Pseudorabies virus tegument protein UL13 recruits RNF5 to inhibit STING-mediated antiviral immunity

Pseudorabies virus (PRV) has evolved various immune evasion mechanisms that target host antiviral immune responses. However, it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune evasion. Here, we show that PRV tegument protein UL13 inhibits STING-mediated antiviral signaling via regulation of STING stability. Mechanistically, UL13 interacts with the CDN domain of STING and recruits the E3 ligase RING-finger protein 5 (RNF5) to promote K27-/K29-linked ubiquitination and degradation of STING. Consequently, deficiency of RNF5 enhances host antiviral immune responses triggered by PRV infection. In addition, mutant PRV lacking UL13 impaired in antagonism of STING-mediated production of type I IFNs and shows attenuated pathogenicity in mice. Our findings suggest that PRV UL13 functions as an antagonist of IFN signaling via a novel mechanism by targeting STING to persistently evade host antiviral responses.     

A novel 3’tRNA-derived fragment tRF-Val promotes proliferation and inhibits apoptosis by targeting EEF1A1 in gastric cancer

At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3’tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.Subject terms: Cancer genomics, Small RNAs     

Chemical Reaction Networks’ Programming for Solving Equations

The computational ability of the chemical reaction networks (CRNs) using DNA as the substrate has been verified previously. To solve more complex computational problems and perform the computational steps as expected, the practical design of the basic modules of calculation and the steps in the reactions have become the basic requirements for biomolecular computing. This paper presents a method for solving nonlinear equations in the CRNs with DNA as the substrate. We used the basic calculation module of the CRNs with a gateless structure to design discrete and analog algorithms and realized the nonlinear equations that could not be solved in the previous work, such as exponential, logarithmic, and simple triangle equations. The solution of the equation uses the transformation method, Taylor expansion, and Newton iteration method, and the simulation verified this through examples. We used and improved the basic calculation module of the CRN++ programming language, optimized the error in the basic module, and analyzed the error’s variation over time.     

Molecular Characteristics and Potent Immunomodulatory Activity of Fasciola hepatica Cystatin

Cystatin, a cysteine protease inhibitor found in many parasites, plays important roles in immune evasion. This study analyzed the molecular characteristics of a cystatin from Fasciola hepatica (FhCystatin) and expressed recombinant FhCystatin (rFhcystatin) to investigate the immune modulatory effects on lipopolysaccharide-induced proliferation, migration, cytokine secretion, nitric oxide (NO) production, and apoptosis in mouse macrophages. The FhCystatin gene encoded 116 amino acids and contained a conserved cystatin-like domain. rFhCystatin significantly inhibited the activity of cathepsin B. rFhCystatin bound to the surface of mouse RAW264.7 cells, significantly inhibited cell proliferation and promoted apoptosis. Moreover, rFhCystatin inhibited the expression of cellular nitric oxide, interleukin-6, and tumor necrosis factor-α, and promoted the expression of transforming growth factor-β and interleukin-10. These results showed that FhCystatin played an important role in regulating the activity of mouse macrophages. Our findings provide new insights into mechanisms underlying the immune evasion and contribute to the exploration of potential targets for the development of new drug to control F. hepatica infection.     

Is negative density‐dependent reproduction regulated by density‐induced stress in root voles? Two field experiments

Density dependence in reproduction plays an important role in stabilizing population dynamics via immediate negative feedback from population density to reproductive output. Although previous studies have shown that negative density‐dependent reproduction is associated with strong spacing behavior and social interaction between individuals, the proximal mechanism for generating negative density‐dependent reproduction remains unclear. In this study, we investigated the effects of density‐induced stress on reproduction in root voles. Enclosed founder populations were established by introducing 6 (low density) and 30 (high density) adults per sex into per enclosure (four enclosures per density in total) during the breeding season from April to July 2012 and from May to August 2015. Fecal corticosterone metabolite (FCM) levels, reproductive traits (recruitment rate and the proportion of reproductively active individuals), and founder population numbers were measured following repeated live trapping in both years. The number of founders was negatively associated with recruitment rates and the proportion of reproductively active individuals, displaying a negative density‐dependent reproduction. FCM level was positively associated with the number of founders. The number of founder females directly affected the proportion of reproductive females, and directly and indirectly through their FCM levels affected the recruitment rate; the effect of the number of male founders on the proportion of reproductive males was mediated by their FCM level. Our results showed that density‐induced stress negatively affected reproductive traits and that density‐induced stress is one ecological factor generating negative density‐dependent reproduction.     

Preexisting Trichinella spiralis infection attenuates the severity of Pseudomonas aeruginosa-induced pneumonia

BackgroundA range of helminth species involve the migration of developing larvae through the lung and establish chronic infections in the host that include potent immune regulatory effects. Trichinella spiralis is one of the most successful parasitic symbiotes. After released by intestinal female adult worms, newborn larvae of T. spiralis travel through the circulatory system to the lung and finally reach skeletal muscle cells. As unique inflammation modulator of intracellular parasitism, T. spiralis shows improved responses to autoimmune disease and viral pulmonary inflammation by exerting immunomodulatory effects on innate and adaptive immune cells.Methodology/Principal findingsC57BL/6 mice were divided into four groups: uninfected; helminth- T. spiralis infected; P. aeruginosa infected; and co-infected. Mice infected with T. spiralis were incubated for 6 weeks, followed by P. aeruginosa intranasal inoculation. Bronchial alveolar lavage fluid, blood and lung samples were analyzed. We found that T. spiralis induced Th2 response in the mouse lung tissue, increased lung CD4⁺ T cells, GATA3, IL-4, IL-5 and IL-13 expression. Pre-existing T. spiralis infection decreased lung neutrophil recruitment, inflammatory mediator IL-1β and IL-6 expression and chemokine CXCL1 and CXCL2 release during P. aeruginosa- pneumonia. Furthermore, T. spiralis co-infected mice exhibited significantly more eosinophils at 6 hours following P. aeruginosa infection, ameliorated pulmonary inflammation and improved survival in P. aeruginosa pneumonia.ConclusionsThese findings indicate that a prior infection with T. spiralis ameliorates experimental pulmonary inflammation and improves survival in P. aeruginosa pneumonia through a Th2-type response with eosinophils.     

Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors

The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays in vitro. Among them, compounds H34, H42, H48, and H52 displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays in vitro and in vivo proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound H52 exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.

HIGHLIGHTS

• Structural fusion was used to screen brain penetrating PARP-1 inhibitors.
• 55 benzodiazepines were evaluated for their PARP-1 inhibition activity.
• Four compounds displayed acceptable inhibition effects on breast cancer cells.
• The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.

     

克隆植物种子繁殖和营养繁殖的适合度分析和度量

植物种群繁殖的适合度指繁殖行为适应环境变化的能力及其对各群更新发展的贡献,不仅表现在个体水平也表现在基因水平。提出度量种子繁殖和营养繁殖在个体和基因水平的适合度的计算公式,并计算了白三叶草繁殖的适合度,较好地解释了种子繁殖和营养繁殖对克隆植物种群更新发展朱同作用。     

山东近海生态资本价值评估——供给服务价值

海洋生态资本是沿海地区社会经济活动的重要生产要素,供给服务价值是海洋生态资本价值的关键构成要素之一。选择养殖生产、捕捞生产和氧气生产3个指标,分别采用市场价格法和替代成本法对山东近海生态系统提供的供给服务价值进行了评估,并揭示山东近海供给服务价值的空间分布规律。山东近海3.16万km²的海域,2008年产出的供给服务价值为574.1亿元,占全省沿海地级市生产总值的3.62%。其中,养殖生产价值452.86亿元,捕捞生产价值66.02亿元,氧气生产价值55.23亿元。山东沿海7个地级市比较,威海和烟台近海的供给服务价值最高,分别为180亿元和169.13亿元;其次是青岛近海,为103.58亿元;滨州、潍坊、日照和东营近海较低且相差不大。山东近海生态系统供给服务价值的分布密度平均为167.7万元/km²。供给服务价值的高值区集中分布于青岛和日照近海,中值区主要分布于威海和烟台近海,滨州、东营和潍坊近海的分布密度较低。山东近海生态系统供给服务价值空间分布遵守从近岸向外海总体降低的规律,有养殖区分布的局部海域,供给服务价值较高。山东近海供给服务与调节服务、支持服务存在正相关的关系,养殖生产、捕捞生产、氧气生产3项服务之间也存在互相促进的关系。山东近海供给服务价值,尤其是养殖生产对山东沿海经济发展有着重要的支撑作用。