanistic insights into how ZK2B10 mediates protection against ZIKV infection.

Topological vortex phase transitions in iron-based superconductors.

We study topological vortex phases in iron-based superconductors. Besides the previously known vortex end Majorana zero modes (MZMs) phase stemming from the existence of a three dimensional (3D) strong topological insulator state, we show that there is another topologically nontrivial phase as iron-based superconductors can be doped superconducting 3D weak topological insulators (WTIs). The vortex bound states in a superconducting 3D WTI exhibit two different types of quantum states, a robust nodal superconducting phase with pairs of bulk MZMs and a full-gap topologically nontrivial superconducting phase which has single vortex end MZM in a certain range of doping level. Moreover, we predict and summarize various topological phases in iron-based superconductors, and find that carrier doping and interlayer coupling can drive systems to have phase transitions between these different topological phases.

MiR-429 regulates rat liver regeneration and hepatocyte proliferation by targeting JUN/MYC/BCL2/CCND1 signaling pathway.

Increasing evidence indicates that miR-429 is involved in tumor suppression in various human cancers. However, its role in liver regeneration remains unexplored. Liver regeneration is a highly orchestrated process that can be regulated by microRNAs (miRNAs), although the mechanisms are largely unclear. In this study, we aimed to identify the role of miR-429 in hepatocyte proliferation during liver regeneration. First, we performed microarray analysis and qRT-PCR. Results indicated that miR-429 level in rat liver markedly decreased 30 h after partial hepatectomy, and miR-429 overexpression disrupted BRL-3A proliferation and the transition of G1 to S phase in rat hepatocyte and promoted hepatocyte apoptosis. By contrast, miR-429 down-regulation had inverse effects. MiR-429 negatively regulated JUN expression in vitro and in vivo. After using JUN siRNA, we found that JUN inhibition mediates the effect of miR-429 in hepatocyte proliferation and growth and miR-429 negatively regulates JUN/MYC/BCL2/CCND1 signaling pathways. Our results also indicated that miR-429 inhibits hepatocyte proliferation and liver regeneration by targeting JUN/MYC/BCL2/CCND1.

Dengue immune sera enhance Zika virus infection in human peripheral blood monocytes through Fc gamma receptors.

Antibody dependent enhancement (ADE) has most often been associated with dengue virus (DENV). Studies using leukemia cell lines suggest that DENV specific antibodies can enhance Zika virus (ZIKV) infectivity, and vice versa. To examine the mechanisms of ADE of ZIKV infection in primary human cells, we assessed 40 serum samples obtained from convalescent DENV-1 or DENV-3 infected subjects. All sera tested exhibited high binding potency, while modest or none neutralization activities against ZIKV. Primary CD14+ monocytes, rather than B and T cells in peripheral blood mononuclear cells (PBMCs), were found to be the mediators of the enhancement of ZIKV infectivity by DENV immune sera. Monocyte-derived immature dendritic cells (DCs), but not mature DCs were highly permissive to ZIKV infection, whereas neither immature nor mature DCs could mediate enhanced ZIKV infection in the presence of DENV immune sera. In addition, antibody blocking of either FcγRI (CD64), or FcγRII (CD32), or FcγRIII (CD16) resulted in diminished ADE of ZIKV infection. Our findings provide an improved understanding of the pathogenesis of ZIKV infection, and inform rational vaccine design.

The preclinical evaluation of immunocontraceptive vaccines based on canine zona pellucida 3 (cZP3) in a mouse model.

BACKGROUND: Stray dogs are the reservoirs and carriers of rabies and are definitive hosts of echinococcosis. To control the overpopulation of stray dogs, zona pellucida 3 (ZP3), a primary receptor for sperm, is a potential antigen for developing contraceptive vaccines. To enhance the immune responses and contraceptive effects of canine ZP3 (cZP3), dog gonadotropin-releasing hormone (GnRH) and a T cell epitope of chicken ovalbumin (OVA) were selected to construct two fusion proteins with cZP3, ovalbumin-GnRH-ZP3 (OGZ) and ovalbumin-ZP3 (OZ), and their contraceptive effects were evaluated in mice. METHODS: The synthesized DNA sequences of OGZ and OZ were cloned into plasmid pET-28a respectively. The fusion proteins OGZ and OZ were identified by SDS-PAGE and Western blot. Mice were immunized with OGZ, OZ and cZP3, and the infertility rates were monitored. Mice immunized with mouse ZP3 (mZP3) or adjuvant alone were used as positive control and negative control, respectively. cZP3- and GnRH-specific antibodies (Abs) were detected by ELISA. The bindings of the Abs to oocytes were detected by indirect immunofluorescence assay. The paraffin sections of mice ovaries were observed under microscope for analyzing pathological characteristics. RESULTS: SDS-PAGE and Western blot analyses showed that the two fusion proteins OGZ and OZ were correctly expressed. ELISA results showed that OGZ vaccine induced both cZP3- and GnRH-specific Abs, and OZ vaccine induced cZP3-specific Ab, which lasted for up to 168 days. The levels of follicle stimulating hormone (FSH) and estradiol (E2) in sera were significantly decreased in OGZ immunized mice. Indirect immunofluorescence results showed that Abs induced by cZP3 and mZP3 could bind to the mouse ZP and dog ZP each other. Compared with the adjuvant group, all vaccine immunized groups significantly decreased the fertility rate and mean litter size. Interestingly, the fertility rate in OGZ-immunized group is the lowest, and only 1 mouse out of 10 mice is fertile. Histological analysis of murine ovarian sections indicated that most of the infertile mice in the immunized groups lacked mature follicles as well as accompanied by inflammatory infiltration. Meanwhile, immunization with OGZ decreased the number of corpora lutea in the infertile mice. CONCLUSIONS: The fusion protein OGZ resulted in the lowest fertility rate and the least mean litter size in the immunized mice. OGZ might be a promising antigen for developing a new contraceptive vaccine for stray dog controlling.