Restoration of CD3+CD56+ NKT-like cell function by TIGIT blockade in inactive carrier and immune tolerant patients of chronic hepatitis B virus infection.

Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.

Effects of Bony Pelvic and Prostate Dimensions on Surgical Difficulty of Robot-Assisted Radical Prostatectomy: An Original Study and Meta-analysis.

BACKGROUND: Due to the deep location of the prostate within the pelvic cavity, procedures of robot-assisted radical prostatectomy (RARP) might be challenged by the prostate size and the limited pelvic cavity space. This study aimed to investigate the roles of bony pelvic and prostate dimensions in RARP procedures by an original study coupled with a meta-analysis. METHODS: In the original study, patients undergoing multiport RARP between 2021 and 2022 were consecutively assessed. The associations of anatomic features with operative time (OT), estimated blood loss (EBL), and positive surgical margin (PSM) were evaluated using linear and logistic regression analyses as well as restricted cubic spline (RCS) analysis. Based on machine-learning algorithms, this study established predictive models for surgical difficulty and interpreted the model using SHapley Additive exPlanation (SHAP). In the meta-analysis, three databases were searched for eligible studies. Quantitative syntheses were subsequently performed. RESULTS: Overall, 219 patients were enrolled in the original study. Prostate volume (PV) and the prostate volume-to-pelvic cavity index (PCI) ratio (PV-to-PCI ratio) were significantly associated with longer OT (P < 0.05). In the RCS models, U-shaped associations were observed between the prostate anteroposterior diameter (PAD) and OT, and between the prostate height (PH) and EBL, and an L-shaped association was observed between the anteroposterior diameter of the pelvic inlet (API) and EBL. The XGBoost model was superior to the logistic regression model in predicting prolonged OT. The meta-analysis demonstrated that greater PV was significantly associated with longer OT (ß = 0.20; 95% confidence interval [CI] 0.12-0.27; odds ratio [OR] = 1.05; 95% CI 1.00-1.11), and a smaller PV could increase the risk of PSM (OR = 0.82; 95% CI 0.77-0.88). CONCLUSIONS: A large prostate within a narrow and deep pelvis might suggest increased surgical difficulty of RARP. The size of the pelvic inlet also had a great impact on RARP. For PAD and PH, there seemed to be an optimal range with the lowest surgical difficulty. Machine-learning models based on the XGBoost algorithm could be successfully applied to predict the surgical difficulty of RARP.

ICOS-ICOSL pathway enhances NKT-like cell antiviral function in pregnant women with COVID-19.

Objective: The immune response initiated by SARS-CoV-2 infection in pregnancy is poorly elucidated. We aimed to access and compare the antiviral cellular responses and lymphocytes activation between healthy pregnancies and pregnant women infected with SARS-CoV-2. Methods: We detected the immunological changes of lymphocytes in peripheral blood of healthy non-pregnant women, non-pregnant women with COVID-19, healthy pregnant women, pregnant women with COVID-19 and convalescent group by flow cytometry. In vitro blockade was used to identify NKT-like cell activation through ICOS-ICOSL pathway. Results: We found that CD3+CD56+ NKT-like cells decreased significantly in COVID-19 positive pregnant women compared to healthy pregnant women. NKT-like cells of pregnant women expressed higher level of activating receptors CD69 and NKp46 after SARS-CoV-2 infection. Particularly, they also increased the expression of the co-stimulatory molecule ICOS. NKT-like cells of pregnant women with COVID-19 up-regulated the expression of IFN-γ, CD107a and Ki67. Meanwhile, we found that ICOSL expression was significantly increased on pDCs in pregnant women with COVID-19. Blocking ICOS in vitro significantly decreased the antiviral activity of NKT-like cells in COVID-19 positive pregnant women, suggesting that ICOS-ICOSL may play an important role in the virus clearance by NKT-like cells. Conclusions: During SARS-CoV-2 infection, NKT-like cells of pregnant women activated through ICOS-ICOSL pathway and played an important role in the antiviral response.

Cadmium immobilization in soil using phosphate modified biochar derived from wheat straw.

The phosphate-modified biochar (BC) immobilizes cadmium (Cd), yet little is known about how phosphate species affect Cd detoxification in contaminated soils. We developed phosphate-modified biochar through the pyrolysis of wheat straw impregnated with three types of phosphate: mono­potassium phosphate (MKP), dipotassium hydrogen phosphate (DKP), and tripotassium phosphate (TKP). The Cd adsorption mechanism of modified biochar was investigated by biochar characterization, adsorption performance evaluation, and soil incubation tests. The results demonstrated that the efficiency of biochar in immobilizing Cd2+ followed the order: TKP-BC > DKP-BC > MKP-BC. The TKP-BC had the highest orthophosphate content, the fastest adsorption rate, and the largest adsorption capacity (Langmuir) of 257.28 mg/g, which is 6.31 times higher than that of the unmodified BC (CK). In contrast, pyrophosphate was predominant in MKP-BC and DKP-BC. The primary adsorption mechanism for Cd2+ was precipitation, followed by cation exchange, as evidenced by the formation of CdP minerals on the BC surface, and an increase of K+ in solution (compared to water-soluble K+) and a decrease of K+ in the biochar during adsorption. Desorption of Cd from the TKP-BC after adsorption was 9.77 %-12.39 % at a pH of 5-9, much lower than that of CK. The soil incubation test showed the diethylenetriaminepentaacetic acid extracted Cd of TKP-BC, MKP-BC, and DKP-BC was reduced by 67.93 %, 18.41 % and 31.30 % over CK, respectively. Using the planar optodes technique, we also found that TKP-BC had the longest effect enhancing in situ soil pH. This study provides a theoretical basis for developing heavy metal pollution control technology using green remediation materials and offers insights into the remediation mechanisms.

Grassland productivity in arid Central Asia depends on the greening rate rather than the growing season length.

Climate change has induced substantial impact on the gross primary productivity (GPP) of terrestrial ecosystems by affecting vegetation phenology. Nevertheless, it remains unclear which among the mean rates of grass greening (RG), yellowing (RY), and the length of growing season (LOS) exhibit stronger explanatory power for GPP variations, and how RG and RY affect GPP variations under warming scenarios. Here, we explored the relationship between RG, RY, LOS, and GPP in arid Central Asia (ACA) from 1982 to 2019, elucidating the response mechanisms of RG, RY, and GPP to the mean temperature (TMP), vapor pressure deficit (VPD), precipitation (PRE), and soil moisture (SM). The results showed that the multi-year average length of greening (LG) in ACA was 22.7 days shorter than that of yellowing (LY) and the multi-year average GPP during LG (GPPlg) was 38.28 g C m-2 d -1 more than that of during LY (GPPly). RG and RY were positively correlated with GPPlg and GPPly, although the degree of correlation between RG and GPPlg was higher than that between RY and GPPly. Increases in RG and RY contributed to an increase in GPPlg (55.44 % of annual GPP) and GPPly (35.44 % of annual GPP). The correlation between RG and GPPlg was the strongest (0.49), followed by RY and GPPly (0.33), and LOS and GPP was the weakest (0.21). TMP, VPD, PRE, and SM primarily affected GPP by influencing RG and RY, rather than direct effects. The positive effects of TMP during LG (TMPlg), PRE during LG (PRElg), and SM during LG (SMlg) facilitated increases in RG and GPPlg, and higher VPD during LY (VPDly) and lower PRE during LY (PREly) accelerated increases in RY. Our study elucidated the impact of vegetation growth rate on GPP, thus providing an alternate method of quantifying the relationship between vegetation phenology and GPP.

Testis-Specific Protein, Y-Encoded-Like 2 Activates JAK2/STAT3 Pathway in Hypothalamic Paraventricular Nucleus to Sustain Hypertension.

BACKGROUND: In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of the testis-specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain high blood pressure during hypertension. METHODS: Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral microinjection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS: TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1ß, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the BP in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1ß and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION: JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high BP in hypertensive rats, making it a potential therapeutic target for hypertension.

Mechanistic insight into near-infrared light-driven Cu2O/WO2 Ohmic contact photothermal catalysts for high-efficiency antibiotic wastewater purification.

Near-infrared (NIR) light-induced photothermal effect is beneficial for accelerating catalytic processes; thus, it is imperative to develop novel photothermal catalysts for promoting practical application. Herein, we synthesized NIR-responsive Cu2O/WO2 Ohmic contact photothermal catalysts through a facile ethylene glycol-assisted liquid-phase reduction method. In this photothermal catalyst, a new-type NIR-responsive Cu2O semiconductor is integrated with an NIR-responsive WO2 semimetal component to form an Ohmic contact, which is more beneficial for simultaneously promoting photocharge separation and enhancing NIR light absorption for a high-efficiency photothermal effect. As expected, the Cu2O/WO2 composite displays higher NIR light-driven photothermal catalytic performance for tetracycline removal from wastewater. Various characterization methods and density functional theory calculations were performed to obtain in-depth mechanistic insights into the NIR light-driven Cu2O/WO2 Ohmic contact photothermal catalysts. Hopefully, this research could provide a useful guideline for researchers focusing on the photothermal engineering of new composite photocatalysts.

Generation of High-Quality African Swine Fever Virus Complete Genome from Field Samples by Next-Generation Sequencing.

African swine fever (ASF) is a lethal contagious viral disease of domestic pigs and wild boars caused by the African swine fever virus (ASFV). The pandemic spread of ASF has caused severe effects on the global pig industry. Whole-genome sequencing provides crucial information for virus strain characterization, epidemiology analysis and vaccine development. Here, we evaluated the performance of next-generation sequencing (NGS) in generating ASFV genome sequences from clinical samples. Thirty-four ASFV-positive field samples including spleen, lymph node, lung, liver and blood with a range of Ct values from 14.73 to 25.95 were sequenced. For different tissue samples collected from the same sick pigs, the proportion of ASFV reads obtained from the spleen samples was 3.69-9.86 times higher than other tissues. For the high-viral-load spleen samples (Ct < 20), a minimum of a 99.8% breadth of ≥10× coverage was revealed for all the samples. For the spleen samples with Ct ≥ 20, 6/12 samples had a minimum of a 99.8% breadth of ≥10× coverage. A high average depth of sequencing coverage was also achieved from the blood samples. According to our results, high-quality ASFV whole-genome sequences could be obtained from the spleen or blood samples with Ct < 20. The high-quality ASFV genome sequence generated in this study was further used for the high-resolution phylogenetic analysis of the ASFV genomes in the early stage of the ASF epidemic in China. Our study demonstrates that NGS may act as a useful tool for efficient ASFV genome characterization, providing valuable information for disease control.

Central administration of AICAR attenuates hypertension via AMPK/Nrf2 pathway in the hypothalamic paraventricular nucleus of hypertensive rats.

BACKGROUND: Oxidative stress and inflammatory cytokines in the hypothalamus paraventricular nucleus (PVN) have been implicated in sympathetic nerve activity and the development of hypertension, but the specific mechanisms underlying their production in the PVN remains to be elucidated. Previous studies have demonstrated that activation of nuclear transcription related factor-2 (Nrf2) in the PVN reduced the production of reactive oxygen species (ROS) and inflammatory mediators. Moreover, AMP-activated protein kinase (AMPK), has been observed to decrease ROS and inflammatory cytokine production when activated in the periphery. 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) is an AMPK agonist. However, little research has been conducted on the role of AMPK in the PVN during hypertension. Therefore, we hypothesized that AICAR in the PVN is involved in regulating AMPK/Nrf2 pathway, affecting ROS and inflammatory cytokine expression, influencing sympathetic nerve activity. METHODS: Adult male Sprague-Dawley rats were utilized to induce two-kidney, one-clip (2K1C) hypertension via constriction of the right renal artery. Bilateral PVN was microinjected with either artificial cerebrospinal fluid or AICAR once a day for 4 weeks. RESULTS: Compared to the SHAM group, the PVN of 2K1C hypertensive rats decreased p-AMPK and p-Nrf2 expression, increased Fra-Like, NAD(P)H oxidase (NOX)2, NOX4, tumor necrosis factor-α and interleukin (IL)-1ß expression, elevated ROS levels, decreased superoxide dismutase 1 and IL-10 expression, and elevated plasma norepinephrine levels. Bilateral PVN microinjection of AICAR significantly ameliorated these changes. CONCLUSION: These findings suggest that repeated injection of AICAR in the PVN suppresses ROS and inflammatory cytokine production through the AMPK/Nrf2 pathway, reducing sympathetic nerve activity and improving hypertension.

Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus.

Background: Long term hypertension seriously promotes target organ damage in the brain and heart, and has increasingly become serious public health problem worldwide. The anti-hypertensive effects of capsaicin has been reported, however, the role and mechanism of capsaicin within the brain on salt-induced hypertension have yet to be elucidated. This study aimed to verify the hypothesis that capsaicin attenuates salt-induced hypertension via the AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus (PVN). Methods: Dahl salt-sensitive (Dahl S) rats were used as animal model for the present study. Rats were randomly divided into four groups based on their dietary regimen (0.3% normal salt diet and 8% high salt diet) and treatment methods (infusion of vehicle or capsaicin in the PVN). Capsaicin was chronically administered in the PVN throughout the animal experiment phase of the study that lasted 6 weeks. Results: Our results demonstrated that PVN pretreatment with capsaicin can slow down raise of the blood pressure elevation and heart rate (HR) of Dahl S hypertensive rats given high salt diet. Interestingly, the cardiac hypertrophy was significantly improved. Furthermore, PVN pretreatment with capsaicin induced decrease in the expression of mRNA expression of NADPH oxidase-2 (NOX2), inducible nitric oxide synthase (iNOS), NOX4, p-IKKß and proinflammatory cytokines and increase in number of positive cell level for Nrf2 and HO-1 in the PVN of Dahl S hypertensive rats. Additionally, the protein expressions of phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT) were decreased, phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) were increased after the PVN pretreatment with capsaicin. Conclusion: Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/iNOS pathway in the PVN.

Activation AMPK in Hypothalamic Paraventricular Nucleus Improves Renovascular Hypertension Through ERK1/2-NF-κB Pathway.

Hypertension is a globally prevalent disease, but the pathogenesis remains largely unclear. AMP-activated protein kinase (AMPK) is a nutrition-sensitive signal of cellular energy metabolism, which has a certain influence on the development of hypertension. Previously, we found a down-regulation of the phosphorylated (p-) form of AMPK, and the up-regulation of the angiotensin II type 1 receptor (AT1-R) and that of p-ERK1/2 in the hypothalamic paraventricular nucleus (PVN) of hypertensive rats. However, the exact mechanism underlying the relationship between AMPK and AT1-R in the PVN during hypertension remains unclear. Thus, we hypothesized that AMPK modulates AT1-R through the ERK1/2-NF-κB pathway in the PVN, thereby inhibiting sympathetic nerve activity and improving hypertension. To examine this hypothesis, we employed a renovascular hypertensive animal model developed via two-kidney, one-clip (2K1C) and sham-operated (SHAM). Artificial cerebrospinal fluid (aCSF), used as vehicle, or 5-amino-1-ß-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, an AMPK activator, 60 µg/day) was microinjected bilaterally in the PVN of these rats for 4 weeks. In 2K1C rats, there an increase in systolic blood pressure (SBP) and circulating norepinephrine (NE). Also, the hypertensive rats had lowered expression of p-AMPK and p-AMPK/AMPK, elevated expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R, increased NF-κB p65 activity in the PVN compared with the levels of these biomarkers in SHAM rats. Four weeks of bilateral PVN injection of AMPK activator AICAR, attenuated the NE level and SBP, increased the expression of p-AMPK and p-AMPK/AMPK, lessened the NF-κB p65 activity, decreased the expression of p-ERK1/2, p-ERK1/2/ERK1/2 and AT1-R in the PVN of 2K1C rats. Data from this study imply that the activation of AMPK within the PVN suppressed AT1-R expression through inhibiting the ERK1/2-NF-κB pathway, decreased the activity of the sympathetic nervous system, improved hypertension.

Methyl-CpG binding protein 2 is associated with the prognosis and mortality of elderly patients with hip fractures

ABSTRACT Objectives To investigate the expression level and clinical significance of Methyl-CpG binding Protein 2 (MECP2) in elderly patients with hip fractures. Methods This prospective observational study included 367 elderly patients with hip fractures between April 2016 and December 2018. All the patients were treated with internal fixation or joint replacement. In addition, 50 healthy elderly individuals were enrolled as healthy controls. The serum levels of MECP2 and inflammatory factors Interleukin (IL)-1β, IL-6, IL-8, and Tumor Necrosis Factor (TNF)-α was determined by enzyme-linked immunosorbent assay. Data on patients' basic characteristics and postoperative complications were collected. The Harris score was used to assess hip function at 1-month, 3-months, and 6-months after surgery. Patient quality of life was measured using the Barthel Index (BI) score 3-months after surgery. The 1-year mortality was analyzed using the Kaplan-Meier curve, and logical regression was used to analyze the risk factors for mortality. Results No significant differences were observed in the basic clinical characteristics of all patients. The serum MECP2 levels were remarkably high in patients with hip fractures and negatively correlated with serum IL-1β, IL-6, and TNF-α levels. Patients with higher MECP2 predicted higher dynamic Harris scores, lower postoperative complications, lower 1-year mortality, and higher BI scores. Logical regression showed that age was the only independent risk factor for postoperative 1-year mortality in elderly patients with hip fractures. Conclusion Lower MECP2 predicted poor prognosis and higher 1-year mortality in elderly patients with hip fractures.