Risk of major depressive increases with increasing frequency of alcohol drinking: a bidirectional two-sample Mendelian randomization analysis.

Introduction: A growing body of evidence suggests that alcohol use disorders coexist with depression. However, the causal relationship between alcohol consumption and depression remains a topic of controversy. Methods: We conducted a two-sample two-way Mendelian randomization analysis using genetic variants associated with alcohol use and major depressive disorder from a genome-wide association study. Results: Our research indicates that drinking alcohol can reduce the risk of major depression (odds ratio: 0.71, 95% confidence interval: 0.54~0.93, p = 0.01), while increasing the frequency of drinking can increase the risk of major depression (odds ratio: 1.09, 95% confidence interval: 1.00~1.18, p = 0.04). Furthermore, our multivariate MR analysis demonstrated that even after accounting for different types of drinking, the promoting effect of drinking frequency on the likelihood of developing major depression still persists (odds ratio: 1.13, 95% confidence interval: 1.04~1.23, p = 0.005). Additionally, mediation analysis using a two-step MR approach revealed that this effect is partially mediated by the adiposity index, with a mediated proportion of 37.5% (95% confidence interval: 0.22 to 0.38). Discussion: In this study, we found that alcohol consumption can alleviate major depression, while alcohol intake frequency can aggravate it.These findings have important implications for the development of prevention and intervention strategies targeting alcohol-related depression.

Grass Carp Reovirus Nonstructural Proteins Avoid Host Antiviral Immune Response by Targeting the RLR Signaling Pathway.

Grass carp reovirus (GCRV) is a highly virulent RNA virus that mainly infects grass carp and causes hemorrhagic disease. The roles of nonstructural proteins NS38 and NS80 of GCRV-873 in the viral replication cycle and viral inclusion bodies have been established. However, the strategies that NS38 and NS80 used to avoid host antiviral immune response are still unknown. In this study, we report the negative regulations of NS38 and NS80 on the RIG-I-like receptors (RLRs) antiviral signaling pathway and the production of IFNs and IFN-stimulated genes. First, both in the case of overexpression and GCRV infection, NS38 and NS80 inhibited the IFN promoter activation induced by RIG-I, MDA5, MAVS, TBK1, IRF3, and IRF7 and mRNA abundance of key antiviral genes involved in the RLR-mediated signaling. Second, both in the case of overexpression and GCRV infection, NS38 interacted with piscine TBK1 and IRF3, but not with piscine RIG-I, MDA5, MAVS, and TNF receptor-associated factor (TRAF) 3. Whereas NS80 interacted with piscine MAVS, TRAF3, and TBK1, but not with piscine RIG-I, MDA5, and IRF3. Finally, both in the case of overexpression and GCRV infection, NS38 inhibited the formation of the TBK1-IRF3 complex, but NS80 inhibited the formation of the TBK1-TRAF3 complex. Most importantly, NS38 and NS80 could hijack piscine TBK1 and IRF3 into the cytoplasmic viral inclusion bodies and inhibit the translocation of IRF3 into the nucleus. Collectively, all of these data demonstrate that GCRV nonstructural proteins can avoid host antiviral immune response by targeting the RLR signaling pathway, which prevents IFN-stimulated gene production and facilitates GCRV replication.

Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3.

Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.

Effect of Different Doses of Intrathecal Dexmedetomidine as an Adjuvant Combined With Hyperbaric Ropivacaine in Patients Undergoing Cesarean Section.

OBJECTIVE: In this study, we aim to investigate the effect of different doses of dexmedetomidine as an adjuvant to hyperbaric ropivacaine in spinal anesthesia for cesarean section. METHODS: Seventy-five parturients with American Society of Anesthesiologists (ASA) I or II were anesthetized with intrathecal ropivacaine (12.5 mg) alone (R group) or in combination with dexmedetomidine 3 µg (RD3 group) and 5 µg (RD5 group) to undergo a cesarean section. The anesthetic parameters, postoperative analgesia, stress responses and neonates outcomes were monitored. RESULTS: The onset time of sensory block to T10, T4, and peak level in the RD3 group and RD5 group were significantly shorter than those in the R group (p < 0.05). The time of the level of sensory block to descend two segments and to T10 in the RD3 group(57.28 ± 16.65 min, 3.87 ± 1.60 h) and RD5 group (71.92 ± 10.10 min, 3.99 ± 1.06 h) were longer than that in the R group (40.64 ± 12.06 min, 1.98 ± 1.01 h) (p < 0.05). The median time of motor blockade to both legs score 3 on the Bromage scale (B3B3) in the RD3 group and RD5 group was shorter than that in the R group (p < 0.001). The time of motor blockade recovery to both legs score 0 on the Bromage scale (B0B0) in the RD5 group (3.6 h) was longer than that in the R group (2 h) or RD3 group (2.2 h) (p < 0.001). Visceral traction response and abdominal muscle relaxation during the operation in the RD3 group and the RD5 group were better than that in the R group. The Visual Analogue Score (VAS) in the 12 h after the operation in the RD3 group (3.30 ± 1.17) and RD5 group (2.80 ± 0.87) was smaller than that in the R group (3.80 ± 1.47) (p < 0.05). The incidence of shivering in the RD3 group and RD5 group was significantly lower than that in the R group (p < 0.05). The postoperative concentrations of c-reactive protein (CRP), interleukin-6 (IL-6) and cortisol in the RD3 and RD5 groups were lower than that in the R group (p < 0.05). CONCLUSION: 3 µg intrathecal dexmedetomidine as an adjuvant to ropivacaine improved intraoperative somato-visceral sensory block characteristics and postoperative analgesia, alleviated shivering in parturients, and did not prolong the time of motor block or produce any side effects, which makes this dose appropriate for cesarean delivery. CINICAL TRIAL REGISTRATION: ChiCTR, identifier ChiCTR1800014454. Registered 15 January 2018, http://www.chictr.org.cn/edit.aspx?pid=24613&htm=4.

NOD1 Promotes Antiviral Signaling by Binding Viral RNA and Regulating the Interaction of MDA5 and MAVS.

Nucleotide oligomerization domain-like receptors (NLRs) and RIG-I-like receptors (RLRs) detect diverse pathogen-associated molecular patterns to activate the innate immune response. The role of mammalian NLR NOD1 in sensing bacteria is well established. Although several studies suggest NOD1 also plays a role in sensing viruses, the mechanisms behind this are still largely unknown. In this study, we report on the synergism and antagonism between NOD1 and MDA5 isoforms in teleost. In zebrafish, the overexpression of NOD1 enhances the antiviral response and mRNA abundances of key antiviral genes involved in RLR-mediated signaling, whereas the loss of NOD1 has the opposite effect. Notably, spring viremia of carp virus-infected NOD1-/- zebrafish exhibit reduced survival compared with wild-type counterparts. Mechanistically, NOD1 targets MDA5 isoforms and TRAF3 to modulate the formation of MDA5-MAVS and TRAF3-MAVS complexes. The cumulative effects of NOD1 and MDA5a (MDA5 normal form) were observed for the binding with poly(I:C) and the formation of the MDA5a-MAVS complex, which led to increased transcription of type I IFNs and ISGs. However, the antagonism between NOD1 and MDA5b (MDA5 truncated form) was clearly observed during proteasomal degradation of NOD1 by MDA5b. In humans, the interactions between NOD1-MDA5 and NOD1-TRAF3 were confirmed. Furthermore, the roles that NOD1 plays in enhancing the binding of MDA5 to MAVS and poly(I:C) are also evolutionarily conserved across species. Taken together, our findings suggest that mutual regulation between NOD1 and MDA5 isoforms may play a crucial role in the innate immune response and that NOD1 acts as a positive regulator of MDA5/MAVS normal form-mediated immune signaling in vertebrates.

Low dose of dexmedetomidine as an adjuvant to bupivacaine in cesarean surgery provides better intraoperative somato-visceral sensory block characteristics and postoperative analgesia.

OBJECT: In this study, we aimed to investigate the beneficial effects of dexmedetomidine on somato-visceral sensory block characteristcs, postoperative analgesia and stress response of intrathecal bupivacaine administration in women undergoing cesarean section, and to find out which dose is better. METHODS: Sixty parturients with the American Society of Anesthesiologists (ASA) physical status I or II were anesthetized with intrathecal bupivacaine(10mg) alone or in combination with dexmedetomidine (3 µg and 5 µg) to undergo cesarean section. The anesthetic parameters, postoperative analgesia and stress responses were monitored. RESULTS: Co-administration of dexmedetomidine(3 µg and 5 µg) prolonged the duration of motor and sensory block compared with bupivacaine(10mg) alone. Less supplemental dose of lidocaine and fentanyl were required in dexmedetomidine(3 µg and 5 µg) co-administration groups. Visceral traction response and abdominal muscle relaxation in operation were better in dexmedetomidine(3 µg and 5 µg) co-administration groups. No difference in haemodynamics was detected among groups. There was no significant difference in Apgar scores, neonatal umbilical pH, oxygen pressure, carbon dioxide pressure and lactate level among groups. Postoperative plasma IL-6 and cortisol levels were lower in dexmedetomidine(3 µg and 5 µg) co-administration groups. At 6 hour after operation the visual analogue scale (VAS) was smaller in dexmedetomidine(3 µg and 5 µg) co-administration groups. The uterine contraction pain at 6 and 12 hour after operation and supplemental analgesics had no difference across three groups. No difference of side effects(shivering, nausea and vomiting, itching), the first anal aerofluxus time and intraoperation tramadol dose were detected among the three groups. CONCLUSION: The use of dexmedetomidine especially at the dose of 3µg as an adjuvant to bupivacaine in cesarean surgery provides better intraoperative somato-visceral sensory block characteristcs and postoperative analgesia, which produced no influence on Apgar scores, side effects and stress response.

[Diurnal changes in greenhouse gases at water-air interface of Xiangxi River in autumn and their influencing factors].

With the closed chamber and gas chromatography method, a 24-hour continuous monitoring was carried out to understand the greenhouse gases fluxes across the water-air interface of the Xiangxi River Bay, the Three-Gorges Reservoir in Autumn. Results indicated that the fluxes of CO2, CH4 and N2O across the water-air interface showed an obvious diurnal variation. The absorption and emission process of CH4 showed strong diurnal variation during the experimental period, reaching the highest emission at 1 am, whereas CO2 and N2O were emitted all day. The fluxes of CO2 ranged from 20.1-97.5 mg x (m2 x h)(-1) at day and 32.7-42.5 mg x (m2 x h)(-1) at night, the fluxes of N2O ranged from 18.4-133.7 microg x (m2 x h)(-1) at day and 42.1-102.6 microg x (m2 x h)(-1) at night. The fluxes of CO2 had positive correlation with wind speed and negative correlation with pH. The fluxes of N2O had positive correlation with pH.