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Zika virus (ZIKV) caused millions of infections during its rapid and expansive spread from Asia to the Americas from 2015 to 2017. Here, we compared the infectivity of ZIKV mutants with individual stable substitutions which emerged throughout the Asian ZIKV lineage and were responsible for the explosive outbreaks in the Americas. A threonine (T) to alanine (A) mutation at the 106th residue of the ZIKV capsid (C) protein facilitated the transmission by its mosquito vector, as well as infection in both human cells and immunodeficient mice. A mechanistic study showed that the T106A substitution rendered the C a preferred substrate for the NS2B-NS3 protease, thereby facilitating the maturation of structural proteins and the formation of infectious viral particles. Over a complete "mosquito-mouse-mosquito" cycle, the ZIKV C-T106A mutant showed a higher prevalence of mosquito infection than did the preepidemic strain, thus promoting ZIKV dissemination. Our results support the contribution of this evolutionary adaptation to the occasional widespread reemergence of ZIKV in nature. [ABSTRACT FROM AUTHOR]

The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARSCoV- 2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273–vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

The absence of 'shovel-ready' anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to construct and validate a risk assessment model to identify risk factors for heart failure (HF) in patients with Takayasu's arteritis (TAK). Methods: Three hundred sixty-five patients with TAK were recruited in the East China Takayasu Arteritis Cohort from January 2012 to December 2019. Patients were assigned into training and validation sets following a 2:1 ratio according to the date of enrollment. Clinical characteristics were compared between heart failure (HF) and non-HF subgroups in the training set, and a risk assessment model for HF and its scoring algorithm was established based on logistic regression, which was tested in the validation set. Results: Among total of 74 (20.27%) TAK patients exhibited HF, and 55 cases (74.32%) were in the training set. The risk factors for HF of TAK patients included onset age >38 years, serum tumor necrosis factor (TNF)-α concentration >10 pg/ml, aortic valve involvement, coronary artery involvement, and pulmonary hypertension. We constructed the model without TNF-α (Model 1) and with TNF-α (Model 2). Patients in the training set with the score ≥ 3 appeared to be associated with an increased risk of HF with an area under curve (AUC) of 0.88 and 0.90 in Model 1 and Model 2 respectively. The AUC reached to 0.88 and 0.89 in the validation set that proved the accuracy of the model. Conclusions: We presented a risk assessment model of HF in TAK, which may help clinicians alert the complication of HF in the patients with specifically cardiac impairments. Key Points • Heart failure was not rare in Chinese Takayasu's arteritis patients, and there were approximately 20% of patients with heart failure in ECTA cohort. • Cardiac involvements on echocardiography include pathological valvular and atrioventricular abnormalities. • The onset age >38 years, serum tumor necrosis factor (TNF)-α concentration >10 pg/ml, aortic valve involvement, coronary artery involvement, and pulmonary hypertension were risk factors for heart failure in Takayasu's arteritis patients. • We constructed the model without TNF-α (Model 1) and with TNF-α (Model 2). Patients with the risk assessment model score of ≥ 3 appeared to be associated with an increased risk of heart failure. [ABSTRACT FROM AUTHOR]

Fractional Chern insulators (FCIs), having properties similar to those of the fractional quantum Hall effect, have been established numerically in various toy models. To fully explore their fundamental physics and to develop practical applications, material realization is indispensable. Here we theoretically predict a realization of FCI in a two-dimensional organometallic material, which is known to have the prerequisite topological flat bands. Using numerical exact diagonalization we demonstrate that the presence of strong electronic correlations and fractional filling of such a system could lead to a rich phase diagram, including Abelian fractional quantum Hall (FQH), Fermi-liquid, and Wigner crystal states. In particular, the FQH state has been confirmed systematically by calculating the topological ground-state degeneracies, topological Chern number, and the quasihole excitation spectrum as well as the particle entanglement spectrum. Future experimental realization of the FQH state in such material may provide a route for developing practical applications of FCI with no need of the extreme conditions. [ABSTRACT FROM AUTHOR]

We demonstrate how the generalized Pauli exclusion principle emerges for quasiparticle excitations in 2D topological phases. As an example, we examine the Levin-Wen model with the Fibonacci data (specified in the text), and construct the number operator for fluxons living on plaquettes. By numerically counting the many-body states with fluxon number fixed, the matrix of exclusion statistics parameters is identified and is shown to depend on the spatial topology (sphere or torus) of the system. Our work reveals the structure of the (many-body) Hilbert space and some general features of thermodynamics for quasiparticle excitations in topological matter. [ABSTRACT FROM AUTHOR]

Highlights: [•] TiO2 was prepared by sol–gel method film and then functionalized with the cyanidin dye. [•] The morphology and the absorption spectra of films were examined. [•] The hybrid organic–inorganic formed film here can detect ammonia reversibly at room temperature. [•] The low humidity could promote the sensitivity of the sensors. [ABSTRACT FROM AUTHOR]

A hybrid fuzzy inference-quantum particle swarm optimization (FI-QPSO) algorithm is developed to estimate the temperature-dependent thermal properties of the grain. The fuzzy inference scheme is established to determine the contraction-expansion coefficient according to the aggregation degree of particles. The heat transfer process in the grain bulk is solved using the finite element method, and the estimation task is formulated as an inverse problem. Numerical experiments are performed to study the effects of the surface heat flux, measurement errors, and the individual space on the estimation results. Comparison with the quantum particle swarm optimization (QPSO) algorithm and conjugate gradient method (CGM) is also conducted, and it shows the validity of the estimation method established in this paper. [ABSTRACT FROM AUTHOR]

We propose a discrete model—the twisted quantum double model—of 2D topological phases based on a finite group G and a 3-cocycle α over G. The detailed properties of the ground states are studied, and we find that the ground-state subspace can be characterized in terms of the twisted quantum double Dα(G) of G. When α is the trivial 3-cocycle, the model becomes Kitaev's quantum double model based on the finite group G, in which the elementary excitations are known to be classified by the quantum double D (G) of G. Our model can be viewed as a Hamiltonian extension of the Dijkgraaf-Witten topological gauge theories to the discrete graph case with gauge group being a finite group. We also demonstrate a duality between a large class of Levin-Wen string-net models and certain twisted quantum double models, by mapping the string-net 6j symbols to the corresponding 3-cocycles. [ABSTRACT FROM AUTHOR]

The factors that control the development of an effective immune response to the recently emerged SARS-CoV-2 virus are poorly understood. In this study, we provide a cross-sectional analysis of the dynamics of B cell responses to SARS-CoV-2 infection in hospitalized COVID-19 patients. We observe changes in B cell subsets consistent with a robust humoral immune response, including significant expansion of plasmablasts and activated receptor-binding domain (RBD)-specific memory B cell populations. We observe elevated titers of Abs to SARS-CoV-2 RBD, full-length Spike, and nucleoprotein over the course of infection, with higher levels of RBD-specific IgG correlating with increased serum neutralization. Depletion of RBD-specific Abs from serum removed a major portion of neutralizing activity in most individuals. Some donors did retain significant residual neutralization activity, suggesting a potential Ab subset targeting non-RBD epitopes. Taken together, these findings are instructive for future vaccine design and mAb strategies. [ABSTRACT FROM AUTHOR]

The factors that control the development of an effective immune response to the recently emerged SARS-CoV-2 virus are poorly understood. In this study, we provide a cross-sectional analysis of the dynamics of B cell responses to SARS-CoV-2 infection in hospitalized COVID-19 patients. We observe changes in B cell subsets consistent with a robust humoral immune response, including significant expansion of plasmablasts and activated receptor-binding domain (RBD)-specific memory B cell populations. We observe elevated titers of Abs to SARS-CoV-2 RBD, full-length Spike, and nucleoprotein over the course of infection, with higher levels of RBD-specific IgG correlating with increased serum neutralization. Depletion of RBD-specific Abs from serum removed a major portion of neutralizing activity in most individuals. Some donors did retain significant residual neutralization activity, suggesting a potential Ab subset targeting non-RBD epitopes. Taken together, these findings are instructive for future vaccine design and mAb strategies [ABSTRACT FROM AUTHOR]

Macular degeneration (MD) is characterized by the progressive deterioration of the macula and represents one of the most prevalent causes of blindness worldwide. Abnormal intracellular accumulation of lipid droplets and pericellular deposits of lipid-rich material in the retinal pigment epithelium (RPE) called drusen are clinical hallmarks of different forms of MD including Doyne honeycomb retinal dystrophy (DHRD) and age-related MD (AMD). However, the appropriate molecular therapeutic target underlying these disorder phenotypes remains elusive. Here, we address this knowledge gap by comparing the proteomic profiles of induced pluripotent stem cell (iPSC)-derived RPEs (iRPE) from individuals with DHRD and their isogenic controls. Our analysis and follow-up studies elucidated the mechanism of lipid accumulation in DHRD iRPE cells. Specifically, we detected significant downregulation of carboxylesterase 1 (CES1), an enzyme that converts cholesteryl ester to free cholesterol, an indispensable process in cholesterol export. CES1 knockdown or overexpression of EFEMP1 R345W , a variant of EGF-containing fibulin extracellular matrix protein 1 that is associated with DHRD and attenuated cholesterol efflux and led to lipid droplet accumulation. In iRPE cells, we also found that EFEMP1R345W has a hyper-inhibitory effect on epidermal growth factor receptor (EGFR) signaling when compared to EFEMP1WT and may suppress CES1 expression via the downregulation of transcription factor SP1. Taken together, these results highlight the homeostatic role of cholesterol efflux in iRPE cells and identify CES1 as a mediator of cholesterol efflux in MD. [ABSTRACT FROM AUTHOR]

Co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses has been reported. We evaluated cell lines commonly used to isolate viruses and diagnose related diseases for their susceptibility to SARS-CoV-2. Although multiple kidney cell lines from monkeys were susceptible to SARS-CoV-2, we found many cell types derived from humans, dogs, minks, cats, mice, and chicken were not. We analyzed MDCK cells, which are most commonly used for surveillance and study of influenza viruses, and found that they were not susceptible to SARS-CoV-2. The low expression level of the angiotensin converting enzyme 2 receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by overexpression of canine angiotensin converting enzyme 2 in trans, strengthened the cellular barrier to productive infection. Moreover, a D614G mutation in the spike protein did not appear to affect SARS-CoV-2 cell tropism. Our findings should help avert inadvertent propagation of SARS-CoV-2 from diagnostic cell lines. [ABSTRACT FROM AUTHOR]

We study the properties of topological phases by calculating the ground-state degeneracy (GSD) of the two-dimensional Levin-Wen (LW) model. Here it is explicitly shown that the GSD depends only on the spatial topology of the system. Then we show that the ground state on a sphere is always nondegenerate. Moreover, we study an example associated with a quantum group, and show that the GSD on a torus agrees with that of the doubled Chern-Simons theory, which is consistent with the conjectured equivalence between the LW model associated with a quantum group and the doubled Chern-Simons theory. [ABSTRACT FROM AUTHOR]

Recently, there have been intense efforts in searching for new topological insulator materials. Based on first-principles calculations, we find that all the ultrathin Bi (111) films are characterized by a nontrivial Z2 number independent of the film thickness, without the odd-even oscillation of topological triviality as commonly perceived. The stable nontrivial Z2 topology is retained by the concurrent band gap inversions at multiple time-reversal-invariant k points with the increasing film thickness and associated with the intermediate interbilayer coupling of the Bi film. Our calculations further indicate that the presence of metallic surface states in thick Bi (111) films can be effectively removed by surface adsorption. [ABSTRACT FROM AUTHOR]

The rapid development of emerging technology products (ETPs) in China's market makes it important to evaluate and forecast ETPs diffusion. Due to the high uncertainty of ETP marketing and inadequate marketing data of China ETPs markets, the traditional forecasting methods cannot be applied to effectively measure it. We use cellular automata embedded small world network (CASWN) and cross-entropy (CE) divergence to measure the differences of the ETP adopters' spatial distribution. The empirical analysis indicates the success probabilities of ETPs can be predicted effectively though CASWN and CE divergence, which can make a precise judgment for the market prospect of an ETP in the shortest time after an ETP launch. Based on this, we can calculate the expected cash flow accurately and the option value of an ETP project for sound decision-making. In the meantime, the CE threshold value of success of ETPs in China market is obtained only by the spatial data of early-stage after an ETP launch, not rely on time series data. So a new tool is provided for the prediction and venture capital policy of an ETP launch in this article. [ABSTRACT FROM AUTHOR]

Our previous study concerning brain trauma has shown that progesterone could regulate toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) signaling pathway in the brain, which also has been proved to play important roles in early brain injury (EBI) after subarachnoid hemorrhage (SAH). The aim of the current study was to investigate whether progesterone administration modulated TLR4/NF-κB pathway signaling pathway in the brain at the early stage of SAH. All SAH animals were subjected to injection of 0.3 ml fresh arterial, non-heparinized blood into prechiasmatic cistern in 20 seconds. Male rats were given 0 or 16 mg/kg injections of progesterone at post-SAH hours 1, 6, and 24. Brain samples were extracted at 48 h after SAH. As a result, SAH could induce a strong up-regulation of TLR4, NF-κB, pro-inflammatory cytokines, MCP-1, and ICAM-1 in the cortex. Administration of progesterone following SAH could down-regulate the cortical levels of these agents related to TLR4/NF-κB signaling pathway. Post-SAH progesterone treatment significantly ameliorated the EBI, such as the clinical behavior scale, brain edema, and blood-brain barrier (BBB) impairment. It was concluded that post-SAH progesterone administration may attenuate TLR4/NF-κB signaling pathway in the rat brain following SAH. [ABSTRACT FROM AUTHOR]

Ln-containing AlPO-5 (Ln = La, Ce, Sm, Dy, Y, Gd) were synthesized hydrothermally in the presence of HF, and characterized by XRD, UV-vis, SEM, N2 adsorption/desorption, FT-IR, solid state 27Al MAS NMR and ICP-AES techniques. The results showed that all the samples had good crystallinity and high specific area. Isomorphous substitution of Ln ions for Al+3 occurred. The lanthanide ions were incorporated into the frameworks or were highly dispersed on extra frameworks of the samples. The newly synthesized catalysts all were efficient for the oxidation of cyclohexane in a solvent-free system, especially Gd–AlPO-5. Near 13% conversion of cyclohexane were achieved on the catalyst Gd(60)–AlPO-5 with Al/Gd of 60 under the conditions of 0.5 MPa O2, 413 K and 4 h reaction. The total selectivity to cyclohexanol and cyclohexanone was up to 92%. In addition, the catalyst Gd(60)–AlPO-5 was recyclable for the titled reaction system. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Extracting knowledge from the transaction records and the personal data of credit card holders has great profit potential for the banking industry. The challenge is to detect/predict bankrupts and to keep and recruit the profitable customers. However, grouping and targeting credit card customers by traditional data-driven mining often does not directly meet the needs of the banking industry, because data-driven mining automatically generates classification outputs that are imprecise, meaningless, and beyond users' control. In this paper, we provide a novel domain-driven classification method that takes advantage of multiple criteria and multiple constraint-level programming for intelligent credit scoring. The method involves credit scoring to produce a set of customers' scores that allows the classification results actionable and controllable by human interaction during the scoring process. Domain knowledge and experts' experience parameters are built into the criteria and constraint functions of mathematical programming and the human and machine conversation is employed to generate an efficient and precise solution. Experiments based on various data sets validated the effectiveness and efficiency of the proposed methods. [ABSTRACT FROM AUTHOR]

Kaposi’s sarcoma-associated herpesvirus ORF57 expression is highly responsive to replication and transcription activator (RTA) and interferon regulatory factor 7 (IRF-7). Three RTA response elements (RREs) have been identified in the ORF57 promoter. Here, we show evidence of another functional RRE located between nt 82003 and 82081, which can complement the loss of RTA activation resulting from RRE1 deletion. Repeats of a recombination signal-binding protein Jκ (RBP-Jκ) site enhanced RTA activation, which could not be suppressed by IRF-7. Alteration of the distance between the RBP-Jκ site and RRE2 modulated responsiveness to RTA and IRF-7. These results will help to elucidate the precise regulation of viral gene expression. [ABSTRACT FROM AUTHOR]

Bipolar linear algebra (BLA) and YinYang-N-Element bipolar cellular networks (BCNs) are presented for equilibrium-based biological simulation and regulation at the system, molecular, and genetic levels. Bipolar fusion, interaction, oscillation, and quantum entanglement with growing, aging, degenerating, equilibrium, and non-equilibrium properties are mathematically characterized; bipolar dynamic equations with metabolic nourishing and regulating relations are formulated; global and local equilibrium conditions are established and proved. Two families of YinYang-N-Element BCNs are compared and analyzed: one family has predefined nourishing and regulation cycles following the classical YinYang-5-Element protocol in Traditional Chinese Medicine (TCM); another family has random connectivity and link weights. Applicability of the theory is illustrated in equilibrium and non-equilibrium simulation of bio-agent interaction and regulation. The significance of this work is two-fold: (1) BLA provides a unique and unifying mathematical foundation for bipolar fusion, interaction, and oscillation in biophysics and bioeconomics; (2) YinYang-N-Element BCNs provide a unique and unifying architecture for modeling equilibrium and non-equilibrium processes at the system, molecular, and genetic levels. [ABSTRACT FROM AUTHOR]

At the macroscale, the hydrodynamics of a fluid can be well described by conventional hydrodynamic models such as the Navier-Stokes equations. However, as the flow passage is shrunk down to the nanometer size, the micro-interaction between the fluid and the confined solid walls becomes significant, and the conventional hydrodynamic model will become insufficient for describing such a flow system. In this work, we propose a generalized hydrodynamic model that is derived from a recently developed kinetic model for strong inhomogeneous fluid systems [Guo, Zhao, and Shi, Phys. Rev. E 71, 035301(R) (2005)]. We show that the present model can reduce to other hydrodynamic models in certain limits, and can be used for flows ranging from nanoscale to macroscale. Based on this generalized model, the static and dynamic behaviors of several simple fluid systems are studied. It is shown that at a small scale, the results predicted by the generalized hydrodynamic model are in agreement with those simulated by the molecular dynamic and the Monte Carlo methods, while for flow systems at a large scale, the results agree with those by the Navier-Stokes equations. [ABSTRACT FROM AUTHOR]

Abstract: The LLM''s BPS solutions of IIB supergravity are known to be closely related to the integer quantum Hall droplets with filling factor , and the giant gravitons in the LLM geometry behave like the quasi-holes in those droplets. In this paper we consider how the fractional quantum Hall effect may arise in this context, by studying the dynamics of giant graviton probes in a special LLM geometry, the background, that corresponds to a circular droplet. The giant gravitons we study are D3-branes wrapping on a 3-sphere in . Their low energy world-volume theory, truncated to the BPS sector, is shown to be described by a Chern–Simons finite-matrix model. We demonstrate that these giant gravitons may condense at right density further into fractional quantum Hall fluid due to the repulsive interaction in the model, giving rise to the new states in IIB string theory. Some features of the novel physics of these new states are discussed. [Copyright &y& Elsevier]

In credit card portfolio management, predicting the cardholder’s spending behavior is a key to reduce the risk of bankruptcy. Given a set of attributes for major aspects of credit cardholders and predefined classes for spending behaviors, this paper proposes a classification model by using multiple criteria linear programming to discover behavior patterns of credit cardholders. It shows a general classification model that can theoretically handle any class-size. Then, it focuses on a typical case where the cardholders’ behaviors are predefined as four classes. A dataset from a major US bank is used to demonstrate the applicability of the proposed method. [ABSTRACT FROM AUTHOR]

In this Letter, we study the open spinning strings and their SYM duals. A new class of folded open spinning strings is found. At planar one-loop level in SYM, by solving the thermodynamic limit of the Bethe ansatz equations for an integrable open spin chain, we find good agreement with string theory predictions for energies of both circular and folded two-spin solutions. A universal relation between the open and closed spinning strings is verified in the spin chain approach. [Copyright &y& Elsevier]

Prevention and treatment of infection by West Nile virus (WNV) and other flaviviruses are public health priorities. We describe a reporting cell line that can be used for high-throughput screening of inhibitors against all targets involved in WNV replication. Dual reporter genes, encoding Renilla luciferase (Rluc) and neomycin phosphotransferase (Neo), were engineered into a WNV subgenomic replicon, resulting in Rluc/NeoRep. Geneticin selection of BHK-21 cells transfected with Rluc/NeoRep yielded a stable cell line that contains persistently replicating replicons. Incubation of the reporting cells with known WNV inhibitors decreased Rluc activity, as well as the replicon RNA level. The efficacies of the inhibitors, as measured by the depression of Rluc activity in the reporting cells, are comparable to those derived from authentic viral infection assays. Therefore, the WNV reporting cell line can be used as a high-throughput assay for anti-WNV drug discovery. A similar approach should be applicable to development of genetics-based antiviral assays for other flaviviruses. [ABSTRACT FROM AUTHOR]

The article focuses on China's fourth national survey of cultural relics, emphasizing the need to prioritize the cultural connotations and historical context of these artifacts over their material condition. Topics discussed include the importance of recording cultural values, utilizing advanced technologies for detailed digitization, and creating a nationally managed virtual platform for public interaction with ancient cultural relics.

• We identified and characterized a novel pollen allergen candidate as triosephosphate isomerase, which was different from already known types of pollen allergens and was recognized as Pla a 7 by WHO/IUIS Allergen Nomenclature Sub-committee. • The natural Pla a 7 displayed 41.4% IgE reactivity with the patients' sera, the reactivity was correlated to the IgE concentration against Platanus acerifolia pollen extract. • This finding is essential to enrich information on allergen components and pave the way for molecular diagnosis or treatment strategies for Platanus acerifolia pollen allergy. Platanus acerifolia is recognized as a source of allergenic pollen worldwide. Currently, five Platanus acerifolia pollen allergens belonging to different protein families have been identified, in which profilin and enolase were characterized by our group recently. Besides, we also screened and identified a novel allergen candidate as triosephosphate isomerase, which was different from already known types of pollen allergens. However, the role of this novel allergen group in Platanus acerifolia pollen allergy was unclear. Therefore, we further investigated the allergenicity and clarify its clinical relevance in this study. The natural triosephosphate isomerase from Platanus acerifolia pollen was purified by three steps of chromatography and identified by mass spectrometry. The cDNA sequence of this protein was matched from in-house transcripts based on internal peptide sequences, which was further confirmed by PCR cloning. The recombinant triosephosphate isomerase was expressed and purified from E. coli. Allergenicity analysis of this protein was carried out by enzyme linked immunosorbent assay, immunoblot, and basophil activation test. A novel allergen group belonging to triosephosphate isomerase was firstly identified in Platanus acerifolia pollen and named as Pla a 7. The cDNA of Pla a 7 contained an open reading frame of 762 bp encoding 253 amino acids. The natural Pla a 7 displayed 41.4% IgE reactivity with the patients' sera by ELISA, in which the absorbance value showed correlation to the serum sIgE against Platanus acerifolia pollen extract. Inhibition of IgE-binding to pollen extracts reached 26%-94% in different Pla a 7-positive sera. The recombinant Pla a 7 exhibited weaker IgE-reactivity in ELISA than its natural form, but showed comparable activity in immunoblot. The allergenicity was further confirmed by basophil activation test. Triosephosphate isomerase (Pla a 7) was first recognized as pollen allergen in Platanus acerifolia pollen, which is a completely different type of pollen allergen from those previously reported. This finding is essential to enrich information on allergen components and pave the way for molecular diagnosis or treatment strategies for Platanus acerifolia pollen allergy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162bl in younger adults have been reported previously from trials in Germany and the United States. METHODS: In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial Developconducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle-formulated, nucleoside-modified RNA vaccine candidates: BNT162bl, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full- length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 Bg, 20 Bg, 30 Bg, and 100 Bg). In all groups but one, participants received two doses, with a 21-day interval be- tween doses; in one group (100 Bg of BNT162bl), participants received one dose. RESULTS: A total of 195 participants underwent randomization. In each of 13 groups Of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162bl was associated with a lower incidence and severity of systemic reactions than BNT162bl, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS - CoV-2- neutralizing geo - metric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. CONCLUSIONS: The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162bl in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) NS5 RNA-dependent RNA polymerase (RdRp), an important drug target, synthesizes viral RNA and is essential for viral replication. While a number of allosteric inhibitors have been reported for hepatitis C virus RdRp, few have been described for DENV RdRp. Following a diverse compound screening campaign and a rigorous hit-to-lead flowchart combining biochemical and biophysical approaches, two DENV RdRp nonnucleoside inhibitors were identified and characterized. These inhibitors show low- to high-micromolar inhibition in DENV RNA polymerization and cell-based assays. X-ray crystallography reveals that they bind in the enzyme RNA template tunnel. One compound (NITD-434) induced an allosteric pocket at the junction of the fingers and palm subdomains by displacing residue V603 in motif B. Binding of another compound (NITD-640) ordered the fingers loop preceding the F motif, close to the RNA template entrance. Most of the amino acid residues that interacted with these compounds are highly conserved in flaviviruses. Both sites are important for polymerase de novo initiation and elongation activities and essential for viral replication. This work provides evidence that the RNA tunnel in DENV RdRp offers interesting target sites for inhibition. [ABSTRACT FROM AUTHOR]

OBJECTIVES: We aimed to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological responses in children hospitalized with multisystem inflammatory syndrome in children (MIS-C) compared with those with coronavirus disease 2019 (COVID-19), those with Kawasaki disease (KD), and hospitalized pediatric controls. METHODS: From March 17, 2020, to May 26, 2020, we prospectively identified hospitalized children with MIS-C (n = 10), symptomatic COVID-19 (n = 10), and KD (n = 5) and hospitalized controls (n = 4) at Children's Healthcare of Atlanta. With institutional review board approval, we obtained prospective and residual blood samples from these children and measured SARS-CoV-2 spike receptor-binding domain (RBD) immunoglobulin M and immunoglobulin G (IgG), full-length spike IgG, and nucleocapsid protein antibodies using quantitative enzyme-linked immunosorbent assays and SARS-CoV-2 neutralizing antibodies using live-virus focus-reduction neutralization assays. We statistically compared the logtransformed antibody titers among groups and performed linear regression analyses. RESULTS: All children with MIS-C had high titers of SARS-CoV-2 RBD IgG antibodies, which correlated with full-length spike IgG antibodies (R² = 0.956; P, .001), nucleocapsid protein antibodies (R² = 0.846; P < .001), and neutralizing antibodies (R² = 0.667; P < .001). Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG antibody titers (geometric mean titer 6800; 95% confidence interval 3495-13 231) than children with COVID-19 (geometric mean titer 626; 95% confidence interval 251-1563; P < .001), children with KD (geometric mean titer 124; 95% confidence interval 91-170; P, .001), and hospitalized controls (geometric mean titer 85; P < .001). All children with MIS-C also had detectable RBD immunoglobulin M antibodies, indicating recent SARS-CoV-2 infection. RBD IgG titers correlated with the erythrocyte sedimentation rate (R² = 0.512; P < .046) and with hospital (R² = 0.548; P = .014) and ICU lengths of stay (R² = 0.590; P = .010). CONCLUSIONS: Quantitative SARS-CoV-2 serology may have a role in establishing the diagnosis of MIS-C, distinguishing it from similar clinical entities, and stratifying risk for adverse outcomes. [ABSTRACT FROM AUTHOR]

Few studies have investigated the prevalence of frailty in the Australian general population. This study determined the prevalence of frailty in a population-based sample of older adults and examined the relationship between frailty and comorbid conditions. Men (n = 347) and women (n = 360) aged ≥ 60 year from the Geelong Osteoporosis Study (GOS) were assessed between 2016-2019 and 2011-2014, respectively. Frailty was identified using a modified Fried frailty phenotype. Prevalence estimates were standardised to the 2011 Australian population. Kruskal-Wallis test and χ2 test were used to analyse data. For women, mean standardised prevalence estimates were 18.3% (14.1-22.5) for frail, 54.1% (47.3-60.8) pre-frail and 22.9% (18.9-26.8) robust. Corresponding estimates for men were 13.1% (9.8-16.3) frail, 47.8% (42.0-53.6) pre-frail and 27.3% (22.7-31.8) robust. Women who were frail were older, shorter, tended to have a higher body mass index (BMI) and used more medications compared to other groups. Compared to robust women, those who were frail were more likely to have cardio-metabolic (OR 3.5 (0.7-20.0)), pulmonary (OR 3.5 (1.5-8.4)) and musculoskeletal (OR 10.1 (2.1-48.0)) conditions. Frail men were older, had a higher BMI and were more likely to have musculoskeletal conditions (OR 5.8 (2.8-12.3)) and tended to be from a lower SES. No further associations were observed. This study reported the prevalence of frail and pre-frail individuals in a population-based sample of Australian men and women. Frailty was associated with musculoskeletal conditions for both men and women; however, associations with cardio-metabolic and pulmonary comorbidities were evident in women only. [ABSTRACT FROM AUTHOR]

The nonstructural protein 1 (NS1) of several flaviviruses, including West Nile, dengue, and yellow fever viruses, is capable of inducing variable degrees of protection against flavivirus infection in animal models. However, the immunogenicity of NS1 protein of Zika virus (ZIKV) is less understood. Here, we determined the efficacy of ZIKV NS1-based vaccine candidates using two delivery platforms, methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV) and a DNA vaccine. We first show that expression of ZIKV NS1 could be significantly enhanced by optimizing the signal peptide. A single dose of mtdVSV-NS1-based vaccine or two doses of DNA vaccine induced high levels of NS1-specfic antibody and T cell immune responses but provided only partial protection against ZIKV viremia in BALB/c mice. In Ifnar1-/- mice, neither NS1-based vaccine provided protection against a lethal high dose (105 PFU) ZIKV challenge, but mtdVSV-NS1-based vaccine prevented deaths from a low dose (10³ PFU) challenge, though they experienced viremia and body weight loss. We conclude that ZIKV NS1 alone conferred substantial, but not complete, protection against ZIKV infection. Nevertheless, these results highlight the value of ZIKV NS1 for vaccine development. [ABSTRACT FROM AUTHOR]

Arboviruses maintain high mutation rates due to lack of proofreading ability of their viral polymerases, in some cases facilitating adaptive evolution and emergence. Here we show that, just before its 2013 spread to the Americas, Zika virus (ZIKV) underwent an envelope protein V473M substitution (E-V473M) that increased neurovirulence, maternal-to-fetal transmission, and viremia to facilitate urban transmission. A preepidemic Asian ZIKV strain (FSS13025 isolated in Cambodia in 2010) engineered with the V473M substitution significantly increased neurovirulence in neonatal mice and produced higher viral loads in the placenta and fetal heads in pregnant mice. Conversely, an epidemic ZIKV strain (PRVABC59 isolated in Puerto Rico in 2015) engineered with the inverse M473V substitution reversed the pathogenic phenotypes. Although E-V473M did not affect oral infection of Aedes aegypti mosquitoes, competition experiments in cynomolgus macaques showed that this mutation increased its fitness for viremia generation, suggesting adaptive evolution for human viremia and hence transmission. Mechanistically, the V473M mutation, located at the second transmembrane helix of the E protein, enhances virion morphogenesis. Overall, our study revealed E-V473M as a critical determinant for enhanced ZIKV virulence, intrauterine transmission during pregnancy, and viremia to facilitate urban transmission. [ABSTRACT FROM AUTHOR]

Background: Chinese medicine Xuebijing (XBJ) has proven to be effective in the treatment of mild coronavirus disease 2019 (COVID-19) cases. But the bioactive compounds and potential mechanisms of XBJ for COVID-19 prevention and treatment are unclear. This study aimed to examine the potential effector mechanisms of XBJ on COVID-19 based on network pharmacology. Methods: We searched Chinese and international papers to obtain the active ingredients of XBJ. Then, we compiled COVID-19 disease targets from the GeneCards gene database and via literature searches. Next, we used the SwissTargetPrediction database to predict XBJ's effector targets and map them to the abovementioned COVID-19 disease targets in order to obtain potential therapeutic targets of XBJ. Cytoscape software version 3.7.0 was used to construct a "XBJ active-compound-potential-effector target" network and protein-protein interaction (PPI) network, and then to carry out network topology analysis of potential targets. We used the ClueGO and CluePedia plugins in Cytoscape to conduct gene ontology (GO) biological process (BP) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of XBJ's effector targets. We used AutoDock vina and PyMOL software for molecular docking. Results: We obtained 144 potential COVID-19 effector targets of XBJ. Fourteen of these targets-glyceraldehyde 3-phosphate dehydrogenase (GAPDH), albumin (ALB), tumor necrosis factor (TNF), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), Caspase-3 (CASP3), signal transducer and activator of transcription 3 (STAT3), MAPK8, prostaglandin-endoperoxide synthase 2 (PTGS2), JUN, interleukin-2 (IL-2), estrogen receptor 1 (ESR1), and MAPK14 had degree values > 40 and therefore could be considered key targets. They participated in extracellular signal–regulated kinase 1 and 2 (ERK1, ERK2) cascade, the T-cell receptor signaling pathway, activation of MAPK activity, cellular response to lipopolysaccharide, and other inflammation- and immune-related BPs. XBJ exerted its therapeutic effects through the renin-angiotensin system (RAS), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), MAPK, phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt)-vascular endothelial growth factor (VEGF), toll-like receptor (TLR), TNF, and inflammatory-mediator regulation of transient receptor potential (TRP) signaling pathways to ultimately construct a "drug-ingredient-target-pathway" effector network. The molecular docking results showed that the core 18 effective ingredients had a docking score of less than − 4.0 with those top 10 targets. Conclusion: The active ingredients of XBJ regulated different genes, acted on different pathways, and synergistically produced anti-inflammatory and immune-regulatory effects, which fully demonstrated the synergistic effects of different components on multiple targets and pathways. Our study demonstrated that key ingredients and their targets have potential binding activity, the existing studies on the pharmacological mechanisms of XBJ in the treatment of sepsis and severe pneumonia, could explain the effector mechanism of XBJ in COVID-19 treatment, and those provided a preliminary examination of the potential effector mechanism in this disease. [ABSTRACT FROM AUTHOR]

Mosquito-borne flaviviruses consist of a positive-sense genome RNA flanked by the untranslated regions (UTRs). There is a panel of highly complex RNA structures in the UTRs with critical functions. For instance, Xrn1-resistant RNAs (xrRNAs) halt Xrn1 digestion, leading to the production of subgenomic flaviviral RNA (sfRNA). Conserved short direct repeats (DRs), also known as conserved sequences (CS) and repeated conserved sequences (RCS), have been identified as being among the RNA elements locating downstream of xrRNAs, but their biological function remains unknown. In this study, we revealed that the specific DRs are involved in the production of specific sfRNAs in both mammalian and mosquito cells. Biochemical assays and structural remodeling demonstrate that the base pairings in the stem of these DRs control sfRNA formation by maintaining the binding affinity of the corresponding xrRNAs to Xrn1. On the basis of these findings, we propose that DRs functions like a bracket holding the Xrn1-xrRNA complex for sfRNA formation. [ABSTRACT FROM AUTHOR]

Flavivirus nonstructural protein 5 (NS5) contains an N-terminal methyltransferase (MTase) domain and a C-terminal polymerase (RNA-dependent RNA polymerase [RdRp]) domain fused through a 9-amino-acid linker. While the individual NS5 domains are structurally conserved, in the full-length protein, their relative orientations fall into two classes: the NS5 proteins from Japanese encephalitis virus (JEV) and Zika virus (ZIKV) adopt one conformation, while the NS5 protein from dengue virus serotype 3 (DENV3) adopts another. Here, we report a crystallographic structure of NS5 from DENV2 in a conformation similar to the extended one seen in JEV and ZIKV NS5 crystal structures. Replacement of the DENV2 NS5 linker with DENV1, DENV3, DENV4, JEV, and ZIKV NS5 linkers had modest or minimal effects on in vitro DENV2 MTase and RdRp activities. Heterotypic DENV NS5 linkers attenuated DENV2 replicon growth in cells, while the JEV and ZIKV NS5 linkers abolished replication. Thus, the JEV and ZIKV linkers likely hindered essential DENV2 NS5 interactions with other viral or host proteins within the virus replicative complex. Overall, this work sheds light on the dynamics of the multifunctional flavivirus NS5 protein and its interdomain linker. Targeting the NS5 linker is a possible strategy for producing attenuated flavivirus strains for vaccine design. [ABSTRACT FROM AUTHOR]

We previously produced a replication-defective West Nile virus lacking NS1 WNV-ΔNS1) that could propagate at low levels (105 IU/ml) in a 293T cell line expressing wild-type (WT) NS1. This finding indicates the potential of developing WNV-ΔNS1 as a non-infectious vaccine. To explore this idea, we developed an NS1-expressing Vero cell line (VeroNS1) that significantly improved the yield of WNV-ΔNS1 (108 IU/ml). We evaluated the safety and efficacy of WNV-ΔNS1 in mice. WNV-ΔNS1 appeared to be safe as no replicative virus on naïve Vero cells after continuously culturing of WNV-ΔNS1 on VeroNS1 cells for fifteen rounds. WNV-ΔNS1 was non-infectious in mice, even when IFNAR-/- mice were administrated with a high dose of WNV-ΔNS1. A single dose of WNV-ΔNS1 vaccination protected mice from a highly lethal challenge of WT WNV. The antibody response against WNV correlated well with the protection of vaccinated mice. Our study demonstrates the potential of the NS1 trans complementation system as a new platform for flavivirus vaccine development. [ABSTRACT FROM AUTHOR]

Background: Chinese medicine Toujie Quwen granule (TJQW) has proven to be effective in the treatment of mild coronavirus disease 2019 (COVID-19) cases by relieving symptoms, slowing the progression of the disease, and boosting the recovery of patients. But the bioactive compounds and potential mechanisms of TJQW for COVID-19 prevention and treatment are unclear. This study aimed to explore the potential therapeutic mechanism of TJQW in coronavirus disease 2019 (COVID-19) based on an integrated network pharmacology approach. Methods: TCMSP were used to search and screen the active ingredients in TJQW. The Swiss TargetPrediction was used to predict the potential targets of active ingredients. Genes co-expressed with ACE2 were considered potential therapeutic targets on COVID-19. Venn diagram was created to show correlative targets of TJQW against COVID-19. Cytoscape was used to construct a "drug-active ingredient-potential target" network, STRING were used to construct protein-protein interaction network, and cytoHubba performed network topology analysis. Enrichment of biological functions and signaling pathways of core targets was performed by using the clusterProfiler package in R software and ClueGO with CluePedia plugins in Cytoscape. Results: A total of 156 active ingredients were obtained through oral bioavailability and drug-likeness screenings. Two hundred twenty-seven potential targets of TJQW were related to COVID-19. The top ten core targets are EGFR, CASP3, STAT3, ESR1, FPR2, F2, BCL2L1, BDKRB2, MPO, and ACE. Based on that, we obtained 19 key active ingredients: umbelliprenin, quercetin, kaempferol, luteolin, praeruptorin E, stigmasterol, and oroxylin A. And the enrichment analysis obtained multiple related gene ontology functions and signaling pathways. Lastly, we constructed a key network of "drug-component-target-biological process-signaling pathway". Our findings suggested that TJQW treatment for COVID-19 was associated with elevation of immunity and suppression of inflammatory stress, including regulation of inflammatory response, viral process, neutrophil mediated immunity, PI3K-Akt signaling pathway, MAPK signaling pathway, Jak-STAT signaling pathway, Complement and coagulation cascades, and HIF-1 signaling pathway. Conclusions: Our study uncovered the pharmacological mechanism underlying TJQW treatment for COVID-19. These results should benefit efforts for people around the world to gain more knowledge about Chinese medicine TJQW in the treatment of this vicious epidemic COVID-19, and help to address this pressing problem currently facing the world. [ABSTRACT FROM AUTHOR]

A experimental observation is presented on the N2O+ photodissociation process, which exhibits a complete channel switching effect in a narrow energy range. The N2O+ ions, prepared at the X 2Π (000) state by (3+1) multiphoton ionization of neutral N2O molecules at 360.6 nm, were excited to different vibrational levels in the A 2Σ+ state in a wavelength range of 275–328 nm. Based on the estimates of total released kinetic energies from the time-of-flight mass spectrum, it was found that the dissociation pathway of N2O+(A 2Σ+), NO+(X 1Σ+)+N(4S) with lower dissociation limit, changes abruptly and completely to NO+(X 1Σ+)+N(2D) with higher dissociation limit, in a excitation energy range of merely 250 cm-1 at λ∼312.5 nm. This phenomenon was explained by competition between the two dissociation pathways across the special excitation energy region. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We present a sample of 48 nearby galaxies with central, biconical outflows identified by the Mapping Nearby Galaxies at APO survey. All considered galaxies have star-formation-driven biconical (SFB) central outflows, with no signs of an active galactic nucleus. We find that the SFB outflows require high central concentration of the star formation rate. This increases the gas velocity dispersion over the equilibrium limit and helps maintain the gas outflows. The central starbursts increase the metallicity, extinction, and the [α/Fe] ratio in the gas. A significant amount of young stellar population at the centers suggests that the SFBs are associated with the formation of young bulges in galaxies. More than 70% of SFB galaxies are group members or have companions with no prominent interaction, or show asymmetry of external isophotes. In 15% of SFB cases, stars and gas rotate in the opposite directions, which points at the gas infall from satellites as the primary reason for triggering the SFB phenomena. [ABSTRACT FROM AUTHOR]

Zika (ZIKV) and dengue (DENV) virus infections elicit a robust but cross-reactive antibody response against the viral envelope protein, while antibody responses against non-structural proteins (NS) are more virus specific. Building on this premise, we have previously developed a flavivirus multiplex microsphere immunoassay (MIA) for the serologic diagnosis of ZIKV and DENV infections. This assay significantly improved diagnostic accuracy; however, MIA could not differentiate more recent from past infections, which still represents a major diagnostic challenge. Therefore, an immunoglobulin G (IgG) based avidity assay was developed and its diagnostic performance evaluated. Specimens from New York State residents were submitted to the Wadsworth Center New York State Department of Health (NYSDOH) for routine clinical testing by Zika IgM ELISA and plaque reduction neutralization test (PRNT). Using our previously developed flavivirus MIA as a platform, we developed an IgG avidity assay to discriminate recent ZIKV from past DENV infections. Zika IgM positive specimens had an average Zika IgG avidity index of 14.8% (95% CI: 11.0-18.4%), while Zika IgM negative but flavivirus MIA and PRNT positive samples had an average Zika IgG avidity index of 34.9% (95% CI: 31.1-38.7%). Specimens positive for dengue antibodies by flavivirus MIA and PRNT had an average dengue IgG avidity index of 68.7% (95% CI: 62.7-75.0%). The IgG avidity assay accurately distinguished recent ZIKV from past DENV infections in patients who traveled to dengue endemic regions. This assay could be very useful in patients with high risk of Zika complications such as pregnant women and monitoring immune responses in vaccine trials. [ABSTRACT FROM AUTHOR]

In this study, a 'microgrid community' (MGC) consisting of multiple microgrids (MGs) is investigated. Each MG is a self-governed entity and independently decides how much power is in need or can provide. Neighbouring MGs are aggregated by a multi-terminal energy router (ER), forming a MGC, which is then connected to the distribution network at one terminal. Other terminals are connected to those MGs and all terminals share a common DC link. A concise trading mechanism is proposed to coordinate the involved MGs. Every MG submits its power requirement to the ER in real time and the ER decides how much to accept, fully or with a discount, according to the DC-link voltage level. Meanwhile, a price stimulation mechanism based on the DC-link voltage deviation is designed to exploit the potential of the MGs in power generation and consumption. The ER has no central controllers and the proposed bargaining process is achieved at each terminal without mutual communications. The control strategy is fully distributed and will benefit the scalability and plug-and-play of such an MGC. Simulation results are provided to validate the proposed solution for the operation of multi-microgrid systems. [ABSTRACT FROM AUTHOR]

The E3 ubiquitin ligase Pellino 1 (Peli1) is a microglia-specific mediator of autoimmune encephalomyelitis. Its role in neurotropic flavivirus infection is largely unknown. Here, we report that mice deficient in Peli1 (Peli1-/-) were more resistant to lethal West Nile virus (WNV) infection and exhibited reduced viral loads in tissues and attenuated brain inflammation. Peli1 mediates chemokine and proinflammatory cytokine production in microglia and promotes T cell and macrophage infiltration into the CNS. Unexpectedly, Peli1 was required for WNV entry and replication in mouse macrophages and mouse and human neurons and microglia. It was also highly expressed on WNV-infected neurons and adjacent inflammatory cells from postmortem patients who died of acute WNV encephalitis. WNV passaged in Peli1-/- macrophages or neurons induced a lower viral load and impaired activation in WT microglia and thereby reduced lethality in mice. Smaducin-6, which blocks interactions between Peli1 and IRAK1, RIP1, and IKKε, did not inhibit WNV-triggered microglia activation. Collectively, our findings suggest a nonimmune regulatory role for Peli1 in promoting microglia activation during WNV infection and identify a potentially novel host factor for flavivirus cell entry and replication. [ABSTRACT FROM AUTHOR]

In this paper we propose a Hamiltonian approach to gapped topological phases on open surfaces. Our setting is an extension of the Levin-Wen model to a 2d graph on an open surface, whose boundary is part of the graph. We systematically construct a series of boundary Hamiltonians such that each of them, when combined with the usual Levin-Wen bulk Hamiltonian, gives rise to a gapped energy spectrum which is topologically protected. It is shown that the corresponding wave functions are robust under changes of the underlying graph that maintain the spatial topology of the system. We derive explicit ground-state wavefunctions of the system on a disk as well as on a cylinder. For boundary quasiparticle excitations, we are able to construct their creation, annihilation, measuring and hopping operators etc. Given a bulk string-net theory, our approach provides a classification scheme of possible types of gapped boundary conditions by Frobenius algebras (modulo Morita equivalence) of the bulk fusion category; the boundary quasiparticles are characterized by bimodules of the pertinent Frobenius algebras. Our approach also offers a set of concrete tools for computations. We illustrate our approach by a few examples. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection during pregnancy can cause devastating congenital abnormities or fetal demise. Zika virus infection could also cause Guillain-Barré syndrome in adults. Mosquito control, vaccine, and therapeutics are 3 potential, effective means to prevent ZIKV infection. Here we review the current status of ZIKV drug discovery. Both small molecule inhibitors and therapeutic antibodies have been identified, some of which have shown promising efficacy in mouse models. Most inhibitors were identified through screening US Food and Drug Administration-approved drugs and clinical trial compounds; however, none of them were potent enough to justify a ZIKV clinical trial. Such a repurposing approach has also been pursued for dengue therapy, with several compounds tested in clinical trials showing no clinical benefits. Because pregnant women are the main target population for ZIKV treatment, therapeutic candidates could be developed through a 2-stage path. The first stage should demonstrate safety and efficacy in nonpregnant patients. Once efficacy has been demonstrated in nonpregnant patients, the candidates should be rapidly advanced to stage 2 for safety and efficacy evaluation in pregnant patients. The 2-stage developmental path is supported by previous results from trials with other viral infections that showed that treatment of pregnant women with antiviral drugs or hyperimmunoglobulins significantly reduced congenital abnormalities in neonates. [ABSTRACT FROM AUTHOR]

Confirmed reports of Zika virus (ZIKV) in human seminal fluid for months after the clearance of viremia suggest the ability of ZIKV to establish persistent infection in the seminiferous tubules, an immune-privileged site in the testis protected by the blood-testis barrier, also called the Sertoli cell (SC) barrier (SCB). However, cellular targets of ZIKV in human testis and mechanisms by which the virus enters seminiferous tubules remain unclear. We demonstrate that primary human SCs were highly susceptible to ZIKV compared to the closely related dengue virus and induced the expression of alpha interferon (IFN-α), key cytokines, and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1] and intracellular adhesion molecule 1 [ICAM-1]). Furthermore, using an in vitro SCB model, we show that ZIKV was released on the adluminal side of the SCB model with a higher efficiency than in the blood-brain barrier model. ZIKV-infected SCs exhibited enhanced adhesion of leukocytes that correlated with decreases in SCB integrity. ZIKV infection did not affect the expression of tight and adherens junction proteins such as ZO-1, claudin, and JAM-A; however, exposure of SCs to inflammatory mediators derived from ZIKV-infected macrophages led to the degradation of the ZO-1 protein, which correlated with increased SCB permeability. Taken together, our data suggest that infection of SCs may be one of the crucial steps by which ZIKV gains access to the site of spermatozoon development and identify SCs as a therapeutic target to clear testicular infections. The SCB model opens up opportunities to assess interactions of SCs with other testicular cells and to test the ability of anti-ZIKV drugs to cross the barrier. IMPORTANCE Recent outbreaks of ZIKV, a neglected mosquito-borne flavivirus, have identified sexual transmission as a new route of disease spread, which has not been reported for other flaviviruses. To be able to sexually transmit for months after the clearance of viremia, ZIKV must establish infection in the seminiferous tubules, the site of spermatozoon development. However, little is known about the cell types that support ZIKV infection in the human testis. Currently, there are no models to study mechanisms of virus persistence in the seminiferous tubules. We provide evidence that ZIKV infection of human Sertoli cells, which are an important component of the seminiferous tubules, is robust and induces a strong antiviral response. The use of an in vitro Sertoli cell barrier to describe how ZIKV or inflammatory mediators derived from ZIKV-infected macrophages compromise barrier integrity will enable studies to explore the interactions of other testicular cells with Sertoli cells and to test novel antivirals for clearing testicular ZIKV infection. [ABSTRACT FROM AUTHOR]

Background: This study is to investigate the effect of fenofibrate on the bone quality of Type 2 diabetes mellitus (T2DM) mouse model. Methods: T2DM mouse model was induced by high-fat-diet, and the mice were treated with fenofibrate (100 mg/kg) (DIO-FENO) or PBS (DIO-PBS) for 4 weeks. The bone microstructure and biomechanical properties of femora were analyzed by micro-CT and 3-Point bending test. The protein expression was detected by immunohistochemical staining and Western blot. The cell apoptosis was evaluated by TUNEL staining. The Bcl2, caspase 3, and osteoblast marker genes were detected by RT-qPCR. Results: The biomechanical properties of bones from DIO-FENO group were significantly lower than those in the control and DIO-PBS groups. Besides, the trabecular number was lower than those of the other groups, though the cortical porosity was decreased compared with that of DIO-PBS group because of the increase of apoptotic cells. The expression of osteocalcin and collagen I were decreased after treatment with fenofibrate in T2DM mice. Moreover, the cell viability was decreased after treated with different concentrations of fenofibrate, and the expression of Runx2 decreased after treated with high dose of fenofibrate. Conclusion: Fenofibrate decreases the bone quality of T2DM mice through decreasing the expression of collagen I and osteocalcin, which may be resulted from the down regulation of Runx2 expression. [ABSTRACT FROM AUTHOR]

We investigate the energy sources of random turbulent motions of ionized gas from Ha emission in eight local star-forming galaxies from the Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey. These galaxies satisfy strict pure star-forming selection criteria to avoid contamination from active galactic nuclei (AGNs) or strong shocks/outflows. Using the relatively high spatial and spectral resolution of SAMI, we find that - on sub-kpc scales, our galaxies display a flat distribution of ionized gas velocity dispersion as a function of star formation rate (SFR) surface density. A major fraction of our SAMI galaxies shows higher velocity dispersion than predictions by feedback-driven models, especially at the low SFR surface density end. Our results suggest that additional sources beyond star formation feedback contribute to driving random motions of the interstellar medium in star-forming galaxies.We speculate that gravity, galactic shear and/or magnetorotational instability may be additional driving sources of turbulence in these galaxies. [ABSTRACT FROM AUTHOR]