Microalgae Film-Derived Water Evaporation-Induced Electricity Generator with Negative Carbon Emission.

Water evaporation-induced electricity generators (WEGs) are regarded as one of the most promising solutions for addressing the increasingly severe environmental pollution and energy crisis. Owing to the potential carbon emission in the preparation process of WEGs, whether WEG represents a clean electricity generation technology is open to question. Here, a brand-new strategy is proposed for manufacturing negative carbon emission WEG (CWEG). In this strategy, the microalgae film is used as the electricity generation interface of WEG, which achieves a stable open-circuit voltage (Voc) of 0.25 V and a short-circuit current (Isc) of 3.3 µA. Since microalgae can capture carbon dioxide during its growing process, CWEG holds great promise to generate electricity without carbon emissions in the full life cycle compared with other WEGs. To the best of the author's knowledge, this is the first work using microalgae films to fabricate WEG. Therefore, it is believed that this work not only provides a new direction for designing high-efficiency and eco-friendly WEG but also offers an innovative approach to the resource utilization of microalgae.

Association between irritable bowel syndrome and Parkinson's disease by Cohort study and Mendelian randomization analysis.

This study aimed to investigate the association between irritable bowel syndrome (IBS) and Parkinson's disease (PD) utilizing prospective cohort study and Mendelian randomization. The dataset contained a substantial cohort of 426,911 participants from the UK Biobank, discussing the association between IBS and PD with Cox proportional hazards models and case-control analysis while adjusting for covariates such as age, gender, ethnicity and education level. In univariate Cox regression model, the risk of PD was reduced in IBS patients (HR: 0.774, 95%CI: 0.625-0.956, P = 0.017), but the statistical significance diminished in the three models after adjusting for other variables. In a few subgroup analyses, IBS patients are less likely to develop into PD, and patients diagnosed with IBS after 2000 also had a lower risk (HR: 0.633, 95%CI: 0.403-0.994, P = 0.047) of subsequently developing PD. In addition, we matched five healthy control participants based on gender and age at the end of the study for each IBS patient diagnosed during the follow-up period, and logistic regression results (OR:1.239, 95%CI: 0.896-1.680, P = 0.181) showed that IBS was not associated with the risk of PD. Mendelian randomization did not find significant evidence of the causal relationship between IBS and Parkinson's disease (OR: 0.801, 95%CI: 0.570-1.278, P = 0.204). Overall, we suggest that IBS status is not associated with the risk of developing PD, and that these findings provide valuable insights into the clinical management and resource allocation of patients with IBS.

Interaction between the SFTSV envelope glycoprotein Gn and STING inhibits the formation of the STING-TBK1 complex and suppresses the NF-κB signaling pathway.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS. IMPORTANCE: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV.

Prediabetes and the incidence of Parkinson's disease: A meta-analysis.

Diabetes has been associated with an elevated risk of Parkinson's disease (PD), yet the relationship between prediabetes (PreD) and the incidence of PD in the adult population remains unclear. Therefore, a systematic review and meta-analysis was conducted to evaluate if PreD is also associated with a higher risk of PD. We conducted comprehensive searches of the PubMed, Embase, and Web of Science databases to identify relevant observational studies with longitudinal follow-up. The random-effects model was employed to synthesize the data, mitigating the potential impact of study heterogeneity on the outcomes. Our analysis incorporated seven datasets from five cohort studies, encompassing 18,170,592 adult participants without a PD diagnosis at baseline. Among them, 2,432,148 (13.3%) had PreD. During the follow-up, a total of 46,682 patients were diagnosed with PD. The pooled results indicated that PreD was associated with an increased incidence of PD (risk ratio [RR] 1.09, 95% confidence interval [CI] 1.02 - 1.16; P = 0.02; I2 = 52%), after adjusting for potential confounding factors such as age, sex, body mass index (BMI), and smoking. Subsequent pilot subgroup analyses suggested that the association between PreD and PD might not be significantly influenced by the country of the study, its design, age or sex of the participants, definition of PreD, or the quality scores of the study (P for subgroup difference all > 0.05). In conclusion, adult population with PreD may have a mildly increased risk of developing PD compared to those with normoglycemia.

Matrix metalloproteinase-9 inhibition prevents aquaporin-4 depolarization-mediated glymphatic dysfunction in Parkinson's disease.

INTRODUCTION: The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive. OBJECTIVE: To explore whether matrix metalloproteinase-9 (MMP-9)-mediated ß-dystroglycan (ß-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/ß-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and ß-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior. RESULTS: Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved ß-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of ß-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss. CONCLUSION: AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated ß-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.

Ageing of grammatical advance planning in spoken sentence production: an eye movement study.

This study used an image-description paradigm with concurrent eye movement recordings to investigate differences of grammatical advance planning between young and older speakers in spoken sentence production. Participants were asked to produce sentences with simple or complex initial phrase structures (IPS) in Experiment 1 while producing individual words in Experiment 2. Young and older speakers showed comparable speaking latencies in sentence production task, whereas older speakers showed longer latencies than young speakers in word production task. Eye movement data showed that compared with young speakers, older speakers had higher fixation percentage on object 1, lower percentage of gaze shift from object 1 to 2, and lower fixation percentage on object 2 in simple IPS sentences, while they showed similar fixation percentage on object 1, similar percentage of gaze shift from object 1 to 2, and lower fixation percentage on object 2 in complex IPS sentences, indicating a decline of grammatical encoding scope presenting on eye movement patterns. Meanwhile, speech analysis showed that older speakers presented longer utterance duration, slower speech rate, and longer and more frequently occurred pauses in articulation, indicating a decline of speech articulation in older speakers. Thus, our study suggests that older speakers experience an ageing effect in the sentences with complex initial phrases due to limited cognitive resources.

Study on brain damage patterns of COVID-19 patients based on EEG signals.

Objective: The coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by the SARA-CoV-2, characterized by high infectivity and incidence. Clinical data indicates that COVID-19 significantly damages patients' perception, motor function, and cognitive function. However, the electrophysiological mechanism by which the disease affects the patient's nervous system is not yet clear. Our aim is to investigate the abnormal levels of brain activity and changes in brain functional connectivity network in patients with COVID-19. Methods: We compared and analyzed electroencephalography signal sample entropy, energy spectrum, and brain network characteristic parameters in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), and beta (13-30 Hz) bands of 15 patients with COVID-19 and 15 healthy controls at rest. Results: At rest, energy values of the four frequency bands in the frontal and temporal lobes of COVID-19 patients were significantly reduced. At the same time, the sample entropy value of the delta band in COVID-19 patients was significantly increased, while the value of the beta band was significantly decreased. However, the average value of the directed transfer function of patients did not show any abnormalities under the four frequency bands. Furthermore, node degree in the temporal lobe of patients was significantly increased, while the input degree of the frontal and temporal lobes was significantly decreased, and the output degree of the frontal and occipital lobes was significantly increased. Conclusion: The level of brain activity in COVID-19 patients at rest is reduced, and the brain functional network undergoes a rearrangement. These results preliminarily demonstrate that COVID-19 patients exhibit certain brain abnormalities during rest, it is feasible to explore the neurophysiological mechanism of COVID-19's impact on the nervous system by using EEG signals, which can provide a certain technical basis for the subsequent diagnosis and evaluation of COVID-19 using artificial intelligence and the prevention of brain nervous system diseases after COVID-19 infection.

Facilitation effect of token syllable frequency in Chinese spoken word production.

Syllable frequency effects in spoken word production have been interpreted as evidence that speakers store syllable-sized motor programmes for phonetic encoding in alphabetic languages such as English or Dutch. However, the cognitive mechanism underlying the syllable frequency effect in Chinese spoken word production remains unknown. To investigate the locus of the syllable frequency effect in spoken Chinese, this study used a picture-word interference (PWI) task in which participants were asked to name the picture while ignoring the distractor word. The design included two variables: the syllable frequency of the target words (high vs. low) and the phonological relationships between distractor and target words (shared atonic syllable or not; related vs. unrelated). We manipulated mixed token and type syllable frequency in Experiment 1, and token syllable frequency but controlled type syllable frequency in Experiment 2. The results showed a facilitation effect of mixed syllable frequency and a similar facilitation effect of token syllable frequency. Importantly, the syllable frequency effect was found to be independent of the phonological facilitation effect. These results suggest that token syllable frequency played a dominant role in the observed facilitation effect, providing evidence that the syllable frequency effect arises in the phonetic encoding of Chinese spoken word production.

Diagnostic performance of metagenomic next-generation sequencing and conventional microbial culture for spinal infection: a retrospective comparative study.

PURPOSE: The study evaluated the diagnostic performance of metagenomic next-generation sequencing (mNGS) as a diagnostic test for biopsy samples from patients with suspected spinal infection (SI) and compared the diagnostic performance of mNGS with that of microbial culture. METHODS: All patients diagnosed with clinical suspicion of SI were enrolled, and data were collected through a retrospective chart review of patient records. Biopsy specimens obtained from each patient were tested via mNGS and microbial culture. Samples were enriched for microbial DNA using the universal DNA extraction kit, whole-genome amplified, and sequenced using MGISEQ-200 instrument. After Low-quality reads removed, the remaining sequences for microbial content were analyzed and aligned using SNAP and kraken2 tools. RESULTS: A total of 39 patients (19 men and 20 women) were deemed suitable for enrollment. The detection rate for pathogens of mNGS was 71.8% (28/39), which was significantly higher than that of microbial culture (23.1%, p = 0.016). Mycobacterium tuberculosis complex was the most frequently isolated. Using pathologic test as the standard reference for SI, thirty-one cases were classified as infected, and eight cases were considered aseptic. The sensitivity and specificity values for detecting pathogens with mNGS were 87.1% and 87.5%, while these rates were 25.8% and 87.5% with conventional culture. mNGS was able to detect 88.9% (8/9) of pathogens identified by conventional culture, with a genus-level sensitivity of 100% (8/8) and a species-level sensitivity of 87.5% (7/8). CONCLUSION: The present work suggests that mNGS might be superior to microbial culture for detecting SI pathogens.

Enterovirus D68 infection upregulates SOCS3 expression to inhibit JAK-STAT3 signaling and antagonize the innate interferon response of the host.

Enterovirus D68 (EV-D68) can cause respiratory diseases and acute flaccid paralysis, posing a great threat to public health. Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects, inducing the expression of hundreds of interferon-stimulated genes (ISGs). EV-D68 activates ISG expression early in infection, but at a later stage, the virus suppresses ISG expression, a strategy evolved by EV-D68 to antagonize interferons. Here, we explore a host protein, suppressor of cytokine signaling 3 (SOCS3), is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon. We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7, a transcriptional regulator of SOCS3, leading to the upregulation of SOCS3 expression. Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). The expression of SOCS3 inhibited the expression of ISG, thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription, protein production, and viral titer. Notably, a truncated SOCS3, generated by deleting the kinase inhibitory region (KIR) domain, failed to promote replication and translation of EV-D68. Based on the above studies, we designed a short peptide named SOCS3 inhibitor, which can specifically bind and inhibit the KIR structural domain of SOCS3, significantly reducing the RNA and protein levels of EV-D68. In summary, our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.

Identification of novel immune-related biomarker and therapeutic drugs in Parkinson disease via integrated bioinformatics analysis.

BACKGROUND: The present study was designed to identify immune-related biomarker and candidate drugs for Parkinson disease (PD) by weighted gene co-expression network analysis. METHODS: Differentially expressed genes were identified in PD and healthy samples in the Gene Expression Omnibus (GEO) database. Besides, immune-related genes were obtained from the immunology database. Then, a co-expression network was constructed by the weighted gene co-expression network analysis package. Diagnostic model for PD was constructed by Lasso and multivariate Cox regression. Furthermore, differentially expressed genes (DEGs) were used to establish PPI and competing endogenous RNA (ceRNA) networks. Functional enrichment and pathway analysis were performed. Drug-hub gene interaction analysis was performed via DGIdb database. RESULTS: PD samples and normal samples were found to have 220 upregulated genes and 216 downregulated genes in the GSE6613 dataset. The differentially expressed genes contained 50 immune-related genes, with 40 upregulated genes and 10 downregulated genes. We obtained 7 hub genes by intersecting the DEGs and candidate hub genes. As potential diagnostic markers, 2 immune-related DEGs were identified among the 7 hub genes. According to functional enrichment analysis, these DEGs were mainly enriched in immune response, inflammatory response, and cytokine-cytokine receptor interactions. Totally, we obtained 182 drug-gene interaction pairs in Drug-Gene Interaction database (DGIdb). CONCLUSION: Our results revealed crucial genes and candidate drugs for PD patients and deepen our understanding of the molecular mechanisms involved in PD.

Erratum: Author correction to 'Discovery of the radio-protecting effect of ecliptae herba, its constituents and targeting p53-mediated apoptosis in vitro and in vivo' [Acta Pharm Sin B 13 (2023) 1216-1230].

[This corrects the article DOI: 10.1016/j.apsb.2022.09.003.].

MRI-based Vertebral Bone Quality Score for Osteoporosis Screening Based on Different Osteoporotic Diagnostic Criteria Using DXA and QCT.

In this study, we aim to evaluate the correlation between T score measured by dual X-ray absorptiometry (DXA), volumetric bone mineral density (vBMD) derived from quantitative computed tomography (QCT) and MRI-based vertebral bone quality (VBQ), explore the diagnostic performance of VBQ in osteoporosis and determine the recognition value of VBQ in osteoporotic fracture in a relatively large cohort of elderly patients scheduled to undergo spinal surgery. A total of 260 patients were enrolled in the study. DXA and QCT were used to evaluate osteoporotic status. We calculated the lumbar VBQ score, analyzed the correlation between T score, vBMD and VBQ, and explored whether VBQ was an influential factor of bone quality and fracture by binary logistic regression as well as the diagnostic performance of VBQ in osteoporosis and fracture by ROC curve. VBQ was negatively correlated with vBMD and T score. (r = - 0.487 vs. r = - 0.220). The VBQ score was a risk factor for osteoporosis under the QCT diagnostic criteria (OR = 2.245, 95% CI 1.456-3.460) and osteoporotic fractures (OR = 1.496, 95% CI 1.097-2.040). It exhibited superior discriminant performance for osteoporosis diagnosed by QCT, with a cutoff value of 3.70 and an AUC of 0.7354. Its cutoff value for osteoporotic fractures was 3.72, and its AUC was 0.6717. In a cohort of elderly patients scheduled to undergo spinal surgery, the VBQ score was more strongly associated with vBMD than the T score and could identify patients with osteoporosis and corresponding vertebral compression fracture (VCF).

Postoperative analgesic efficacy and safety of imrecoxib versus celecoxib in hip osteoarthritis patients undergoing total hip arthroplasty: a multi-center, randomized, controlled, non-inferiority study.

BACKGROUND: Imrecoxib, a novel cyclooxygenase-2 inhibitor, possesses a certain postoperative analgesic effect for several orthopedic surgeries. This multi-center, randomized, controlled, non-inferiority study intended to investigate the postoperative analgesic efficacy and safety profile of imrecoxib (versus celecoxib) in hip osteoarthritis patients undergoing total hip arthroplasty (THA). METHODS: 156 hip osteoarthritis patients planned for THA were randomized into imrecoxib (N = 78) and celecoxib (N = 78) groups. Patients were orally administrated with imrecoxib or celecoxib 200 mg at 2 h (h) after THA, 200 mg every 12 h to day (D)3, and 200 mg every 24 h to D7; additionally, each patient received patient-controlled analgesia (PCA) for 2 days. RESULTS: Resting pain visual analogue scale (VAS) score at 6 h, 12 h, D1, D2, D3, and D7 post THA was not varied between imrecoxib and celecoxib groups (all P > 0.050), neither was moving pain VAS score (all P > 0.050). Importantly, the upper of 95% confidence interval of pain VAS score margin between imrecoxib and celecoxib groups was within the non-inferiority threshold (Δ = 1.0), indicating the fact that non-inferiority was established. The additional and total consumption of PCA was not varied between imrecoxib and celecoxib groups (both P > 0.050). Also, no difference was seen in Harris hip score, European Quality of Life 5-Dimensions (EQ-5D) total and VAS scores at month (M)1, M3 between the two groups (all P > 0.050). Besides, the incidences of all adverse events were not different between imrecoxib and celecoxib groups (all P > 0.050). CONCLUSION: Imrecoxib is non-inferior to celecoxib for postoperative analgesia in hip osteoarthritis patients undergoing THA.

Correlation Study between Quality and Sensory Characteristics of Kelp Paste by Aspergillus oryzae and Aspergillus niger during Fermentation.

In order to clarify the relationship between quality and sensory characteristics of kelp paste during fermentation, this study analyzed the quality and sensory characteristics of kelp paste through physicochemical indexes, nutritional components, electronic nose and electronic tongue. The results showed that with the extension of fermentation time, the contents of amino nitrogen, total acid, ammonium salt and ash increased gradually, while the pH value, moisture, fat, protein and carbohydrate decreased gradually. Short-chain alkanes such as nitrogen oxides and methane were the main causes of odor. Freshness, salinity and richness were the main indexes of kelp paste taste. Many quality indexes, such as amino nitrogen and protein, were significantly related to the odor sensor, which can better reflect the odor produced in the fermentation process of kelp paste. There was a significant correlation between quality indicators and important taste indicators such as umami, richness and salty taste, which can better reflect the taste of kelp paste during fermentation. To sum up, there was a significant correlation between the quality characteristics and sensory quality of kelp paste, so the relationship between quality characteristics and sensory characteristics in kelp paste can be clarified.

Effects of Porphyra haitanensis polysaccharides on gelatinization and gelatinization kinetics of starches with different crystal types.

The effects of Porphyra haitanensis polysaccharide (PHP) on the gelatinization and gelatinization kinetics of corn starch (CS), potato starch (PS) and lotus seed starch (LS) were studied. The gelatinization, rheological and thermal enthalpy properties of the samples were measured by a rapid viscosity analyzer (RVA), a rheometer, and a differential scanning calorimeter (DSC), respectively. And the kinetic equations were further established. RVA confirmed that the addition of 0.4 %, 0.8 % and 1.2 % PHP elevated the gelatinization viscosity of CS and LS but decreased that of the PS, and also elevated the thermal balance of CS, PS, and LS, especially PS (The breakdown viscosity was decreased to 363.00 ± 6.08, 370.00 ± 1.15, and 362.00 ± 0.58, respectively). And the rheometer indicated that the addition of 0.4 %, 0.8 % and 1.2 % PHP improved the apparent viscosity of CS, PS and LS, especially PS (The consistency coefficient was increased to 18.26 ± 0.02, 21.71 ± 0.04, and 23.26 ± 0.01, respectively). Eventually, DSC displayed that the addition of 0.4 %, 0.8 % and 1.2 % PHP extended the gelatinization temperature and enthalpy of CS, PS, and LS, especially PS. Among them, the gelatinization temperature (63.40 ± 0.03, 70.26 ± 0.02 and 74.61 ± 0.01, respectively) and the gelatinization enthalpy (1.55 ± 0.01) of PS increased the most with 1.2 % PHP. Moreover, gelatinization kinetics displayed that the addition of 0.4 %, 0.8 % and 1.2 % PHP decreased the rate constants of CS, PS, and LS and accelerated the activation energies of CS (666.37 ± 4.23, 623.89 ± 4.21 and 558.39 ± 2.35, respectively) and PS (752.53 ± 4.13, 699.61 ± 3.78 and 662.15 ± 4.52, respectively) while reducing that of the LS (938.87 ± 3.38, 669.98 ± 4.61 and 491.48 ± 4.29, respectively). Therefore, the addition of PHP at all concentrations inhibited the gelatinization procedure of CS and PS but promoted that of the LS. This study provided a theoretical basis for the creation of new products based on PHP and starch.

Naringenin attenuates cerebral ischemia/reperfusion injury by inhibiting oxidative stress and inflammatory response via the activation of SIRT1/FOXO1 signaling pathway in vitro.

PURPOSE: To explore the protection of naringenin against oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell injury, a cell model of cerebral ischemia/reperfusion (I/R) injury in vitro, focusing on SIRT1/FOXO1 signaling pathway. METHODS: Cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, malondialdehyde (MDA) content, 4-hydroxynonenoic acid (4-HNE) level, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured by commercial kits. Inflammatory cytokines levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expressions were monitored by Western blot analysis. RESULTS: Naringenin significantly ameliorated OGD/R-induced cytotoxicity and apoptosis in HT22 cells. Meanwhile, naringenin promoted SIRT1 and FOXO1 protein expressions in OGD/R-subjected HT22 cells. In addition, naringenin attenuated OGD/R-induced cytotoxicity, apoptosis, oxidative stress (the increased ROS, MDA and 4-HNE levels, and the decreased SOD, GSH-Px and CAT activities) and inflammatory response (the increased tumor necrosis factor-α, interleukin [IL]-1ß, and IL-6 levels and the decreased IL-10 level), which were blocked by the inhibition of the SIRT1/FOXO1 signaling pathway induced by SIRT1-siRNA transfection. CONCLUSIONS: Naringenin protected HT22 cells against OGD/R injury depending on its antioxidant and anti-inflammatory activities via promoting the SIRT1/FOXO1 signaling pathway.

Enterovirus D68 VP3 Targets the Interferon Regulatory Factor 7 To Inhibit Type I Interferon Response.

Enterovirus D68 (EV-D68) is a globally emerging pathogen causing severe respiratory illnesses mainly in children. The protease from EV-D68 could impair type I interferon (IFN-I) production. However, the role of the EV-D68 structural protein in antagonizing host antiviral responses remains largely unknown. We showed that the EV-D68 structural protein VP3 interacted with IFN regulatory factor 7 (IRF7), and this interaction suppressed the phosphorylation and nuclear translocation of IRF7 and then repressed the transcription of IFN. Furthermore, VP3 inhibited the TNF receptor associated factor 6 (TRAF6)-induced ubiquitination of IRF7 by competitive interaction with IRF7. IRF7Δ305-503 showed much weaker interaction ability to VP3, and VP3Δ41-50 performed weaker interaction ability with IRF7. The VP3 from enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) was also found to interact with the IRF7 protein. These results indicate that the enterovirus structural protein VP3 plays a pivotal role in subverting host innate immune responses and may be a potential target for antiviral drug research. IMPORTANCE EV-D68 is a globally emerging pathogen that causes severe respiratory illnesses. Here, we report that EV-D68 inhibits innate immune responses by targeting IRF7. Further investigations revealed that the structural protein VP3 inhibited the TRAF6-induced ubiquitination of IRF7 by competitive interaction with IRF7. These results indicate that the control of IRF7 by VP3 may be a mechanism by which EV-D68 represses IFN-I production.

Alzheimer Disease and Epilepsy: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. This study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (ß-amyloid [Aß] 42 and phosphorylated tau [pTau]), and epilepsies with 2-sample, bidirectional Mendelian randomization (MR) method. METHODS: Genetic instruments were obtained from large-scale genome-wide meta-analysis of AD (Ncase/proxy = 111,326, Ncontrol = 677,663), CSF biomarkers of AD (Aß42 and pTau, N = 13,116), and epilepsy (Ncase = 15,212, Ncontrol = 29,677) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy, focal epilepsy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with tonic-clonic seizures, focal epilepsy with hippocampal sclerosis (focal HS), and lesion-negative focal epilepsy. Main analyses were performed using generalized summary data-based MR. Sensitivity analyses included inverse variance weighted, MR pleiotropy residual sum and outlier, MR-Egger, weighted mode, and weighted median. RESULTS: For forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (odds ratio [OR] 1.053, 95% CI 1.002-1.105, p = 0.038) and focal HS (OR 1.013, 95% CI 1.004-1.022, p = 0.004). These associations were consistent across sensitivity analyses and replicated using a separate set of genetic instruments from another AD genome-wide association study. For reverse analysis, there was a suggestive effect of focal HS on AD (OR 3.994, 95% CI 1.172-13.613, p = 0.027). In addition, genetically predicted lower CSF Aß42 was associated with an increased risk of generalized epilepsy (ß = 0.090, 95% CI 0.022-0.158, p = 0.010). DISCUSSION: This MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal HS. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

The SFTSV Nonstructural Proteins Induce Autophagy to Promote Viral Replication via Interaction with Vimentin.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. Studies have shown that SFTSV nucleoprotein (N) induces BECN1-dependent autophagy to promote viral assembly and release. However, the function of other SFTSV proteins in regulating autophagy has not been reported. In this study, we identify SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells as the virus component mediating SFTSV-induced autophagy. We found that SFTSV NSs-induced autophagy was inclusion body independent, and most phenuivirus NSs had autophagy-inducing effects. Unlike N protein-induced autophagy, SFTSV NSs was key in regulating autophagy by interacting with the host's vimentin in an inclusion body-independent manner. NSs interacted with vimentin and induced vimentin degradation through the K48-linked ubiquitin-proteasome pathway. This negatively regulating Beclin1-vimentin complex formed and promoted autophagy. Furthermore, we identified the NSs-binding domain of vimentin and found that overexpression of wild-type vimentin antagonized the induced effect of NSs on autophagy and inhibited viral replication, suggesting that vimentin is a potential antiviral target. The present study shows a novel mechanism through which SFTSV nonstructural protein activates autophagy, which provides new insights into the role of NSs in SFTSV infection and pathogenesis. IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly emerging tick-borne pathogen that causes multifunctional organ failure and even death in humans. As a housekeeping mechanism for cells to maintain steady state, autophagy plays a dual role in viral infection and the host's immune response. However, the relationship between SFTSV infection and autophagy has not been described in detail yet. Here, we demonstrated that SFTSV infection induced complete autophagic flux and facilitated viral proliferation. We also identified a key mechanism underlying NSs-induced autophagy, in which NSs interacted with vimentin to inhibit the formation of the Beclin1-vimentin complex and induced vimentin degradation through K48-linked ubiquitination modification. These findings may help us understand the new functions and mechanisms of NSs and may aid in the identification of new antiviral targets.