Association of accelerated aging with the incidence risk of Cardiometabolic diseases in people with severe mental illnesses: A prospective analysis in UK Biobank.

Cardiometabolic diseases (CMDs) comorbidities among people with severe mental illnesses (SMI) are associated with a high healthcare burden and premature mortality. This study aims to evaluate whether biological aging has an interaction with SMI on incident CMDs, and to examine the association of four biological aging indicators with CMDs incidence in this population. Data were sourced from the UK Biobank, a large prospective cohort study. Four indicators were used to assess biological aging including frailty phenotype, frailty index, KDM-biological age acceleration and phenotypic age acceleration. Cox proportional hazards regression models were used to examine the associations. We observed higher prevalence of frailty and accelerated biological age with SMI than those without SMI. Further analysis found significant interaction effect of pre-frailty and SMI (PPre-frail*SMI=0.005) as well as biological age acceleration and SMI (PQ3 (>P75)*SMI=0.038). 14.7 % of the participants with SMI developed CMDs during the follow-up. Compared with non-frail participants, those with frailty (frailty phenotype: HR=1.68, 95 % CI: 1.50, 1.88, P < 0.001; frailty index: HR=2.44, 95 % CI: 2.11-2.81, P < 0.001) and biological age acceleration (KDM-biological age acceleration (Q3): HR=1.91, 95 % CI: 1.74, 2.11, P < 0.001; phenotypic age acceleration (Q3): HR=2.07, 95 % CI: 1.86, 2.30, P < 0.001) had a significantly higher risk of CMDs in the adjusted model. A series of sensitivity analyses were conducted to illustrate the robustness of the findings. These findings highlight the important implications for concerning about the high incidence of CMDs comorbidities and intervention of aging in people with SMI.

Development of novel nitric oxide production inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold.

Nitric oxide (NO), the smallest signaling molecule known, can be excessively produced by overexpressed inducible nitric oxide synthase (iNOS), and eventually leads to multiple inflammatory related diseases. Thus, reducing the overexpression of NO represents as very potential anti-inflammatory strategy. In current study, a series of compounds were designed and synthesized based on the hybridization of 7H-pyrrolo[2,3-d]pyrimidine and cinnamamide fragments in order to develop novel NO production inhibitors. Among them, compound S2h displayed a vigorous inhibitory activity on NO production with an IC50 value of 3.21 ± 0.67 µM, which was much lower than that of the positive control Nω-nitro-L-arginine (L-NNA, IC50 = 28.36 ± 3.13 µM). Due to its obeying Lipinski's and Veber's rules that guarantee compounds with good oral bioavailability, S2h effectively suppressed the paw swelling in carrageenan-induced mice. Additionally, compound S2h formed clear interactions with iNOS protein according to the docking analysis. Therefore, compounds S2h is a promising lead compound for further development of potent iNOS inhibitors or anti-inflammatory agents.

Reflective optical imaging for scattering medium using chaotic laser.

Significance: Optical imaging is a non-invasive imaging technology that utilizes near-infrared light, allows for the image reconstruction of optical properties like diffuse and absorption coefficients within the tissue. A recent trend is to use signal processing techniques or new light sources and expanding its application. Aim: We aim to develop the reflective optical imaging using the chaotic correlation technology with chaotic laser and optimize the quality and spatial resolution of reflective optical imaging. Approach: Scattering medium was measured using reflective configuration in different inhomogeneous regions to evaluate the performance of the imaging system. The accuracy of the recovered optical properties was investigated. The reconstruction errors of absorption coefficients and geometric centers were analyzed, and the feature metrics of the reconstructed images were evaluated. Results: We showed how chaotic correlation technology can be utilized for information extraction and image reconstruction. This means that a higher signal-to-noise ratio and image reconstruction of inhomogeneous phantoms under different scenarios successfully were achieved. Conclusions: This work highlights that the peak values of correlation of chaotic exhibit smaller reconstruction error and better reconstruction performance in optical imaging compared with reflective optical imaging with the continuous wave laser.

Carotid Ultrasound Combined with Plasma Atherosclerosis Index (AIP) in the Severe Analysis of Coronary Heart Disease Treated with Atorvastatin.

Background: Atherosclerotic coronary heart disease (CHD) stands as a paramount cardiovascular concern and the primary cause of mortality. To underscore the significance of our study, it is crucial to highlight the existing gaps in current diagnostic methods and prognostic assessments of CHD. By addressing these gaps, our research aims to contribute valuable insights and advancements in the understanding and management of this prevalent cardiovascular condition. Objective: The primary objective of this study is to investigate the correlation between carotid ultrasound, the Atherogenic Index of Plasma (AIP), and the severity of CHD. Methods: We enrolled 59 patients diagnosed with coronary heart disease and categorized them into two groups (multi-vessel and single-vessel disease groups) based on disease severity. The study employed carotid ultrasound, which measures Intima-Media Thickness (IMT) and carotid artery stenosis, among other indicators. Additionally, we calculated the AIP. This approach allowed us to thoroughly analyze the correlation between these key indicators and the severity of coronary heart disease lesions. Results: The study included 59 patients, 38 with single-vessel disease and 21 with multi-vessel disease. In the multivessel disease group, we observed significantly elevated levels of AIP, IMT, and carotid stenosis compared to the single-vessel disease group. Specifically, AIP, IMT, and carotid stenosis levels were higher in the multi-vessel group. Furthermore, our analysis revealed a positive correlation between AIP and IMT (r = 0.038, P = .003), while no significant correlation was found between AIP and carotid stenosis. Additionally, there was a moderate correlation between IMT and carotid stenosis. Conclusion: The combined assessment of AIP and carotid ultrasonography emerges as a promising approach for evaluating the severity of CHD. Notably, the multi-vessel disease group exhibited higher AIP levels compared to the single-vessel disease group, along with increased IMT and carotid artery stenosis. Our findings highlight a positive correlation between AIP and IMT, as well as between IMT and the degree of carotid stenosis. These associations underscore the potential of AIP, in conjunction with carotid ultrasonography parameters, as valuable indicators for gauging CHD severity. The clinical implications of these findings warrant further exploration, particularly in their potential integration into existing diagnostic or prognostic models for CHD. This integrated approach may offer enhanced precision in distinguishing between single-vessel and multi-vessel disease, contributing to more informed clinical decision-making.

Design and synthesis of highly selective Janus kinase 3 covalent inhibitors for the treatment of rheumatoid arthritis.

Selective inhibition of Janus kinase 3 (JAK3) is a promising strategy for the treatment of autoimmune diseases. Based on the discovery of a hydrophobic pocket unutilized between the lead compound RB1 and the JAK3 protein, a series of covalent JAK3 inhibitors were prepared by introducing various aromatic fragments to RB1. Among them, J1b (JAK3 IC50 = 7.2 nM, other JAKs IC50 > 1000 nM) stood out because of its low toxicity (MTD > 2 g/kg) and superior anti-inflammatory activity in Institute of Cancer Research mice. Moreover, the acceptable bioavailability (F% = 31.69%) ensured that J1b displayed excellent immune regulation in collagen-induced arthritis mice, whose joints in the high-dose group were almost recovered to a normal state. Given its clear kinase selectivity (Bmx IC50 = 539.9 nM, other Cys909 kinases IC50 > 1000 nM), J1b was nominated as a highly selective JAK3 covalent inhibitor, which could be used to safely treat arthritis and other autoimmune diseases.

Individualized Use of 6-Mercaptopurine in Chinese Children with ALL: A Multicenter Randomized Controlled Trial.

Continuous 6-mercaptopurine (6-MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose-limiting hematopoietic toxicity. However, evidence-based guidelines for gene-based 6-MP dosing have not been established for Chinese children with acute lymphoblastic leukemia (ALL). This multicenter, randomized, open-label, active-controlled clinical trial randomly assigned Chinese children with low- or intermediate-risk ALL in a 1:1 ratio to receive TPMT-NUDT15 gene-based dosing of 6-MP (N = 44, 10 to 50 mg/m2 /day) or standard dosing (N = 44, 50 mg/m2 /day) during maintenance therapy. The primary end point was the incidence of 6-MP myelosuppression in both groups. Secondary end points included frequencies of 6-MP hepatotoxicity, duration of myelosuppression and leukopenia, event-free survival, and steady-state concentrations of active metabolites (6-thioguaninenucleotides and 6-methylmercaptopurine nucleotides) in erythrocytes. A 2.2-fold decrease in myelosuppression, the primary end point, was observed in the gene-based-dose group using ~ 50% of the standard initial 6-MP dose (odds ratio, 0.26, 95% confidence interval, 0.11 to 0.64, P = 0.003). Patients in the gene-based-dose group had a significantly lower risk of developing thiopurine-induced myelosuppression and leukopenia (P = 0.015 and P = 0.022, respectively). No significant differences were observed in the secondary end points of the incidence of hepatotoxicity and steady-state concentrations of active metabolites in erythrocytes between the two groups. TPMT- and NUDT15-based dosing of 6-MP will significantly contribute toward further reducing the incidence of leukopenia in Chinese children with ALL. This trial is registered at www.clinicaltrial.gov as #NCT04228393.

Phosphate burden induces vascular calcification through a NLRP3-caspase-1-mediated pyroptotic pathway.

AIMS: The aim of this study is to clarify the role of NLRP3 inflammasome in phosphate burden-induced vascular smooth muscle cell (VSMC) calcification. MAIN METHODS: VSMC calcification was induced using a high concentration of inorganic phosphate. After pharmacological inhibition or genetic silencing of the NLRP3 inflammasome, pyroptosis, or potassium efflux, the cells were examined by RT-qPCR, immunofluorescence, and western blotting to identify the NLRP3-mediated pathway for VSMC calcification. KEY FINDINGS: Calcified VSMCs with α-smooth muscle actin (α-SMA) disarray presented features of pyroptosis, including caspase-1 maturation, cleaved gasdermin D (GSDMD), and a high supernatant level of lactate dehydrogenase A. Pharmacological inhibitions of caspase-1 and pyroptosis attenuated VSMC calcification, whereas interleukin-1ß receptor antagonism did not. Unlike canonical NLRP3 activation, osteogenic VSMCs did not upregulate NLRP3 expression. However, NLRP3 genetic silencing or inhibitions, which targets different domains of the NLRP3 protein, could ameliorate VSMC calcification by aborting caspase-1 and GSDMD activation. Furthermore, potassium efflux through the inward-rectifier potassium channel, and not through the P2X7 receptor, triggered NLRP3 inflammasome activation and VSMC calcification. SIGNIFICANCE: In the present study, we identified a potassium efflux-triggered NLRP3-caspase-1-mediated pyroptotic pathway for VSMC calcification that is unique and different from the canonical NLRP3 inflammasome activation. Therefore, targeting this pathway may serve as a novel therapeutic strategy for vascular calcification.

Amphibian pore-forming protein ßγ-CAT drives extracellular nutrient scavenging under cell nutrient deficiency.

Nutrient acquisition is essential for animal cells. ßγ-CAT is a pore-forming protein (PFP) and trefoil factor complex assembled under tight regulation identified in toad Bombina maxima. Here, we reported that B. maxima cells secreted ßγ-CAT under glucose, glutamine, and pyruvate deficiency to scavenge extracellular proteins for their nutrient supply and survival. AMPK signaling positively regulated the expression and secretion of ßγ-CAT. The PFP complex selectively bound extracellular proteins and promoted proteins uptake through endolysosomal pathways. Elevated intracellular amino acids, enhanced ATP production, and eventually prolonged cell survival were observed in the presence of ßγ-CAT and extracellular proteins. Liposome assays indicated that high concentration of ATP negatively regulated the opening of ßγ-CAT channels. Collectively, these results uncovered that ßγ-CAT is an essential element in cell nutrient scavenging under cell nutrient deficiency by driving vesicular uptake of extracellular proteins, providing a new paradigm for PFPs in cell nutrient acquisition and metabolic flexibility.

Corrigendum: Impact of climate change and rubber (Hevea brasiliensis) plantation expansion on reference evapotranspiration in Xishuangbanna, Southwest China.

[This corrects the article DOI: 10.3389/fpls.2022.830519.].

Association of Healthy Lifestyles with Non-Alcoholic Fatty Liver Disease: A Prospective Cohort Study in Chinese Government Employees.

BACKGROUND: Evidence indicates that certain healthy lifestyle factors are associated with non-alcoholic fatty liver disease (NAFLD). However, little is known about the effect of combined healthy lifestyle factors. OBJECTIVE: To assess the association of combined healthy lifestyle factors with the incidence of NAFLD. METHODS: This cohort study was conducted in Changsha, Hunan Province, China. The healthy lifestyles factors studied were not being a current smoker, having a healthy diet, engaging in physical activity, having a normal body mass index (BMI) and engaging in non-sedentary behavior. NAFLD was diagnosed based on abdominal ultrasonography. Logistic regression models were conducted to investigate the associations being studied. RESULTS: Of the 5411 participants, 1280 participants had NAFLD, with a prevalence of 23.7% at baseline. The incidence of NAFLD among participants without NAFLD at baseline was found to be 7.2% over a mean follow-up of 1.1 years. Compared with participants with 0-1 low-risk factors, the OR of NAFLD was 0.50 (95% CI: 0.29-0.82, p = 0.008) for those with at least 4 low-risk factors. Similar associations were observed in subgroup analyses and sensitivity analyses. CONCLUSION: This study suggests that a combined healthy lifestyle pattern may considerably decrease the risk of NAFLD in Chinese government employees.

Inguinal Fat Compensates Whole Body Metabolic Functionality in Partially Lipodystrophic Mice with Reduced PPARγ Expression.

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of PpargC/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of PpargC/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in PpargC/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in PpargC/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of PpargC/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Electro-Triggered Cascade Cyclization to Access Phosphinyl-Substituted N-Containing Heterocycles.

An electro-triggered cascade cyclization strategy was disclosed with concomitant phosphinylation and N-heterocycle construction. It provides a novel and environmentally friendly approach to access phosphinyl-substituted N-heterocycles with no external metal catalyst, oxidant, or heating. Mechanistic studies have revealed that anodic oxidation of H-phosphorus compounds occurs first to generate the key P-centered radical directly and cathodic reduction leads to the concurrent release of molecular hydrogen or methane. This protocol features simple operation, broad substrate scope, clean and mild conditions, and atom and step economy to form heterocycle-containing organophosphorus scaffolds.

Unexpected serum phosphorus lost in an amniotic fluid embolism patient.

BACKGROUND: Serum phosphorus concentration reflects body energy equilibrium and functions of the kidney and the coagulation system. It is regulated by serum calcium concentration and parathyroid hormone (PTH). CASE REPORT: We present a case of constant low concentrations of serum phosphorus in a 34-year-old female who was diagnosed with amniotic fluid embolism (AFE) and was continuously treated with extracorporeal membrane oxygenation (ECMO), continuous renal replacement therapy (CRRT) and blood component transfusion during an observational period of 11 days. CONCLUSION: This case highlights that the release of inorganic phosphorus from platelets and plasma into the blood prompts PTH secretion. The administration of active vitamin D supplement and PTH antagonism should be considered to neutralize the negative regulatory effect of PTH on serum phosphorus and to benefit patients' recovery in the intensive care unit.

Anti-angiogenic therapy for advanced primary pulmonary lymphoepithelioma-like carcinoma: a retrospective multicenter study.

PURPOSE: Primary pulmonary lympho-epithelioma-like carcinoma (PPLELC) is a rare subtype of primary non-small cell lung cancer (NSCLC). Currently, there is still lack of research data on anti-angiogenic therapy of advanced PPLELC. The purpose of this study was to investigate the efficacy and safety of anti-angiogenic therapy combined with chemotherapy compared with traditional chemotherapy for these patients. METHODS: Advanced PPLELC patients admitted to six grade A hospitals from January 2013 to January 2021 were selected. The patients received anti-angiogenic therapy combined with chemotherapy (AT group) or chemotherapy (CT group) alone. RESULTS: A total of 65 patients were included in this study, including 31 patients in the AT group treated with anti-angiogenic therapy combined with chemotherapy and 34 patients in the CT group treated with chemotherapy alone. As of October 1, 2021, the median progression-free survival (PFS) in the AT group was 11.2 months [95% confidence interval (CI), 5.9-16.5]. The median PFS in the CT group was 7.0 months [95%CI, 5.1-8.9] [Hazard Ratio (HR), 0.49; 95%CI, 0.29-0.83; P = 0.008]. The 1-year PFS rates were 41.9% and 17.6%, respectively. The overall response rates (ORR) of two groups were 45.2% (95% CI, 0.27-0.64), 38.2% (95% CI, 0.21-0.56), (P = 0.571). The disease control rates (DCR) of two groups were 93.5% (95% CI, 0.84-1.03), 88.2% (95% CI, 0.77-1.00), (P = 0.756). CONCLUSION: Among patients with advanced PPLELC, the PFS of patients with anti-angiogenic therapy combined with chemotherapy is better than that of patients with chemotherapy alone. Anti-angiogenic therapy combined with chemotherapy is an optional treatment scheme.

Tyrosine Kinase Inhibitors for Pediatric Leukemia: History and Current Status.

Tyrosine kinase inhibitors (TKIs) block the activity of tyrosine kinases by competitive inhibition of ATP at the catalytic tyrosine kinase binding site and inhibit oncogenic signaling. One important target of TKIs is BCR-ABL1, which is constitutively activated in leukemia cells. In this review, we briefly describe the development of TKIs from the first generation to the third generation, and summarize their use in the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia in children. We highlight several future directions in the development of TKIs for pediatric leukemia therapy. In conclusion, we focus on chronic myeloid leukemia and acute lymphoblastic leukemia as the examples of pediatric blood cancer that significantly benefit from TKIs-based target therapy. Further development of TKIs will allow us to better manage pediatric leukemia.

Pore-forming protein ßγ-CAT promptly responses to fasting with capacity to deliver macromolecular nutrients.

During animal fasting, the nutrient supply and metabolism switch from carbohydrates to a new reliance on the catabolism of energy-dense lipid stores. Assembled under tight regulation, ßγ-CAT (a complex of non-lens ßγ-crystallin and trefoil factor) is a pore-forming protein and trefoil factor complex identified in toad Bombina maxima. Here, we determined that this protein complex is a constitutive component in toad blood, that actively responds to the animal fasting. The protein complex was able to promote cellular albumin and albumin-bound fatty acid (FA) uptake in a variety of epithelial and endothelial cells, and the effects were attenuated by a macropinocytosis inhibitor. Endothelial cell-derived exosomes containing largely enriched albumin and FAs, called nutrisomes, were released in the presence of ßγ-CAT. These specific nutrient vesicles were readily taken up by starved myoblast cells to support their survival. The results uncovered that pore-forming protein ßγ-CAT is a fasting responsive element able to drive cell vesicular import and export of macromolecular nutrients.

Long-term exposure to ambient black carbon is associated with sleep disturbance in college students.

BACKGROUND: Evidence suggests an association of air pollution with sleep quality. However, there is limited knowledge regarding the effect of black carbon, a key component of ambient particulate matter, on sleep. OBJECTIVES: To investigate the association of long-term exposure to black carbon and sleep quality in a group of college students. METHODS: A retrospective cohort study was conducted in five universities in different regions of China. The concentrations of black carbon and other environment factors were defined as the averages during the 6 years prior to the recruitment. Averagely daily dose of black carbon exposure was estimated according to the respiratory rate. Sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI) with a cutoff >5 indicating sleep disturbance. Linear regression and logistic regression models were used to estimate the association. The sensitivity analyses were conducted to estimate the effects of 1-month, 6-month and 1-year mean levels of exposure to black carbon on sleep quality. RESULTS: A total of 20,053 incoming college students were included. 29.3% reported impaired sleep quality, with a mean PSQI score of 4.3 ± 2.2. The logistic regression showed that the risk of impaired sleep quality was positively associated with black carbon exposure, especially in the highest quantile (OR: 1.26, 95% CI: 1.11-1.43) compared with the lowest quartile after adjusting for potential confounders. Subgroup analysis showed that the effect of black carbon on sleep quality was stronger in participants with higher BMI, lower household income, and lower parental educational level. The results of sensitivity analyses were similar with main analyses. CONCLUSION: Long-term exposure to black carbon is associated with sleep disturbance in college students. Improvement of air quality may help improve sleep quality.

[Establishment of An Animal Model of Acute B Lymphoblastic Leukemia with Minimal Residual Disease].

OBJECTIVE: To establish an animal model of acute B lymphoblastic leukemia (B-ALL) with minimal residual disease. METHODS: The transplanted tumor was formed by subcutaneous injection of 2×107 Nalm-6 cells, and the body weight, activity status and tumor formation status of nude mice were observed. Peripheral blood, bone marrow, liver and spleen and other tissues of nude mice were taken for pathological examination to understand whether the success of subcutaneous modeling was accompanied by systemic metastasis. RESULTS: There were 2×107 Nalm-6 cells injected subcutaneously in nude mice, (11.0±2.5) days later, the tumors of (3-4) × (3-4) mm were observed, the body weight of the nude mice was reduced and activity showed no limited. Infiltration of tumor cells in liver, spleen and bone marrow were observed in pathological sections. CONCLUSION: The animal model of subcutaneous tumor of B-ALL was successfully established in nude mice.