Tankyrases inhibit innate antiviral response by PARylating VISA/MAVS and priming it for RNF146-mediated ubiquitination and degradation.

During viral infection, sensing of viral RNA by retinoic acid-inducible gene-I-like receptors (RLRs) initiates an antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA (virus-induced signal adaptor; also known as mitochondrial antiviral signaling protein [MAVS]). VISA is regulated by various posttranslational modifications (PTMs), such as polyubiquitination, phosphorylation, O-linked ß-d-N-acetylglucosaminylation (O-GlcNAcylation), and monomethylation. However, whether other forms of PTMs regulate VISA-mediated innate immune signaling remains elusive. Here, we report that Poly(ADP-ribosyl)ation (PARylation) is a PTM of VISA, which attenuates innate immune response to RNA viruses. Using a biochemical purification approach, we identified tankyrase 1 (TNKS1) as a VISA-associated protein. Viral infection led to the induction of TNKS1 and its homolog TNKS2, which translocated from cytosol to mitochondria and interacted with VISA. TNKS1 and TNKS2 catalyze the PARylation of VISA at Glu137 residue, thereby priming it for K48-linked polyubiquitination by the E3 ligase Ring figure protein 146 (RNF146) and subsequent degradation. Consistently, TNKS1, TNKS2, or RNF146 deficiency increased the RNA virus-triggered induction of downstream effector genes and impaired the replication of the virus. Moreover, TNKS1- or TNKS2-deficient mice produced higher levels of type I interferons (IFNs) and proinflammatory cytokines after virus infection and markedly reduced virus loads in the brains and lungs. Together, our findings uncover an essential role of PARylation of VISA in virus-triggered innate immune signaling, which represents a mechanism to avoid excessive harmful immune response.

Transport of self-propelled particles across a porous medium: trapping, clogging, and the Matthew effect.

We study the transport of self-propelled particles from one free chamber to another across two stripe-like areas of dense porous medium. The medium is mimicked by arrays of obstacles. We find that active motion could greatly speed up the transport of particles. However, more and more particles become trapped in the obstacle arrays with the enhancement of activity. At high persistence (low rotational diffusion rate) and moderate particle concentration, we observe the Matthew effect in the aggregation of particles in the two obstacle arrays. This effect is weakened by introduction of randomness or deformability into the obstacle arrays. Moreover, the dependence on deformability shows the characteristics of first-order phase transition. In rare situations, the system could be stuck in a dynamic unstable state, e.g. the particles alternatively gather more in one of the two obstacle arrays, exhibiting oscillation of particle number between the arrays. Our results reveal new features in the transport of active objects in a complex medium and have implications for manipulating their collective assembly.

Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma.

BACKGROUND: Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. METHODS: A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. RESULTS: Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK-STAT3, inflammatory response and TNF-alpha signaling pathways. CONCLUSION: Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.

The Role of Serine Peptidase Inhibitor Kazal Type 13 (SPINK13) as a Clinicopathological and Prognostic Biomarker in Patients with Clear Cell Renal Cell Carcinoma.

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p<0.01). Gene set enrichment analysis (GSEA) showed that SPINK13 expression was involved in complement, apical junction, epithelial-mesenchymal transition (EMT), glycolysis, hypoxia, and inflammation signaling pathways. CONCLUSIONS Increased expression of SPINK13 was associated with poor prognosis in patients with CCRCC.

Off-Line Evaluation of Mobile-Centric Indoor Positioning Systems: The Experiences from the 2017 IPIN Competition.

The development of indoor positioning solutions using smartphones is a growing activity with an enormous potential for everyday life and professional applications. The research activities on this topic concentrate on the development of new positioning solutions that are tested in specific environments under their own evaluation metrics. To explore the real positioning quality of smartphone-based solutions and their capabilities for seamlessly adapting to different scenarios, it is needed to find fair evaluation frameworks. The design of competitions using extensive pre-recorded datasets is a valid way to generate open data for comparing the different solutions created by research teams. In this paper, we discuss the details of the 2017 IPIN indoor localization competition, the different datasets created, the teams participating in the event, and the results they obtained. We compare these results with other competition-based approaches (Microsoft and Perf-loc) and on-line evaluation web sites. The lessons learned by organising these competitions and the benefits for the community are addressed along the paper. Our analysis paves the way for future developments on the standardization of evaluations and for creating a widely-adopted benchmark strategy for researchers and companies in the field.

Prediction of topological crystalline insulators and topological phase transitions in two-dimensional PbTe films.

Topological phases, especially topological crystalline insulators (TCIs), have been intensively explored and observed experimentally in three-dimensional (3D) materials. However, two-dimensional (2D) films are explored much less than 3D TCIs, and even 2D topological insulators. Based on ab initio calculations, here we investigate the electronic and topological properties of 2D PbTe(001) few-layer films. The monolayer and trilayer PbTe are both intrinsic 2D TCIs with a large band gap reaching 0.27 eV, indicating a high possibility for room-temperature observation of quantized conductance. The origin of the TCI phase can be attributed to the px,y-pz band inversion, which is determined by the competition of orbital hybridization and the quantum confinement effect. We also observe a semimetal-TCI-normal insulator transition under biaxial strains, whereas a uniaxial strain leads to Z2 nontrivial states. In particular, the TCI phase of a PbTe monolayer remains when epitaxially grown on a NaI semiconductor substrate. Our findings on the controllable quantum states with sizable band gaps present an ideal platform for realizing future topological quantum devices with ultralow dissipation.

Prenatal restraint stress is associated with demethylation of corticotrophin releasing hormone (CRH) promoter and enhances CRH transcriptional responses to stress in adolescent rats.

Maternal stress can disturb normal fetal neurodevelopmental progress, and lead to negative behavioral and neuroendocrine consequences for the offspring. These effects may be related to alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Early life events disrupting the function of the HPA axis may be associated with epigenetic modification. This study investigated the effect of maternal stress on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter and HPA axis response to acute stress in the adolescent offspring of Sprague-Dawley rats. Pregnant dams were randomly assigned to two groups: restraint stress group and normal control group. Adolescent male and female offspring were used from each group. The results showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism.

Tunable electronic and magnetic properties in germanene by alkali, alkaline-earth, group III and 3d transition metal atom adsorption.

We performed first-principles calculations to study the adsorption characteristics of alkali, alkali-earth, group III, and 3d transition-metal (TM) adatoms on germanene. We find that the adsorption of alkali or alkali-earth adatoms on germanene has minimal effects on geometry of germanene. The significant charge transfer from alkali adatoms to germanene leads to metallization of germanene, whereas alkali-earth adatom adsorption, whose interaction is a mixture of ionic and covalent, results in semiconducting behavior with an energy gap of 17-29 meV. For group III adatoms, they also bind germanene with mixed covalent and ionic bonding character. Adsorption characteristics of the transition metals (TMs) are rather complicated, though all TM adsorptions on germanene exhibit strong covalent bonding with germanene. The main contributions to the strong bonding are from the hybridization between the TM 3d and Ge pz orbitals. Depending on the induced-TM type, the adsorbed systems can exhibit metallic, half-metallic, or semiconducting behavior. Also, the variation trends of the dipole moment and work function with the adsorption energy across the different adatoms are discussed. These findings may provide a potential avenue to design new germanene-based devices in nanoelectronics.

Study and analysis of the correlation between lumbar spondylolisthesis and Modic changes.

Background: This study aimed to explore the risk factors of Modic changes in lumbar spondylolisthesis. Methods: The distribution of Modic changes in different types of lumbar spondylolisthesis, degree of spondylolisthesis, and degree of intervertebral disc degeneration in patients with lumbar spondylolisthesis was observed and analyzed. Statistical analysis was conducted to assess whether intervertebral disc degeneration, local mechanical changes, etc. affect the occurrence of Modic changes. The risk factors of Modic changes in lumbar spondylolisthesis were further illustrated. Results: The age in the lumbar spondylolisthesis with Modic changes group was younger than that in the lumbar spondylolisthesis without Modic changes group, and the bone mineral density was better in the lumbar spondylolisthesis with Modic changes group than that in the lumbar spondylolisthesis without Modic changes group, P < 0.05. The two groups statistically differed in intervertebral disc height (IDH) and disc angle on magnetic resonance imaging (MRI). In the classification of Modic changes, the incidence of type II was the highest. The incidence of Modic changes is higher in isthmic spondylolisthesis than in degenerative spondylolisthesis. With the aggravation of lumbar spondylolisthesis and intervertebral disc degeneration, the incidence of Modic changes gradually increased. Modic changes are most commonly seen in both the upper and lower endplates. Logistic regression analysis showed that the occurrence of Modic changes in lumbar spondylolisthesis was significantly correlated with IDH, disc angle on MRI, type of spondylolisthesis, degree of spondylolisthesis, and degree of intervertebral disc degeneration, P < 0.05. Conclusions: The occurrence of Modic changes is related to the type of spondylolisthesis, the degree of spondylolisthesis, the degree of disc degeneration, the decrease of intervertebral disc height, and local stress angulation.

Early outcomes, associated factors and predictive values of clinical outcomes of tandospirone in generalized anxiety disorder: a post-hoc analysis of a randomized, controlled, multicenter clinical trial.

OBJECTIVE: To examine the early outcomes, associated factors and predictive values of clinical outcomes of different tandospirone doses in patients with a generalized anxiety disorder (GAD). METHODS: This was a posthoc analysis of "a randomized, controlled multicenter clinical trial of the efficacy and safety of different doses of tandospirone on GAD". A total of 274 patients with GAD were included and randomized into the high-dose (tandospirone 60 mg/d) and low-dose (tandospirone 30 mg/d) groups for a 6-week treatment. The Hamilton Anxiety (HAMA), Clinical Global Impression-Severity (CGI-S), Short-Form-12 (SF-12) scales were used for assessment. The trial was registered at clinical trail.gov (NCT01614041). RESULTS: (1) In the first week of treatment, 35.8% of patients in the high-dose group fulfilled the early onset criteria, which was significantly higher than 19.0% found in the low-dose group (p = 0.002). In the second week of treatment, 22.6% of patients in the high-dose group achieved an early response, versus 12.4% in the low-dose group, indicating a significant difference (p = .026). (2) Factors associated with early onset at week 1 included baseline HAMA total score (OR = 0.916, 95%CI 0.882-0.952), age (OR = 0.974, 95%CI 0.950-0.998), drug dose (30 mg vs. 60 mg; OR = 0.298, 95%CI 0.156-0.568) and SF-12 physiological total score (OR = 1.030, 95%CI 1.010-1.050). (3) Early onset was significantly associated with response rate (OR = 18.34, 95%CI 12.10-27.81), remarkable response rate (OR = 27.56, 95%CI 11.65-65.17) and recovery rate (OR = 11.85, 95%CI 4.98-28.18). Group (high dose group vs. low dose group) (χ2 = 8.535, p = .003) and baseline HAMA total score (χ2 = 70.840, p < .001) were independent predictors of onset time. CONCLUSIONS: The early outcomes of high-dose tandospirone in the treatment of GAD are better than those of the low-dose group. Patients with younger age at onset, milder anxiety symptoms and better physiological functions administered high-dose tandospirone showed rapid onset, great early outcomes, high recovery rate and good prognosis. Drug onset time had a good predictive effect on treatment outcome.

Updated severity and prognosis score of pulmonary alveolar proteinosis: A multi-center cohort study in China.

Background: The high-resolution computed tomography (HRCT) score is an important component of the severity and prognosis score of pulmonary alveolar proteinosis (SPSP). However, the HRCT score in SPSP only considers the extent of opacity, which is insufficient. Methods: We retrospectively evaluated HRCT scores for 231 patients with autoimmune pulmonary alveolar proteinosis (APAP) from three centers of the China Alliance for Rare Diseases. The SPSPII was created based on the overall density and extent, incorporating the SPSP. The severity of APAP patients was assessed using disease severity scores (DSS), SPSP, and SPSPII to determine the strengths and weaknesses of the different assessment methods. We then prospectively applied the SPSPII to patients before treatment, and the curative effect was assessed after 3 months. Results: The HRCT overall density and extent scores in our retrospective analysis were higher than the extent scores in all patients and every original extent score severity group, as well as higher related to arterial partial oxygen pressure (PaO2) than extent scores. The mild patients accounted for 61.9% based on DSS 1-2, 20.3% based on SPSP 1-3, and 20.8% based on SPSPII 1-3. Based on SPSP or SPSPII, the number of severe patients deteriorating was higher in the mild and moderate groups. When applied prospectively, arterial PaO2 differed between any two SPSPII severity groups. The alveolar-arterial gradient in PaO2 (P[A-a]O2), % predicted carbon monoxide diffusing capacity of the lung (DLCO), and HRCT score were higher in the severe group than in the mild and moderate groups. After diagnosis, mild patients received symptomatic treatment, moderate patients received pure whole lung lavage (WLL) or granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy, and severe patients received WLL and GM-CSF therapy. Importantly, the SPSPII in mild and severe groups were lower than baseline after 3 months. Conclusion: The HRCT density and extent scores of patients with APAP were better than the extent score. The SPSPII score system based on smoking status, symptoms, PaO2, predicted DLCO, and overall HRCT score was better than DSS and SPSP for assessing the severity and efficacy and predicting the prognosis. Trial registration: ClinicalTrial.gov, identifier: NCT04516577.

High RRM2 expression has poor prognosis in specific types of breast cancer.

BACKGROUND: RRM2 plays an important role in different malignant tumors, but there are few studies in breast cancer. Public databases were used to analyze the expression of RRM2 in breast cancer and its prognostic value. MATERIALS AND METHODS: A total of 2,509 breast cancer samples were downloaded from the METABRIC database. The relationship between RRM2 expression and clinical pathology was evaluated. Using the BCIP database and real-time-PCR, and western blotting, RRM2 mRNA and protein expression of RRM2 in breast cancer tissues and cell lines were evaluated. Univariate and multivariate analysis defined independent prognostic factors that affected the overall survival of patients with breast cancer. The Kaplan-Meier method was used to study the relationship between the high expression of RRM2 and overall survival and distant metastasis-free survival (DMFS) of breast cancer patients. Finally, We performed Gene Set Enrichment Analysis (GSEA) and obtained the relevant pathways associated with high expression of RRM2 potentially influencing breast cancer progression. RESULTS: RRM2 expression was significantly correlated with age, tumor size, grade, menopausal status, molecular typing, ER, PR, and Her-2 of patients with breast cancer(P<0.05). Univariate and multivariate regression analysis showed that RRM2, the number of positive lymph nodes, ER, Her-2, tumor size, and tumor stage can be used as independent prognostic factors for overall survival of patients with breast cancer. Kaplan-Meier analysis showed that in patients with Luminal A and Normal like breast cancers and Stage1 and stage2 breast cancers, patients with high expression of RRM2 had worse overall survival and DMFS. The analysis of the GSEA pathway showed that RRM2 is mainly enriched in the ERBB signaling pathway and other pathways. CONCLUSION: The high expression of RRM2 has a worse prognosis in patients with breast cancer with specific features. It can be used as a biomarker for the prognosis of breast cancer.

Acacetin improves cognitive function of APP/PS1 Alzheimer's disease model mice via the NLRP3 inflammasome signaling pathway.

Background: Acacetin (5,7-dihydroxy-4'-methoxyflavone), one of the main extractions from Saussurea involucrata, has anti-inflammatory effects. Our previous study found that acacetin inhibited the Nod-like receptor pyrin domain containing 3 (NLRP3) signaling pathway after cerebral ischemia-reperfusion injury. NLRP3 inflammasome plays a role in Alzheimer's disease (AD) process. However, few studies have examined the effects of acacetin in AD. Methods: We randomly divided APP swe/PS1dE9 double transgenic mice into acacetin group (intraperitoneal injection of 25 mg/kg acacetin) and AD model group (intraperitoneal injection of same volume of saline). C57BL/6 mice were selected as control group (same treatment with AD model group). After treating for 30 days, a Morris water maze test was conducted to evaluate spatial learning and memory of the mice. Senile plaque (SP) formation was evaluated by immunohistochemistry. NLRP3 inflammasome-related inflammatory factors and amyloid-ß-42 were detected by Western blot or enzyme-linked immunosorbent assay. Results: Acacetin improved spatial learning and memory of AD mice and reduced APP/ß expression, thereby decreasing SP formation in the brain. Acacetin also reduced the expression of NLRP3, cysteinyl aspartate-specific proteinase 1 (caspase-1), and interleukin-1ß (IL-1ß) and the release of inflammatory factors, tumor necrosis factor-α (TNF-α) and IL-1ß. Conclusions: Acacetin improved the learning and memory abilities of AD mice and exerted a protective effect on AD by inhibiting the NLRP3 signaling pathway and reducing SP formation.

Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation.

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation's pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

Effect of native defects and Co doping on ferromagnetism in HfO2: first-principles calculations.

First-principles calculations of undoped HfO(2) and cobalt-doped HfO(2) have been carried out to study the magnetic properties of the dielectric material. In contrast to previous reports, it was found that the native defects in HfO(2) could not induce strong ferromagnetism. However, the cobalt substituting hafnium is the most stable defect under oxidation condition, and the ferromagnetic (FM) coupling between the cobalt substitutions is favorable in various configurations. We found that the FM coupling is mediated by the threefold-coordinated oxygen atoms in monoclinic HfO(2) and could be further enhanced in electron-rich condition.

A second polymorph of catena-poly[[(1,10-phenanthroline-κN,N')copper(II)]-di-µ-thio-cyanato-κN:S;κS:N].

In the title coordination polymer, [Cu(NCS)(2)(C(12)H(8)N(2))](n), the Cu(II) atom is situated on a twofold rotation axis and is coordinated by two N atoms from the bidentate 1,10-phenanthroline ligand and four thio-cyanate groups to confer a CuN(4)S(2) octa-hedral geometry and resulting in a layer structure extending parallel to (100).

Systematic identification of autophagy-related proteins in Aedes albopictus.

Autophagy is a conserved cellular process playing a role in maintenance of cellular homeostasis and response to changing nutrient conditions via degradation and recirculation of cellular redundant components. Autophagy-related proteins (Atg) play important function in autophagy pathway. Aedes albopictus mosquito is an effective vector transmitting multiple viruses which cause serious human diseases. Moreover, Aedes albopictus mosquito is becoming a serious threat to human health due to its widening distribution in recent years and thus worth of more research attention. It was reported that autophagy might play a role in viral infection in Aedes mosquito. To better understand the interaction between autophagy and arbovirus infection in mosquito system, it is necessary to identify autophagy pathway in the system. However, autophagy in Aedes albopictus mosquito is still poorly understood so far. We recently identified AaAtg8, the first Atg protein reported in Aedes albopictus mosquito. This work further identified twelve atg genes in Aedes albopictus mosquito. Sequence and phylogenetic analysis of the twelve atg genes were performed. Expression profiles of all the twelve Aaatg genes in different developmental stages and genders of Aedes albopictus mosquito were conducted. Effects of chemicals inhibiting or inducing autophagy on the levels of eight identified AaAtg proteins were examined. The function of two identified AaAtg proteins AaAtg6 and AaAtg16 and their response to arbovirus SINV infection were studied preliminarily. Taken together, this work systematically identified Aedes albopictus atg genes and provided basic information which might help to elucidate the autophagy pathway and the role of autophagy in arbovirus infection in Aedes mosquito system.

The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis.

Cisplatin (cis-dichloro-diammine platinum, CDDP) is a well-known chemotherapeutic drug against a broad spectrum of human malignancies. However, the clinical utility of this effective chemotherapy agent is dose limited by its toxic side effects such as nephrotoxicity and ototoxicity. Necroptosis is a form of programmed necrotic cell death that is mediated by serine/threonine kinases, RIPK1 and RIPK3, together with MLKL. In this study, we identified that the multitargeted kinase inhibitor KW-2449 inhibited cisplatin-induced necroptosis, while potentiated cisplatin-induced apoptosis in cancer cells. Mechanistic studies indicated that KW-2449 directly inhibited RIPK1 kinase activity to block necroptosis. Oral administration of KW-2449 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of cisplatin-induced nephrotoxicity. Taken together, our study shows that KW-2449 is a novel necroptosis inhibitor by targeting RIPK1 kinase activity and has great clinic potential for the treatment of cisplatin-induced nephrotoxicity.

Fine mapping epitope on Glycoprotein-Gn from Severe Fever with Thrombocytopenia Syndrome Virus.

Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) was recently identified as a tick-borne pathogen that threat to human health. Since 2010, many countries including China, South Korea, and Japan have reported Human SFTS caused by SFTSV infection. The glycoprotein encoded by the SFTSV M gene is the major antigenic component on the viral surface, and responsible for the viral entry, which makes it an important viral antigen and a clinical diagnostic target. The present study aimed to map linear B cell epitopes (BCEs) on the N-terminal glycoprotein (Gn) from SFTSV strain WCH/97/HN/China/2011 using the modified biosynthetic peptide method. Five fine epitopes (E1, 196FSQSEFPD203; E2, 232GHSHKII238; E3, 256VCYKEGTGPC265; E4, 285FCKVAG290, and E5, 316SYGGM320) were identified using the rabbit antisera. Western blot analysis showed that all the five epitopes interacted with the positive serum of sheep that had been naturally infected with SFTSV. Three-dimensional structural modeling analysis showed that all identified BCEs were located on the surface of the SFTSV-Gn and contained flexible loops. The sequence alignment revealed high conservation of the identified BCEs among 13 SFTSV strains from different lineage. These mapped epitopes will escalate the understanding of the epitope distribution and pathogenic mechanism of SFTSV, and could provide a basis for the development of a SFTSV multi-epitope detection antigen.

[Influence of estradiol on tryptophan hydroxylase and 5-hydroxytryptamine content in raphe nuclei of rats under forced swimming stress].

OBJECTIVE: To investigate the effect of estradiol (E2) on tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) content in raphe nuclei of rats under forced swimming stress and explore the role of estrogen and stress in disease mechanism of depression in women. METHODS: At Week 3 post-ovariectomy, 35 ovariectomized (OVX) female SD rats were randomly divided into 5 groups (n = 7): non-stress group, control group, estradiol (E2) group and fluoxetine (FLX) group and E2 plus FLX group. Animals were administered with different drugs for 2 weeks. At Day 14, animals except those in the non-stress group were subjected to the 15 min forced swimming test (FST). At 2 hours post-FST, all animals including those in the non-stress group were perfused with 4% paraformaldehyde and brains removed for TPH and 5-HT immunofluorescence staining. We compared the content of TPH and 5-HT by observing and calculating the integrated optical density (IOD) of immunofluorescent-positive signals in raphe nuclei. RESULTS: (1) The IOD value of TPH- and 5-HT-positive region in raphe nuclei of rats in the control group was significantly lower than that of the non-stress group (P < 0.01); (2) the IOD value of TPH- and 5-HT-positive region in raphe nuclei of rats in the E2, FLX and E2 plus FLX groups was significantly higher than that in the control group (P < 0.05). CONCLUSION: Forced swimming stress can decrease the TPH and 5-HT content in raphe nuclei. Such changes can be prevented by a pre-administration of estradiol. Similar results are observed with antidepressant fluoxetine. These effects may underlie the role of estradiol and stress in the disease mechanism of depression in women.