ISGylation by HERCs facilitates STING activation.

Optimal activation of stimulator of interferon genes (STING) protein is crucial for host defenses against pathogens and avoiding detrimental effects. Various post-translational modifications control STING activity. However, the function of interferon (IFN)-stimulated gene (ISG) 15 modification (ISGylation) in controlling STING stability and activation is unclear. Here, we show that the E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation. Concordantly, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo. Notably, severe acute respiratory syndrome coronavirus 2 protein papain-like protease cleaves HERC5-mediated ISGylation of STING, suppressing host antiviral responses. These data identify a mechanism by which HERCs-mediated ISGylation controls STING stability and activation and uncover the correlations and interactions of ISGylation and ubiquitination during STING activation.

Robustness improvement of a nitrogen-vacancy magnetometer by a double driving method.

The nitrogen vacancy (NV) color center in diamonds is an electron spin that can measure magnetic fields with high sensitivity and resolution. Furthermore, the robustness of an NV-based quantum system should be improved for further application in other sensing methods and in the exploration of basic physics. In this work, the robustness of an NV magnetometer is improved by the double driving method. The sensitivity of the NV magnetometer was improved 2.1 times by strengthening the pumping power from 100 to 600 mW. In this process, thermal drift was introduced, which affects the measurement accuracy. The temperature drift of a diamond matrix was measured using an infrared camera, and the temperature change of a diamond host drifted to ∼80 K under high laser and microwave power. To address the drift of temperature owing to sensitivity improvement by pumping enhancement, the double driving method was introduced, to suppress the drift of the resonance frequency, to improve the robustness of a continuous-wave NV magnetometer. The magnetic noise density was improved from 10 to 1.2 nT/Hz1/2. This study checked the source of temperature noise in the process of measuring with the NV color centers and proposes a double driving measurement method to track the resonant frequency change due to environmental temperature drift and improve sensitivity. The findings of this study are useful in applying complex pulse protocols in high-level sensing applications based on solid-state spin.

Mitochondrial folate metabolism-mediated α-linolenic acid exhaustion masks liver fibrosis resolution.

Sustainable TGF-ß1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-ß1 signaling remains unclear. In this study, we revealed that dietary folate restriction promoted the resolution of liver fibrosis in mice with nonalcoholic steatohepatitis. In activated hepatic stellate cells, folate shifted toward mitochondrial metabolism to sustain TGF-ß1 signaling. Mechanistically, nontargeted metabolomics screening identified that α-linolenic acid (ALA) is exhausted by mitochondrial folate metabolism in activated hepatic stellate cells. Knocking down serine hydroxymethyltransferase 2 increases the bioconversion of ALA to docosahexaenoic acid, which inhibits TGF-ß1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in nonalcoholic steatohepatitis mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/TGF-ßR1 reproduction is a feedforward signaling to sustain profibrotic TGF-ß1 signaling, and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.

CSRR Structure Design for NV Spin Manipulation with Microwave Strength and Fluorescence Collection Synchronous Enhancement.

In this work, we designed, simulated, and tested a complementary split ring resonator (CSRR) for the purpose of applying a strong and uniform microwave field for the manipulation of nitrogen vacancy (NV) ensembles. This structure was fabricated by etching two concentric rings on a flat metal film that was deposited on a printed circuit board. A metal transmission on the back plane was used as the feed line. The fluorescence collection efficiency was improved by about 2.5 times with the CSRR structure compared to that without CSRR. Furthermore, the maximum Rabi frequency could reach 11.3 MHz, and the Rabi frequency variation was smaller than 2.8% in an area of 250 × 75 µm. This could pave the way to achieving high-efficiency control of the quantum state for spin-based sensor applications.

The efficacy and safety of the Xuesaitong soft capsule in the treatment of patients with ischemic stroke: systematic review and meta-analysis.

BACKGROUND: Ischaemic stroke is a common neurological disease and a leading cause of severe disability and death in developed countries. In most cases, stroke is thought to be a multifactorial disorder or complex trait for which classic patterns of inheritance cannot be shown. Xuesaitong is one of the most commonly used medicines for treating ischemic stroke in China. However, compared to the conventional therapy, the effectiveness and safety of Xuesaitong for ischemic stroke needs to be further systematically reviewed and determined. METHODS: Relevant randomized controlled trials (RCTs) examining the use of the Xuesaitong soft capsule in the treatment of patients with ischemic stroke were identified from databases, including the China National Knowledge Infrastructure, Wanfang, PubMed, Embase, and Web of Science databases. Next, 2 researchers independently extracted information from the included studies, analyzed the data using STATA 15.0 software, and evaluated the quality of the included studies using RevMan 5.3. RESULTS: A total of 17 RCTs (comprising 1,942 patients with ischemic stroke) were included in the meta-analysis. The meta-analysis results showed that the Xuesaitong soft capsule treatment increased patients' total effective rate compared to conventional or other drug treatments, and improved patients' Clinical Severity Score (CSS scores) or Barthel index (BI) score. A further subgroup analysis stratified by different treatment times showed that Xuesaitong soft capsule treatment at 4 and 8 weeks improved CSS scores more than treatment at 2 weeks in patients with ischemic stroke. Additionally, the Xuesaitong soft capsule also significantly improved plasma viscosity, whole-blood viscosity at high and low shear rates, fibrinogen, hematocrit, and the effect on traditional Chinese medicine (TCM) single symptoms or signs in patients with ischemic stroke. DISCUSSION: In summary, compared to conventional or other drug treatments, the Xuesaitong soft capsule treatment was beneficial in improving patients' TCM symptoms (e.g., crooked mouth and tongue, and dizziness) and various indicators. Further, Xuesaitong soft capsule may be a safe and effective drug for the treatment of ischemic stroke. And large-scale randomized clinical trials are needed to further confirm our findings.

[Effects of Pollution Control of Xiaoqing River on Environment Factors and Phytoplankton Community in the Laizhou Bay].

The spatial distribution of environmental factors, chlorophyll a (Chla), phytoplankton abundance, and community structure in the Laizhou Bay were investigated in August 2018 (wet season after pollution control) to clarify the effects of the pollution control of the Xiaoqing River, which is a major source of pollution, on environmental factors and phytoplankton community structure in this area. The results showed that the environmental factors changed significantly after pollution control of the Xiaoqing River. The concentrations of dissolved inorganic nitrogen (DIN), dissolved inorganic silicon (DSi), NO3-, and NO2- decreased significantly, with values only 40.1% to 60.4% of those from the same period of in 2017 (the nearest year before the pollution control), whereas dissolved inorganic phosphorus (DIP) and NH4 increased by 2.5 and 1.4 times that of their concentrations in 2017. The spatial distribution of environmental factors changed significantly, with the nutrient concentrations around the Xiaoqing River estuary noticeably decreasing. The abundance of phytoplankton cells was 21.5×106 cell·m-3, which was close to the results of a previous study, whereas the ρ(Chla) was 2.43 µg·L-1, which decreased obviously. Both microscopic analysis and pigment taxonomy suggested that phytoplankton community structure in the Laizhou Bay changed clearly, with the dominant community shifting from diatoms alone to the co-dominance of diatoms and cyanobacteria. Chaetoceros curvisetus, Skeletonema costatum, and Cerataulina pelagica, which were commonly observed in the Laizhou Bay before pollution control of the Xiaoqing River, decreased in 2018, whereas the abundance of common dominant freshwater species (e.g., Merismopedia sp. and Synedra spp.) increased significantly. Redundancy analysis (RDA) showed that the phytoplankton community was significantly related to nitrogen, phosphate (negative correlation), and salinity (negative correlation) after pollution control of the Xiaoqing River, indicating that the variation in nutrient concentration and the structure of river runoff input may be the main factors affecting phytoplankton community and dominant species structure.

Fraxinellone alleviates kidney fibrosis by inhibiting CUG-binding protein 1-mediated fibroblast activation.

Chronic Kidney Disease (CKD) is a serious threat to human health. In addition, kidney fibrosis is a key pathogenic intermediate for the progression of CDK. Moreover, excessive activation of fibroblasts is key to the development of kidney fibrosis and this process is difficult to control. Notably, fraxinellone is a natural compound isolated from Dictamnus dasycarpus and has a variety of pharmacological activities, including hepatoprotective, anti-inflammatory and anti-cancer effects. However, the effect of fraxinellone on kidney fibrosis is largely unknown. The present study showed that fraxinellone could alleviate folic acid-induced kidney fibrosis in mice in a dose dependent manner. Additionally, the results revealed that fraxinellone could effectively down-regulate the expression of CUGBP1, which was highly up-regulated in human and murine fibrotic renal tissues. Furthermore, expression of CUGBP1 was selectively induced by the Transforming Growth Factor-beta (TGF-ß) through p38 and JNK signaling in kidney fibroblasts. On the other hand, downregulating the expression of CUGBP1 significantly inhibited the activation of kidney fibroblasts. In conclusion, these findings demonstrated that fraxinellone might be a new drug candidate and CUGBP1 could be a promising target for the treatment of kidney fibrosis.

Landscape of SARS-CoV-2 spike protein-interacting cells in human tissues.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. However, the mechanism of tissue tropism of SARS-CoV-2 remains unclear. Here, recombinant receptor-binding subdomain 1 of spike protein of SARS-CoV-2 (RBD-SD1) was used as a probe to investigate the potential tropism of SARS-CoV-2 in thirty-three types of normal human tissues. RBD-SD1 probe was observed to interact with cells in reported SARS-CoV-2 infected organs. Interestingly, the RBD-SD1 probe strongly interacted with bone marrow cells in an angiotensin-converting enzyme 2 (ACE2)-independent manner. In addition, SARS-CoV-2 induced the ACE2 mRNA expression in human primary bone marrow cells, suggesting human bone marrow cells may be sensitive to SARS-CoV-2 infection. Therefore, human bone marrow cells could be strongly infected by SARS-CoV-2, which may play an important role in the pathogenesis of COVID-19. These findings provide a deeper understanding of SARS-CoV-2 infection routes, thus contributing to the treatment of COVID-19.

Efficacy of Getong Tongluo Capsule () for Convalescent-Phase of Ischemic Stroke and Primary Hypertension: A Multicenter, Randomized, Double-Blind, Controlled Trial.

OBJECTIVE: To evaluate whether the efficacy of Getong Tongluo Capsule (, GTC, consisted of total flavone of Radix Puerariae) on improving patients' quality of life and lowering blood pressure are superior to the extract of Ginkgo biloba (EGB) for patients with convalescent-phase ischemic stroke and primary hypertension. METHODS: This randomized, positive-drug- and placebo-controlled, double-blind trial was conducted from September 2015 to October 2017. Totally 477 eligible patients from 18 hospitals in China were randomly assigned in a 2:1:1 ratio to the following interventions, twice a day for 12 weeks: (1) GTC 250 mg plus EGB-matching placebo 40 mg (237 cases, GTC group), (2) EGB 40 mg plus GTC-matching placebo 250 mg (120 cases, EGB group) or (3) GTC-matching placebo 250 mg plus EGB-matching placebo 40 mg (120 cases, placebo group). Moreover, all patients were orally administered aspirin enteric-coated tablets 100 mg, once a day for 12 weeks. The primary outcome was the Barthel Index (BI). The secondary outcomes included the control rate of blood pressure and National Institutes of Health Stroke Scale (NIHSS) scores. The incidence and severity of adverse events (AEs) were calculated and assessed. RESULTS: The BI relative independence rates, the clinical recovery rates of NIHSS, and the total effective rates of NIHSS in the GTC and EGB groups were significantly higher than the placebo group at 12 weeks after treatment (P<0.05), and no statistical significance was found between the GTC and EGB groups (P>0.05). The control rate of blood pressure in the GTC group was significantly higher than the EGB and placebo groups at 12, 18 and 24 weeks after treatment (P<0.01). There were no statistically significant differences in the incidences of AEs, adverse drug reactions, or serious AEs among the 3 groups (P>0.05). CONCLUSION: GTC exhibited significant efficacy in improving patients' quality of life as well as neurological function and controlling hypertension. (Registration No. ChiCTR1800016667).

NV center pumped and enhanced by nanowire ring resonator laser to integrate a 10 µm-scale spin-based sensor structure.

In this work, we propose a 10 µm-scale spin-based sensor structure, which mainly consists of a nanowire (NW) ring resonator laser, nitrogen-vacancy (NV) defects in a nanodiamond (ND) and a microwave (MW) antenna. The NW laser was bent into a ring with a gap to pump the NV defects in the ND which was assembled in the gap with the diameter of ∼8 µm. And the fluorescent light of NV defects was enhanced by the NW ring resonator about 8 times. Furthermore, the NW laser pulse was produced by the optical switch and a simple plus-sequences was designed to get the Rabi oscillation signal. Based on the Rabi oscillation, a Ramsey-type sequence was used to detect the magnetic field with the sensitivity of 83 nT √Hz-1 for our 10 µm-scale spin-based sensor structure. It proves the spin state in our structure allows for coherent spin manipulation for more complex quantum control schemes. And our structure fulfills the fundamental requirements to develop chip-scale spin-based sensors.

Effects of straw leachates from Cry1C-expressing transgenic rice on the development and reproduction of Daphnia magna.

The transgenic rice line T1C-19 provides high resistance to lepidopteran pests because of the synthesis of the Bacillus thuringiensis (Bt) insecticidal protein Cry1C. It thus shows good prospect for commercial planting in China. Species of Cladocera, an order of aquatic arthropods commonly found in aquatic ecosystems such as rice paddies, might be exposed to the insecticidal protein released from Bt-transgenic rice-straw residues. For the study reported herein, we used Daphnia magna (water flea) as a representative of Cladocera to evaluate whether aquatic arthropods are adversely affected when exposed to Bt rice-straw leachates. We exposed D. magna to M4 medium containing various volume percentages of medium that had been incubated with T1C-19 rice straw or rice straw from its non-transformed near-isoline Minghui 63 (MH63) for 21 days. Compared with pure M4 medium (control), the fitness and developmental and reproduction parameters of D. magna decreased significantly when exposed to rice-straw leachates; conversely, no significant differences between the T1C-19 and MH63 rice-straw leachate treatments were observed, indicating that the Bt rice straw leachate did not adversely affect this non-target species.

Safety Assessment of Bacillus thuringiensis Insecticidal Proteins Cry1C and Cry2A with a Zebrafish Embryotoxicity Test.

As a result of the large-scale planting of transgenic Bacillus thuringiensis (Bt) crops, fish would be exposed to freely soluble Bt insecticidal protein(s) that are released from Bt crop tissues into adjacent bodies of water or by way of direct feeding on deposited plant material. To assess the safety of two Bt proteins Cry1C and Cry2A to fish, we used zebrafish as a representative species and exposed their embryos to 0.1, 1, and 10 mg/L of the two Cry proteins until 132 h post-fertilization and then several developmental, biochemical, and molecular parameters were evaluated. Chlorpyrifos (CPF), a known toxicant to aquatic organisms, was used as a positive control. Although CPF exposure resulted in significant developmental, biochemical, and molecular changes in the zebrafish embryos, there were almost no significant differences after Cry1C or Cry2A exposure. Thus, we conclude that zebrafish embryos are not sensitive to Cry1C and Cry2A insecticidal proteins at test concentrations.

Lycium Barbarum: A Traditional Chinese Herb and A Promising Anti-Aging Agent.

Lycium barbarum has been used in China for more than 2,000 years as a traditional medicinal herb and food supplement. Lycium barbarum contains abundant Lycium barbarum polysaccharides (LBPs), betaine, phenolics, carotenoids (zeaxanthin and ß-carotene), cerebroside, 2-O-ß-d-glucopyranosyl-l-ascorbic acid (AA-2ßG), ß-sitosterol, flavonoids and vitamins (in particular, riboflavin, thiamine, and ascorbic acid). LBPs are the primary active components of Lycium barbarum. In this review, we discuss the pharmacological activities of LBPs and other major components. They have been reported to mediate significant anti-aging effects, through antioxidant, immunoregulative, anti-apoptotic activities and reducing DNA damage. Thus, the basic scientific evidence for anti-aging effects of LBPs is already available. However, additional studies are needed to understand mechanisms by which LBPs mediate anti-aging properties. Novel findings from such studies would likely pave the way for the clinical application of traditional chinese medicine Lycium barbarum in modern evidence-based medicine.

Time-dependent co-relation of BDNF and CREB mRNAs in adult rat brains following acute psychological stress in the communication box paradigm.

Psychological stress affects human health, and chronic stress leads to life-threatening diseases, such as depression and post-traumatic stress disorder. Psychological stress coping mechanisms involve the brain-derived neurotrophic factor (BDNF) and downstream cAMP response element binding protein (CREB), which are targets of the adverse effects of stress paradigms. Fourty-seven adult male Sprague-Dawley rats were divided into control, physical stress and six psychological stress groups which were assayed at 0h, 0.5h, 1h, 2h, 6h and 24h after communication box (CB) stress induction. Behavioral assessment using open field and elevated plus maze tests determined that CB stress significantly increased anxiety. After CB stress, the alternation of mRNA levels of BDNF and CREB were assessed at different time points by in situ hybridization. The mRNA levels of BDNF and CREB were significantly decreased, then gradually recovered over 24h to maximum levels in the hippocampus (CA1 region), prefrontal cortex (PFC), central amygdaloid nuclei (AG), shell of accumbens nucleus (NAC), periaqueductal gray (PAG) and ventral tegmental area, except for the ventral tegmental area (VTA). Moreover, mRNA levels of BDNF and CREB were positively correlated in all examined brain regions, except for the VTA region at 0 and 24h after CB stress induction. These findings suggest that BDNF and CREB may belong to the same pathway and be involved in psychological stress response mechanisms, and protect the organism from stress induced, aversive processes leading to disease.

Nonspecific Effect of Stress on Brain Gray Matter Volume in Drug-naive Female Patients with First Depressive Episode.

BACKGROUND: This study aimed to observe the differences in brain gray matter volume in drug-naive female patients after the first episode of major depression with and without stressful life events (SLEs) before the onset of depression. METHODS: Forty-three drug-naive female patients voluntarily participated in the present study after the first major depressive episode. The life event scale was used to evaluate the severity of the impact of SLEs during 6 months before the onset of the major depressive episode. High-field magnetic resonance imaging (MRI) scans were obtained, and the VBM and SPM8 software process were used to process and analyze the MRI. RESULTS: Compared to that in patients without SLEs, the volume of brain gray matter was lower in the bilateral temporal lobe, right occipital lobe, and right limbic lobe in the SLE group. However, the gray matter volume did not differ significantly between the two groups after the application of false discovery rate (FDR) correction. CONCLUSIONS: Although the results of the present study suggest the absence of significant differences in brain gray matter volume between female drug-naive patients after the first episode of major depression with and without SLEs after FDR correction, the study provides useful information for exploring the definitive role of stress in the onset of depression.

HIV incidence among men who have sex with men in Beijing: a prospective cohort study.

OBJECTIVES: (1) To assess the HIV incidence rate among men who have sex with men (MSM) in a large cohort study in Beijing, China and (2) to identify sociodemographic and behavioural risk factors of HIV seroconversion among MSM in Beijing, China. DESIGN: A prospective cohort study. SETTING: Baseline and follow-up visits were conducted among MSM in Beijing, China. PARTICIPANTS: A cohort of 797 HIV-seronegative MSM was recruited from August to December 2009, with follow-up occurring after 6 and 12 months. PRIMARY AND SECONDARY OUTCOME MEASURES: At baseline and follow-up visits, participants reported sociodemographic and sexual behaviour information, and were tested for HIV, herpes simplex virus-2 (HSV-2) and syphilis with whole blood specimens. Cox regression analysis was used to identify factors associated with HIV seroconversion. RESULTS: Most study participants (86.8%) were retained by the 12-month follow-up. The HIV, HSV-2 and syphilis incidence rates were 8.09 (95% CI 6.92 to 9.26), 5.92 (95% CI 5.44 to 6.40) and 8.06 (95% CI 7.56 to 8.56) cases per 100 person-years, respectively. HIV seroconversion was significantly associated with being <25 years old, having <12 years of education, having >1 male sex partner in the past 6 months, and being syphilis positive or HSV-2 positive. CONCLUSIONS: The HIV incidence among MSM in Beijing is serious. Interventions and treatment of sexually transmitted diseases (STD) should be combined with HIV control and prevention measures among MSM.

[Study on the incidence of HIV and associated risk factors through a prospective cohort among men who have sex with men in Beijing, China].

OBJECTIVE: To investigate the dynamic change and associated risk factors of HIV sero-conversion rate in Beijing. METHODS: 809 sero-negative men who have sex with men (MSM) were recruited in the cohort from August to December in 2009. HIV sero-antibody, medicinal examination and behavior questionnaire interview were carried out every six months. RESULTS: 962 MSM with overall baseline prevalence of HIV infection as 6.34% (61/962) together with 809 sero-negative MSM, were enrolled in the cohort. Of the 809 sero-negative participants, 95.1% (769/ 809), 85.5% (692/809) and 71.0% (574/809) of them were retained in the 6-month, 12-month and 18-month follow-up visits, with 19, 29 and 17 of them became HIV sero-conversion at 6-month, 12-month, and 18-month follow-up visits and the HIV incidence rates appeared to be 5.47, 12.37 and 6.86 per 100 person-years respectively. The HIV incidence was 7.59 per 100 person-years in the 18 months follow-up visit. Factors including: younger than 25-years old (HR = 2.32, 95%CI: 1.39 - 3.87), having more than 8 MSM partners (HR = 2.50, 95%CI: 1.49 - 4.20), less than 2000¥ every month income (HR = 1.76, 95%CI: 1.05 - 2.95), having more than 4 homosexual partners in the last six months (HR = 3.50, 95%CI: 2.11 - 5.81), showing phimosis and redundant prepuce (HR = 2.47, 95%CI: 1.50 - 4.07) as well as positive syphilis test (HR = 2.62, 95%CI: 1.53 - 4.49) etc., were significantly associated with HIV incidence. CONCLUSION: High HIV incidence was shown among MSM in Beijing and had spread fast in this population, calling for more favorable prevention measures to be taken.

The toxic influence of paraquat on hippocampus of mice: involvement of oxidative stress.

Environmental paraquat (PQ) exposure has been suggested to be a potential risk factor for neurodegenerative disorders such as Parkinson's disease (PD). The hippocampus plays an important role in the learning and memory abilities of the brain. This study aims to demonstrate the effect and mechanism of paraquat toxicity on the hippocampus of mice. Kunming mice were randomly divided into four groups (one control and three treatment groups) and the dosage levels were defined as 0, 0.89, 2.67 and 8mg/kg body weight. Paraquat was given orally, once a day and for 28 consecutive days. After treatment with paraquat, the hippocampus cells were found to be irregular and the cytoplasm was found to be condensed. The nissl bodies were reduced and apoptotic or necrotic neuron was observed. Morris water maze tests showed that the response latency increased significantly in animals that were administered paraquat. The level of malondialdehyde (MDA) and generation of reactive oxygen species (ROS) in the hippocampus of mice increased significantly. The activities of total superoxide dismutase (SOD) in the hippocampus of mice decreased significantly after treatment with paraquat. An analysis of the energy metabolism of hippocampus showed that the concentration of adenosine-triphosphate (ATP) decreased significantly in the hippocampus after treatment with paraquat, which implied that the energy synthesis of mitochondria with hippocampal neurocytes declined. The level of 8-OHdG in mitochondrial DNA (mtDNA) increased significantly after treatment with paraquat, which indicated that the oxidative damage of mtDNA increased. This suggests that paraquat had a toxic influence on the hippocampus of mice, and that the mechanism of toxicity might be associated with the mitochondrial injury of hippocampal neurocytes induced by oxidative stress.