Zika virus (ZIKV) has evolved into a global health threat because of its unexpected causal link to microcephaly. Phylogenetic analysis reveals that contemporary epidemic strains have accumulated ...multiple substitutions from their Asian ancestor. Here we show that a single serine-to-asparagine substitution Ser139→Asn139 (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs) and led to more severe microcephaly in the mouse fetus, as well as higher mortality rates in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
A
bstract
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.
Sentiment analysis, which refers to the task of detecting whether a textual item (e.g., a product review and a blog post) expresses a positive or negative opinion in general or about a given entity ...(e.g., a product, person, or policy), has received increasing attention in recent years. It serves as an important role in natural language processing. User generated content, like tourism reviews, developed dramatically during the past years, generating a large amount of unstructured data from which it is hard to obtain useful information. Due to the changes in textual order, sequence length and complicated logic, it is still a challenging task to predict the exact sentiment polarities of the user reviews, especially for fine-grained sentiment classification. In this paper, we first propose sentiment padding, a novel padding method compared with zero padding, making the input data sample of a consistent size and improving the proportion of sentiment information in each review. Inspired by the most recent studies with respect to neural networks, we propose deep learning based sentiment analysis models named lexicon integrated two-channel CNN–LSTM family models, combining CNN and LSTM/BiLSTM branches in a parallel manner. Experiments on several challenging datasets, like Stanford Sentiment Treebank, demonstrate that the proposed method outperforms many baseline methods.
•We proposed sentiment padding to improve the proportion of sentiment information in each review.•We presented lexicon integrated two-channel CNN–BiLSTM model.•This paper studied the influence of the skip connection operation on two-channel deep model.•Experiment showed superiority of the proposed model on analyzing English and Chinese reviews.
Lycopene (Lyc) as a natural antioxidant has attracted widespread attention. Di(2-ethylhexyl) phthalate (DEHP) can cause serious spleen injury in animals via the environment and food chain. For ...investigation of whether Lyc could alleviate DEHP-exerted pyroptosis in spleen through inhibiting the Caspase-1/NLRP3 pathway activation, 140 male mice were randomly divided into 7 groups: control group, vehicle control group, Lyc group (5 mg/kg BW/day), DEHP-exposed group (500 or 1000 mg/kg BW/day, respectively), and DEHP + Lyc groups by daily administration for 28 days. Pathological results showed that the supplementation of Lyc alleviated DEHP-induced inflammatory infiltration. Moreover, the addition of Lyc inhibited DEHP-induced Caspase-1, NLRP3, ASC, NF-κB, IL-1β, and IL-18 overexpression and GSDMD down-expression. These results indicate that Lyc could inhibit DEHP-induced Caspase-1-dependent pyroptosis and the inflammatory response. Taken together, the study provided new evidence that Lyc may be a strategy to mitigate spleen injury induced by DEHP.
The ongoing outbreak of viral pneumonia in China and across the world is associated with a new coronavirus, SARS-CoV-2
. This outbreak has been tentatively associated with a seafood market in Wuhan, ...China, where the sale of wild animals may be the source of zoonotic infection
. Although bats are probable reservoir hosts for SARS-CoV-2, the identity of any intermediate host that may have facilitated transfer to humans is unknown. Here we report the identification of SARS-CoV-2-related coronaviruses in Malayan pangolins (Manis javanica) seized in anti-smuggling operations in southern China. Metagenomic sequencing identified pangolin-associated coronaviruses that belong to two sub-lineages of SARS-CoV-2-related coronaviruses, including one that exhibits strong similarity in the receptor-binding domain to SARS-CoV-2. The discovery of multiple lineages of pangolin coronavirus and their similarity to SARS-CoV-2 suggests that pangolins should be considered as possible hosts in the emergence of new coronaviruses and should be removed from wet markets to prevent zoonotic transmission.
The core purpose of cancer immunotherapy is the sustained activation and expansion of the tumor specific T cells, especially tumor-infiltrating cytotoxic T lymphocytes (CTLs). Currently, one of the ...main foci of immunotherapy involving nano-sized carriers is on cancer vaccines and the role of professional antigen presenting cells, such as dendritic cells (DCs) and other phagocytic immune cells. Besides the idea that cancer vaccines promote T cell immune responses, targeting immune inhibitory pathways with nanoparticle delivered regulatory agents such as small interfering RNA (siRNA) to the difficultly-transfected tumor-infiltrating T cells may provide more information on the utility of nanoparticle-mediated cancer immunotherapy. In this study, we constructed nanoparticles to deliver cytotoxic T lymphocyte-associated molecule-4 (CTLA-4)-siRNA (NPsiCTLA-4) and showed the ability of this siRNA delivery system to enter T cells both in vitro and in vivo. Furthermore, T cell activation and proliferation were enhanced after NPsiCTLA-4 treatment in vitro. The ability of direct regulation of T cells of this CTLA-4 delivery system was assessed in a mouse model bearing B16 melanoma. Our results demonstrated that this nanoparticle delivery system was able to deliver CTLA-4-siRNA into both CD4+ and CD8+ T cell subsets at tumor sites and significantly increased the percentage of anti-tumor CD8+ T cells, while it decreased the ratio of inhibitory T regulatory cells (Tregs) among tumor infiltrating lymphocytes (TILs), resulting in augmented activation and anti-tumor immune responses of the tumor-infiltrating T cells. These data support the use of potent nanoparticle-based cancer immunotherapy for melanoma.
T cell mediated immunotherapy is an effective treatment option for malignant melanoma. It is critical for such immunotherapy to obtain a sufficient number of functional/activated T cells. However, CTLA-4 plays a potent inhibitory role in T cell activation and proliferation, which significantly curbs T cell-mediated tumor rejection. Hence, we investigated a method to exploit a nanoparticle delivery system to efficiently deliver siRNA (NPsiCTLA-4) targeting an immune checkpoint molecule, i.e. cytotoxic T lymphocyte-associated molecule-4, to manipulate or modulate tumor-infiltrating T cells and to assess the effects of NPsiCTLA4 on the blockade of CTLA-4 and the resulting enhancement of T cell mediated anti-tumor immunotherapy. Display omitted
Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus ...(ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients.
Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer to improve product flexibility and workability. Lycopene (LYC) is a natural compound and has promising preventive potentials, ...especially antireproductive toxicity, but the specific underlying mechanism is yet to be fully defined. Our study investigated the effect of LYC on DEHP-induced spermatogenesis disorders. Male ICR mice were treated with DEHP (500 or 1000 mg/kg BW/day) and/or LYC (5 mg/kg BW/day) for 28 days. Our results indicated that LYC could relieve the DEHP-induced injury of seminiferous tubules and spermatogenic cells, swelling of endoplasmic reticulum (ER), and an increase of mitochondria. LYC prevented increased levels of nuclear damage to DNA and the deformity rate and decreased values of sperm motility, number, and density. Moreover, LYC treatment decreased DEHP-induced nuclear accumulation of aryl hydrocarbon receptor (AHR) and AHR nuclear translocator (ARNT), and the expressions of their downstream target genes such as cytochrome P450-dependent monooxygenases (CYP) 1A1, 1A2, and 1B1 were markedly reduced to normal in the LYC treatment group. Our study showed that LYC can prevent DEHP-induced spermatogenic disorders via an AHR/ARNT signaling system. This study provided new evidence of AHR as a target for LYC, which can prevent DEHP-induced toxicity.
An increasing number of epidemiologic studies show that women have a special exposure profile to phthalates, and the exposures have attracted attention regarding their potential health hazards. Here, ...we developed a model for studying the ovarian action of di-(2-ethylhexyl) phthalate (DEHP) and its major metabolite monoethylhexyl phthalate (MEHP). In vivo, treatment with DEHP (250, 500, and 1000 mg kg^-1) induced decreased thickness of ovarian granulosa cell layer and mitochondrial damage in quail, caused oxidative stress, interfered with the transcription of hypothalamic-pituitary-ovarian axis (HPOA) steroid hormone-related factors (increased transcription of StAR, 3β-HSD, P450scc, and LH and decreased transcription of 17β-HSD, P450arom, FSH, and ERβ), and blocked the secretion of steroid hormones (decreased FSH, E2, and T levels and increased LH, P, and PRL levels). In vitro, granulosa cells were cultured with MEHP (50, 100, and 200 μM), activator of PPARγ (rosiglitazone, 50 μM), or antagonist of PPARγ (GW9662, 10 μM) for 24 h and gene and protein expression were analyzed by real time RT-PCR and western blot. Rosiglitazone, like MEHP, significantly decreased mRNA and protein levels of P450arom. Antagonist GW9662 partially blocked the suppression of P450arom by MEHP, suggesting that MEHP acts through PPARγ, but not exclusively. Our model shows that MEHP acts on granulosa cells in quail by stimulating PPARs, which leads to decreased gene and protein expression of P450arom. Therefore, the environmental endocrine disruptor DEHP and its major metabolite MEHP act through a receptor-mediated signaling pathway to inhibit the production of estradiol, interfere with the modulation of HPOA, suppress the synthesis of sex hormones, and cause sex hormone secretion disorders, resulting in severe toxicity in the female reproductive system. A framework for an adverse outcome pathway of DEHP/MEHP-induced ovarian toxicity was constructed, which can facilitate an improved understanding of the mechanism of female reproductive toxicity.
The environmental contaminant DEHP and its metabolite MEHP act through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, interfere with the regulation of the hypothalamus-pituitary-ovarian gonadal axis, hinder the synthesis of sex hormones, and trigger sex hormone secretion disorders, leading to serious dose-dependent toxicity of the reproductive system. A framework for an adverse outcome pathway of DEHP/MEHP-induced ovarian toxicity was constructed, which can facilitate an improved understanding of the mechanism of female reproductive toxicity. Display omitted
•Exposure to DEHP induced ovarian developmental disorders in quail.•DEHP disrupted sex hormone levels by interfering with the regulation of HPOA.•MEHP decreased aromatase level in the granulosa cell by activating the PPARs.•DEHP and its metabolite MEHP lead to toxicity on the reproductive system.•A framework for an AOP of DEHP/MEHP-induced ovarian toxicity was constructed.
The function of follicular regulatory T (TFR) cells, especially in regulating IgE production in patients with allergic diseases, is poorly understood.
We sought to investigate the phenotype, ...function, and clinical relevance of TFR cells in patients with allergic rhinitis (AR).
The phenotype and frequency of tonsillar and circulating TFR cells were characterized by using flow cytometry. TFR cell function was examined in an assay by coculturing with follicular helper T cells and B cells. The associations between TFR cells and the clinical features in patients with AR before and after allergen immunotherapy (AIT) were analyzed.
TFR cells were detected in germinal centers of tonsils, but compared with subjects without AR, the frequencies decreased in patients with AR who were allergic to house dust mites. Circulating TFR cells in blood were phenotypically and numerically correlated with tonsillar TFR cells, and a reduction of circulating TFR cells but not total or CXCR5− regulatory T cells was noted in patients with AR compared with healthy control subjects. Moreover, circulating TFR cells in patients with AR showed a specific defect in suppressing IgE production but were capable of suppressing production of other immunoglobulin types. We identified negative associations of circulating TFR cell frequencies and function with antigen-specific IgE levels or disease severity in patients with AR. After AIT, the frequencies and function of circulating TFR cells were improved, which positively associated with disease remission.
Impairment in TFR cells might contribute to aberrant IgE production in patients with AR, and AIT improves defective TFR cell function. TFR cells might serve as a potential biomarker to monitor clinical response to AIT.
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