An Essential Role of PI3k in the Control of West Nile Virus Infection

The phosphatidyl-inositol-3 kinases (PI3K) pathway regulates a variety of cellular processes, including cell proliferation, RNA processing, protein translation, autophagy, apoptosis and antiviral immunity. Many viruses depend on PI3K signaling for replication. However, its role in flaviviral infection has not been clearly defined. Here we report that PI3K signaling is critical for the control of West Nile virus (WNV) infection by regulating type I IFN (IFN-I) response. Inhibition of PI3K activity by 3-methyl adenine (3-MA), Wortmannin (WM) and LY294002 (LY) increased viral titers by 3-16 folds in primary mouse macrophages, embryonic fibroblasts and human cell lines. Both 3-MA and LY repressed IFN-I mRNA and protein expression significantly. Surprisingly, WM enhanced the mRNA expression of IFN-I and TNF-alpha, and TNF-alpha protein production modestly, while dramatically decreased the secreted IFN-I. Further studies showed that the catalytic subunit p110delta of class I PI3K played a role in induction of antiviral immune responses. Lastly translocation of interferon regulatory factor 7(IRF7) from the cytosol to the nuclei was effectively blocked in the presence of PI3K inhibitors. Our results clearly define an antiviral role of PI3K by modulating immune responses and demonstrate differential mode of action of three PI3K inhibitors on IFN-I

Urban greenery and mental wellbeing in adults: Cross-sectional mediation analyses on multiple pathways across different greenery measures

Multiple mechanisms have been proposed to explain how greenery enhances their mental wellbeing. Mediation studies, however, focus on a limited number of mechanisms and rely on remotely sensed greenery measures, which do not accurately capture how neighborhood greenery is perceived on the ground. To examine: 1) how streetscape and remote sensing-based greenery affect people's mental wellbeing in Guangzhou, China; 2) whether and, if so, to what extent the associations are mediated by physical activity, stress, air quality and noise, and social cohesion; and 3) whether differences in the mediation across the streetscape greenery and NDVI exposure metrics occurred. Mental wellbeing was quantified by the WHO-5 wellbeing index. Greenery measures were extracted at the neighborhood level: 1) streetscape greenery from street view data via a convolutional neural network, and 2) the NDVI remote sensing images. Single and multiple mediation analyses with multilevel regressions were conducted. Streetscape and NDVI greenery were weakly and positively, but not significantly, correlated. Our regression results revealed that streetscape greenery and NDVI were, individually and jointly, positively associated with mental wellbeing. Significant partial mediators for the streetscape greenery were physical activity, stress, air quality and noise, and social cohesion; together, they explained 62% of the association. For NDVI, only physical activity and social cohesion were significant partial mediators, accounting for 22% of the association. Mental health and wellbeing and both streetscape and satellite-derived greenery seem to be both directly correlated and indirectly mediated. Our findings signify that both greenery measures capture different aspects of natural environments and may contribute to people's wellbeing by means of different mechanisms

Glycosphingolipid GM3 is Indispensable for Dengue Virus Genome Replication

Dengue virus (DENV) causes the most prevalent arthropod-borne viral disease of humans worldwide. Glycosphingolipids (GSLs) are involved in virus infection by regulating various steps of viral-host interaction. However, the distinct role of GSLs during DENV infection remains unclear. In this study, we used mouse melanoma B16 cells and their GSL-deficient mutant counterpart GM95 cells to study the influence of GSLs on DENV infection. Surprisingly, GM95 cells were highly resistant to DENV infection compared with B16 cells. Pretreatment of B16 cells with synthetase inhibitor of GM3, the most abundant GSLs in B16 cells, or silencing GM3 synthetase T3GAL5, significantly inhibited DENV infection. DENV attachment and endocytosis were not impaired in GM95 cells, but DENV genome replication was obviously inhibited in GM95 cells compared to B16 cells. Furthermore, GM3 was colocalized with DENV viral replication complex on endoplasmic reticulum (ER) inside the B16 cells. Finally, GM3 synthetase inhibitor significantly reduced the mortality rate of suckling mice that challenged with DENV by impairing the viral replication in mouse brain. Taken together, these data indicated that GM3 was not required for DENV attachment and endocytosis, however, essential for viral genome replication. Targeting GM3 could be a novel strategy to inhibit DENV infection

The Value of Combining Wu Ling San Plus and Minus with Repaglinide in the Treatment of Obese Type 2 Diabetes

Objective: To investigate the clinical value and practical effects of the treatment of obese type 2 diabetes mellitus patients with Wu Ling San plus and minus combined with Repaglinide. Methods: Twenty-two obese type 2 diabetic patients attending the outpatient clinic of Yixing Traditional Chinese Medicine Hospital from September 2020 to March 2022 were randomly selected as the subjects of this study, and all of them were divided into treatment group (n=11, Wu Ling San plus and minus + Repaglinide) and control group (n=11, single Repaglinide) according to the computerized random series grouping method. The clinical data and overall efficacy of the two groups were compared. Results: After treatment, the treatment group had better blood glucose, blood lipids and other basic indicators than the control group (P<0.05); all Chinese medicine symptoms scores and complication rates of the treatment group were lower than those of the control group (P<0.05). Conclusion: The treatment of obese type 2 diabetes mellitus patients with Wu Ling San plus reduction + Repaglinide has significant efficacy and high drug safety, and can stabilize many indicators of blood glucose and blood lipids, reduce the risk of complications and control their body weight, which can be promoted and used in the treatment of related clinical conditions

Interleukin-17A Promotes CD8 T Cell Cytotoxicity to Facilitate West Nile Virus Clearance

CD8 T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a/) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 T cells isolated from Il17a/ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL17A, as late as day 6 post infection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 T cell cytotoxicity, which may have broad implications in other microbial infections and cancers

UBXN3B Positively Regulates STING-Mediated Antiviral Immune Responses

The ubiquitin regulatory X domain-containing proteins (UBXNs) are likely involved in diverse biological processes. Their physiological functions, however, remain largely unknown. Here we present physiological evidence that UBXN3B positively regulates stimulator-of-interferon genes (STING) signaling. We employ a tamoxifen-inducible Cre-LoxP approach to generate systemic Ubxn3b knockout in adult mice as the Ubxn3b-null mutation is embryonically lethal. Ubxn3b(-/-), like Sting(-/-) mice, are highly susceptible to lethal herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infection, which is correlated with deficient immune responses when compared to Ubxn3b(+/+) littermates. HSV-1 and STING agonist-induced immune responses are also reduced in several mouse and human Ubxn3b(-/-) primary cells. Mechanistic studies demonstrate that UBXN3B interacts with both STING and its E3 ligase TRIM56, and facilitates STING ubiquitination, dimerization, trafficking, and consequent recruitment and phosphorylation of TBK1. These results provide physiological evidence that links the UBXN family with antiviral immune responses

Dissimilar thermal transport properties in κ\kappa-Ga2_2O3_3 and β\beta-Ga2_2O3_3 revealed by machine-learning homogeneous nonequilibrium molecular dynamics simulations

The lattice thermal conductivity (LTC) of Ga$_2$O$_3$ is an important property due to the challenge in the thermal management of high-power devices. We develop machine-learned neuroevolution potentials for single-crystalline $\beta$-Ga$_2$O$_3$ and $\kappa$-Ga$_2$O$_3$, and apply them to perform homogeneous nonequilibrium molecular dynamics simulations to predict their LTCs. The LTC of $\beta$-Ga$_2$O$_3$ was determined to be 10.3 $\pm$ 0.2 W/(m K), 19.9 $\pm$ 0.2 W/(m K), and 12.6 $\pm$ 0.2 W/(m K) along [100], [010], and [001], respectively, aligning with previous experimental measurements. For the first time, we predict the LTC of $\kappa$-Ga$_2$O$_3$ along [100], [010], and [001] to be 4.5 $\pm$ 0.0 W/(m K), 3.9 $\pm$ 0.0 W/(m K), and 4.0 $\pm$ 0.1 W/(m K), respectively, showing a nearly isotropic thermal transport property. The reduced LTC of $\kappa$-Ga$_2$O$_3$ versus $\beta$-Ga$_2$O$_3$ stems from its restricted low-frequency phonons up to 5 THz. Furthermore, we find that the $\beta$ phase exhibits a typical temperature dependence slightly stronger than $\sim T^{-1}$, whereas the $\kappa$ phase shows a weaker temperature dependence, ranging from $\sim T^{-0.5}$ to $\sim T^{-0.7}$.Comment: 8 pages, 7 figure

The Combination of Human Urinary Kallidinogenase and Mild Hypothermia Protects Adult Rats Against Hypoxic-Ischemic Encephalopathy-Induced Injury by Promoting Angiogenesis and Regeneration

Objectives: Human Urinary Kallidinogenase (HUK) is a tissue kallikrein that plays neuroprotective role in ischemic conditions via different mechanisms. Mild hypothermia (MH) is another robust neuroprotectant that reduces mortality but does not profoundly ameliorate the neurological outcome in hypoxic-ischemic encephalopathy (HIE) patients. However, whether the combination of HUK and MH can be used as a promising neuroprotective treatment in HIE is unknown. Methods: One-hundred and forty-four adult Wistar rats were randomly divided into five groups: Sham, HIE, HUK, MH and a combination of HUK and MH treatment. The HIE rat model was established by right carotid dissection followed by hypoxia aspiration. The survival curve was created within 7 days, and the neurological severity scores (NSS) were assessed at days 0, 1, 3, and 7. Nissl staining, Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), immunofluorescent staining and western blotting were used to evaluate neuronal survival, apoptosis and necrosis, tight-junction proteins Claudin-1 and Zonula occludens-1 (ZO-1), vascular endothelial growth factor (VEGF), doublecortex (DCX), bradykinin receptor B1 (BDKRB1), BDKRB2 and Ki67 staining. Results: The combined treatment rescued all HIE rats from death and had a best survival curve compared to HIE. The Combination also reduced the NSS scores after HIE at days 7, better than HUK or MH alone. The combination of HUK and MH reserved more cells in Nissl staining and inhibited neuronal apoptosis and necrosis as well as significantly attenuated HIE-induced decreases in claudin-1, ZO-1, cyclin D1 and BDKRB1/B2 in comparison to HUK or MH treatment alone. Moreover, the combined treatment increased the expression of VEGF and DCX as well as the number of Ki67-labeled cells. Conclusions: This study demonstrates that both HUK and MH are neuroprotective after HIE insult; however, the combined therapy with HUK and MH enhanced the efficiency and efficacy of either therapy alone in the treatment of HIE, at least partially by promoting angiogenesis and regeneration and rescuing tight-junction loss. The combination of HUK and MH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following HIE insult. Highlights: -The combination of HUK and MH distinctly reduces neurological dysfunction in HIE rats.-HUK enhances the neuroprotective effects of MH in HIE.-MH attenuates tight-junction disruption, upregulates the BDKR B1/2, DCX and cyclin D1.-The combination of MH and HUK enhances the expressions of MH/HUK mediated-BDKR B1/2, DCX, cyclin D1 and Ki67 positive cells

Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson\u27s Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage

Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson\u27s disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores\u27 distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD