Characterization and noncovalent inhibition of the K63-deubiquitinase activity of SARS-cov-2 PLpro.

SARS-CoV-2 papain-like protease (PLpro) could facilitate viral replication and host immune evasion by respectively hydrolyzing viral polyprotein and host ubiquitin conjugates, thereby rendering itself as an important antiviral target. Yet few noncovalent PLpro inhibitors of SARS-CoV-2 have been reported with improved directed towards pathogenic deubiquitinating activities inhibition. Herein, we report that coronavirus PLpro proteases have distinctive substrate bias and are conserved to deubiquitylate K63-linked polyubiquitination, thereby attenuating host type I interferon response. We identify a noncovalent compound specifically optimized towards halting the K63-deubiquitinase activity of SARS-CoV-2 PLpro, but not other coronavirus (CoV) counterparts or host deubiquitinase. Contrasting with GRL-0617, a SARS-CoV-1 PLpro inhibitor, SIMM-036 is 50-fold and 7-fold (half maximal inhibitory concentration (IC50)) more potent to inhibit viral replication during SARS-CoV-2 infection and restore the host interferon-ß (IFN-ß) response in human angiotensin-converting enzyme 2 (hACE2)-HeLa cells, respectively. Structure-activity relationship (SAR) analysis further reveals the importance of BL2 groove of PLpro, which could determine the selectivity of K63-deubiquitinase activity of the enzyme.

Fabrication of bulk superhydrophobic wood by grafting porous poly(divinylbenzene) to wood structure using isocyanatoethyl methacrylate.

Superhydrophobic treatment of wood can effectively reduce the interaction between wood and moisture, avoiding deformation, cracking, mould, and other defects caused by water absorption, which can extend the service life of wood and broaden the application field. Currently, the poor abrasion resistance of superhydrophobic wood is a crucial problem limiting its widespread application, and the preparation of superhydrophobic wood with robustness, abrasion resistance, and chemical resistance remains a huge challenge. In this work, robust bulk superhydrophobic wood with excellent abrasion resistance and chemical durability was fabricated by synthesizing porous poly(divinylbenzene) in wood cell cavities using graft copolymerization and solvothermal methods. The contact angles and rolling angles on the superhydrophobic wood surface were approximately 156° and 3°, respectively. Superhydrophobicity was carried through the entire structure of the wood. Even after severe damage by abrasion and sawing, as well as tests with organic solvents and harsh environments, the superhydrophobic properties of wood remained stable. Meanwhile, the superhydrophobic wood exhibited great self-cleaning and antifouling properties. In addition, the water uptake and dimensional stability of the wood were significantly improved. This work developed a simple, efficient, and durable strategy for the fabrication of superhydrophobic wood with robustness, abrasion resistance, and chemical resistance, which was expected to be applied to the wood industry to achieve the high-value applications of wood products and extend their service life.

Effects of cooking with solid fuel on hearing loss in Chinese adults-Based on two cohort studies.

The association between cooking fuel and hearing loss still needs more research to clarify, and two longitudinal cohort studies were explored to find if solid fuel use for cooking affected hearing in Chinese adults. The data from Chinese Health and Retirement Longitudinal Survey (CHARLS) and Chinese Longitudinal Healthy Longevity Survey (CLHLS) were analyzed. Participants (older than 18) without hearing loss at baseline and follow-up visits were included, which were divided into clean fuel and solid fuel groups. Hearing loss rate was from follow-up visits (both in year 2011) until the recent one (year 2018 in CHARLS and 2019 in CLHLS). Cox regressions were applied to examine the associations with adjustment for potential confounders. Fixed-effect meta-analysis was used to pool the results. A total of 9049 participants (average age 8.34 ± 9.12 [mean ± SD] years; 4247 [46.93%] males) were included in CHARLS cohort study and 2265 participants (average age, 78.75 ± 9.23 [mean ± SD] years; 1148 [49.32%] males) in CLHLS cohort study. There were 1518 (16.78%) participants in CHARLS cohort and 451 (19.91%) participants in CLHLS cohort who developed hearing loss. The group of using solid fuel for cooking had a higher risk of hearing loss (CHARLS: HR, 1.16; 95% CI 1.03-1.30; CLHLS: HR, 1.43; 95% CI 1.11-1.84) compared with the one of using clean fuel. Pooled hazard ratio showed the incidence of hearing loss in the solid fuel users was 1.17 (1.03, 1.29) times higher than that of clean fuel users. Hearing loss was associated with solid fuel use and older people were at higher risk. It is advised to replace solid fuel by clean fuel that may promote health equity.

Development of a Decision Aid for Family Surrogate Decision Makers of Critically Ill Patients Requiring Renal Replacement Therapy in ICU: User-Centered Design for Rapid Prototyping.

Objectives Renal replacement therapy (RRT) is increasingly adopted for critically ill patients diagnosed with acute kidney injury, but the optimal time for initiation remains unclear and prognosis is uncertain, leading to medical complexity, ethical conflicts, and decision dilemmas in intensive care unit (ICU) settings. This study aimed to develop a decision aid (DA) for family surrogate of critically ill patients to support their engagement in shared decision-making process with clinicians. Methods Development of DA employed a systematic process with user-centered design (UCD) principle, which included: (i) competitive analysis: searched, screened, and assessed the existing DAs to gather insights for design strategies, developmental techniques, and functionalities; (ii) user needs assessment: interviewed family surrogates to explore target user group's decision-making experience and identify their unmet needs; (iii) evidence syntheses: integrate latest clinical evidence and pertinent information to inform the content development of DA.Results The competitive analysis included 16 relevant DAs, from which we derived valuable insights from existing resources. User decision needs were explored among a cohort of 15 family surrogates, revealing four thematic issues in decision-making, including stuck into dilemmas, sense of uncertainty, limited capacity, and delayed decision confirmation. A total of 27 articles were included for evidence syntheses. Relevant decision-making knowledge on disease and treatment, as delineated in the literature sourced from decision support system or clinical guidelines, were formatted as the foundational knowledge base. Twenty-one items of evidence were extracted and integrated into the content panels of benefits and risks of RRT, possible outcomes, and reasons to choose. The DA was drafted into a web-based phototype using the elements of UCD. This platform could guide users make preparation of decision-making through a sequential four-step progress: identifying treatment options, weighing the benefits and risks, clarifying personal preferences and values, and formulating a schedule for formal shared decision-making with clinicians.Conclusions We developed a rapid prototype of DA tailored for family surrogate decision makers of critically ill patients in need of RRT in ICU setting. Future studies are needed to evaluate its usability, feasibility, and clinical effects of this intervene.

Combination of chidamide and PD-1 blockade in Refractory/Relapsed aggressive large B-cell lymphomas with high risk of failing CAR-T therapy.

BACKGROUND: Refractoriness and relapse after chimeric antigen receptor T-cell therapy have emerged as major challenges for immunotherapy of aggressive large B-cell lymphoma. Thus far, there is no consensus on how to address treatment failure and whether to administer maintenance therapy following CAR-T cell therapy. METHODS: From August 2017 through November 2022, 52 patients with refractory/relapsed aggressive LBCL who had a high risk of resistance to CAR-T cell therapy were given chidamide in combination with a PD-1 inhibitor as maintenance therapy following either CAR19/22 T-cell cocktail therapy or CAR19/22 T-cell cocktail therapy plus autologous stem cell transplantation (ASCT). Another 52 aggressive LBCL patients who had comparable baseline characteristics and received similar therapeutic regimens but did not receive any interventions following CAR-T cell therapy or CAR-T cell therapy plus ASCT were regarded as the control group to evaluate the efficacy and safety of the combination of chidamide and a PD-1 inhibitor. RESULTS: Among the 52 patients who received chidamide and a PD-1 inhibitor as maintenance therapy, with a median follow-up of 26.5 months (range: 1.1-53.8), neither the median progression-free survival (PFS) nor overall survival (OS) was reached, and the expected 2-year OS and PFS rates were 89 % and 77 %, respectively, which were superior to those of the control group (p < 0.001). Long-term chidamide administration and a specific genetic subtype of EZB were strongly associated with a better response after chidamide plus PD-1 blockade therapy. Additionally, long-term chidamide administration was significantly associated with prolonged persistence and reactivation of CD19-directed CAR-T cells in the peripheral blood. Adverse effects (AEs) were moderate and reversible, and no treatment-related deaths occurred. CONCLUSION: Our results indicate that the combination of chidamide and PD-1 blockade as maintenance therapy could improve the outcomes of aggressive LBCL patients at high risk of failing CAR-T cell therapy.

Efficacy of programmed cell death 1 inhibitor maintenance after chimeric antigen receptor T cells in patients with relapsed/refractory B-cell non-Hodgkin-lymphoma.

INTRODUCTION: Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options. METHODS: A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy. RESULTS: In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy. CONCLUSION: PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.

High-multiplex single-cell imaging analysis reveals tumor immune contexture associated with clinical outcomes after CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has made great progress in treating lymphoma, yet patient outcomes still vary greatly. The lymphoma microenvironment may be an important factor in the efficacy of CAR T therapy. In this study, we designed a highly multiplexed imaging mass cytometry (IMC) panel to simultaneously quantify 31 biomarkers from 13 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) who received CAR19/22 T cell therapy. A total of 20 sections were sampled before CAR T cell infusion or after infusion when relapse occurred. A total of 35 cell clusters were identified, annotated, and subsequently redefined into 10 metaclusters. The CD4+ T cell fraction was positively associated with remission duration. Significantly higher Ki67, CD57, and TIM3 levels and lower CD69 levels in T cells, especially the CD8+/CD4+ Tem and Te cell subsets, were seen in patients with poor outcomes. Cellular neighborhood containing more immune cells was associated with longer remission. Fibroblasts and vascular endothelial cells resided much closer to tumor cells in patients with poor response and short remission after CAR T therapy. Our work comprehensively and systematically dissects the relationship between cell composition, state, and spatial arrangement in the DLBCL microenvironment and the outcomes of CAR T cell therapy, which is beneficial to predict CAR T therapy efficacy.

Clinical analysis of 82 cases of acute promyelocytic leukemia with PML-RARα short isoform in children and adults.

Background: Acute promyelocytic leukemia (APL) with PML/RARα fusion gene is a distinct variant of acute myeloid leukemia. According to the different break sites of the PML gene, there are three transcripts: Long (bcr1), Variant (bcr2) and Short (bcr3). Methods: We retrospectively analyzed 82 APL cases with PML-RARα short isoform. Results: A total of 384 patients with APL were seen, of which 85(22.14%) had PML/RARα short isoform (bcr3) and 82 met the inclusion criteria. The median age was 33.5 years (range, 2-72 years). The incidences of hemorrhage in the intermediate- and high-risk group were higher, but only the incidence between medium and low risk differed statistically (P=0.006), and the incidences of fever, fatigue, splenomegaly, and lymph node enlargement and differentiation syndrome (DS) in those groups were not statistically significant (P>0.05). FLT3 gene mutation rate and the mortality rate of the high-risk group were significantly higher than that of other groups (P=0.040 and P=0.004, P=0.041 and P=0.037, respectively). The mortality rate was lowest (4.26%) in the group treated with ATRA combined with arsenic and anthracycline. The 3-year OS and the 3-year DFS of the low and intermediate-risk group were better (P=0.019 and P=0.017, respectively). Conclusions: ATRA combined with arsenic and anthracycline had significant impact on outcomes in APL with PML-RARα short isoform.

Comparison of nutritional value of snakehead fish from Guangdong and Deqing varieties.

Environmental pollution and overfishing of wild fish resources have led to a significant decrease in snakehead fish, thus leading to the increased demand for breeding the snakehead fish. Guangdong and Deqing snakehead fish are two common consumed varieties. However, their nutritional value was unclear. Therefore, this study aimed to evaluate the nutritional value of snakehead fish from Guangdong and Deqing varieties feeding with different fodders by analyzing and comparing the proximate composition, fatty acids and amino acids. Results showed that the contents of carbohydrate, energy and fat contents in Guangdong variety were lower than that in Deqing variety feeding commercial fodder or offal. Besides, Guangdong variety contained the highest contents of polyunsaturated fatty acids (27.99 ± 1.99%) and EPA + DHA (2.70 ± 0.04%), as well as total essential amino acid content (2550.29), compared to Deqing variety feeding commercial fodder or offal. Overall, snakehead fish from Guangdong variety displayed the highest nutritional value, and thus was a reasonable choice for farmers and consumers. The findings of this study would help farmers to choose the suitable feeding variety and patterns of snakehead fish from the perspective of fish nutritional value, which is beneficial to the sustainable fish farming.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. METHODS: In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. RESULTS: The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93-51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). CONCLUSIONS: For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy.

Interspecific root interaction enhances cadmium accumulation in Oryza sativa when intercropping with cadmium accumulator Artemisia argyi.

The contamination of arable land with heavy metals, such as Cd, is a serious concern worldwide. Intercropping with Cd accumulators can be used for efficient safe crop production and phytoremediation of Cd-contaminated soil. However, the effect of intercropping on Cd uptake by main crops and accumulators varies among plant combinations. Rhizosphere interaction may mediate Cd uptake by intercropped plants, but the mechanism is unclear. Thus, in the present study, we aimed to examine the effect of rhizosphere interaction on Cd uptake by intercropping rice (Oryza sativa L.) with mugwort (Artemisia argyi Levl. et Vant.) in Cd-contaminated paddy soil. We grew O. sativa and A. argyi in pots designed to allow different levels of interaction: complete root interaction (no barrier), partial root interaction (nylon mesh barrier), and no root interaction (plastic film barrier). Our results indicated that both complete and partial root interaction increased the shoot and root mass of A. argyi, but did not decrease the shoot, root, and grain mass of O. sativa. Interspecific root interaction significantly increased the Cd content in the shoots, roots, and grains of O. sativa and the shoots of A. argyi. Increased content of total organic acids in the rhizosphere, which increased the content of available Cd, was a possible mechanism of increased Cd uptake in both plants under interspecific root interaction. Our findings demonstrate that an intercropping system can extract more Cd from contaminated soil than a monocropping system of either A. argyi or O. sativa. However, the intercropping system did not facilitate safe crop production because it substantially increased grain Cd content in O. sativa.

Therapeutic potential of natural products against Alzheimer's disease via autophagic removal of Aß.

The pathological features of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include the deposition of extracellular amyloid beta (Aß) plaques and intracellular tau neurofibrillary tangles. A decline in cognitive ability is related to the accumulation of Aß in patients with AD. Autophagy, which is a primary intracellular mechanism for degrading aggregated proteins and damaged organelles, plays a crucial role in AD. In this review, we summarize the most recent research progress regarding the process of autophagy and the effect of autophagy on Aß. We further discuss some typical monomers of natural products that contribute to the clearance of Aß by autophagy, which can alleviate AD. This provides a new perspective for the application of autophagy modulation in natural product therapy for AD.

Andrographolide derivative Andro-III modulates neuroinflammation and attenuates neuropathological changes of Alzheimer's disease via GSK-3ß/NF-κB/CREB pathway.

Andrographolide has anti-inflammatory and neuroprotective effects, making it a potential therapeutic option for Alzheimer's disease (AD). Our research group optimized its structure in a previous study to minimize the risk of renal toxicity, which would beneficial for future clinical research. This study aims to examine the impact of Andro-III on enhancing cognitive learning ability in 3xTg-AD mice, as well as the mechanisms involved. Andro-III improved spatial learning ability, prevented the loss of Nysted's vesicles, reduced the accumulation of ß-amyloid (Aß) and tau proteins, and suppressed microglial activation. Further research found that the expression of nuclear factor kappa-B RelA (NF-κB p65) expression and glycogen synthase kinase-3ß (GSK-3ß) activity were inhibited, while CREB was upregulated in brain tissue treated with Andro-III. Moreover, Andro-III downregulated the expression of IBA1 and inflammatory factors in microglial cells of mice induced by Aß. The regulation of the GSK-3ß/NF-κB/CREB pathway was similar to that observed in 3xTg-AD mice. Therefore, Andro-III modulates neuroinflammation and attenuates neuropathological changes of AD via the GSK-3ß/NF-κB/CREB pathway.

Ethanol extract of Andrographis paniculata alleviates aluminum-induced neurotoxicity and cognitive impairment through regulating the p62-keap1-Nrf2 pathway.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-ß protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aß deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro. METHODS: UPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA. RESULTS: The main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells. CONCLUSIONS: AP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.

Assessment of early diabetic retinopathy severity using ultra-widefield Clarus versus conventional five-field and ultra-widefield Optos fundus imaging.

To compare early diabetic retinopathy (DR) severity level and the abilities in detecting early DR lesions among conventional five-field, ultrawide-field (UWF) Optos, and UWF Clarus fundus imaging methods. This was a single-center, prospective, clinic-based, and comparative study. In total, 157 consecutive patients with diabetes mellitus were enrolled in this study. All patients underwent comprehensive ophthalmological examinations. Following mydriasis, each eye was examined with conventional five-field, UWF Optos, and UWF Clarus fundus imaging methods. The initial UWF images were overlaid with a template mask that obscured the retina, which created a five-field view from UWF images (covered UWF images). The covered UWF images were then graded, after which the template mask was removed, and the original UWF images were also evaluated. All images were graded using the International Clinical DR severity scale. DR grades were compared and analyzed by weighted kappa statistics among the three fundus imaging methods. In total, 157 consecutive patients with diabetes (302 eyes) were enrolled in this study. Weighted kappa statistics for agreement were 0.471 (five-field vs. covered Optos), 0.809 (five-field vs. covered Clarus), 0.396 (covered Optos vs. covered Clarus), 0.463 (five-field vs. Optos), 0.521 (five-field vs. Clarus 133°), 0.500 (five-field vs. Clarus 200°), 0.323 (Optos vs. Clarus 133°), and 0.349 (Optos vs. Clarus 200°). The area under curve of covered Clarus images was higher than that of conventional five-field images at three different thresholds. Compared with conventional five-field and Optos fundus imaging methods, Clarus fundus imaging methods exhibited excellent performance in assessing early DR severity. Thus, Clarus fundus imaging methods were superior for early detection of DR.

The impact of educational lifestyle intervention on body weight and psychological health among overweight/obese patients with severe mental disorders.

BACKGROUND: There was a high prevalence of overweight/obesity among patients with severe mental disorders (SMD). However, studies on the lifestyle-based interventions in patients with SMD are limited. OBJECTIVE: To examine the effects of an educational lifestyle intervention on body weight and psychological health among Chinese community-dwelling overweight/obese patients with SMD. METHODS: Community-dwelling overweight/obese patients with SMD was recruited from Shenzhen, China in October 2020. They were randomly allocated into intervention group (IG) and control group (CG). Participants in IG received a 12-month educational lifestyle intervention, while the CG was exposed to routine care. A generalized estimating equation model was used to assess the effect of the intervention over time. RESULTS: A total of 176 subjects (88 in IG and 88 in CG) aged 42.2 ± 10.9 years were included in this study. After adjusting for potential confounders, body weight (p = 0.001), body mass index (BMI, p = 0.001), and waist circumference (p = 0.027) in IG significantly decreased compared with CG after 12 months. Besides, IG had significantly higher life satisfaction than CG after intervention (p = 0.026), whereas significant reductions in depressive symptoms were observed in IG from 26.1 % at baseline to 13.6 % after the intervention (p = 0.027), and the between-group differences were marginally significant (p = 0.086). CONCLUSION: An educational lifestyle intervention can effectively reduce body weight parameters and improve psychological health in overweight/obese patients with SMD.

NN-Based Reinforcement Learning Optimal Control for Inequality-Constrained Nonlinear Discrete-Time Systems With Disturbances.

Based on actor-critic neural networks (NNs), an optimal controller is proposed for solving the constrained control problem of an affine nonlinear discrete-time system with disturbances. The actor NNs provide the control signals and the critic NNs work as the performance indicators of the controller. By converting the original state constraints into new input constraints and state constraints, the penalty functions are introduced into the cost function, and then the constrained optimal control problem is transformed into an unconstrained one. Further, the relationship between the optimal control input and worst-case disturbance is obtained using the Game theory. With Lyapunov stability theory, the control signals are ensured to be uniformly ultimately bounded (UUB). Finally, the effectiveness of the control algorithms is tested through a numeral simulation using a third-order dynamic system.

Avermectin reduces bone mineralization via the TGF-ß signaling pathway in zebrafish.

Avermectin, a widely used insecticide, is primarily effective against animal parasites and insects. Given its extensive application in agriculture, a large amount of avermectin accumulates in natural water bodies. Studies have shown that avermectin has significant toxic effects on various organisms and on the nervous system, spine, and several other organs in humans. However, the effects of avermectin on bone development have not been reported yet. In this study, zebrafish embryos were treated with different concentrations of avermectin to explore the effects of avermectin on early bone development. The results showed that avermectin disturbed early bone development in zebrafish, caused abnormal craniofacial chondrogenesis, and reduced bone mineralization. Avermectin treatment significantly reduced mineralization in zebrafish scales and increased osteoclast activity. Real-time quantitative PCR results showed that avermectin decreased the expression of genes related to osteogenesis and transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling pathways. The TGF-ß inhibitor SB431542 rescued avermectin-induced bone mineralization and osteogenesis related gene expression in zebrafish during early development. Thus, this study provides insight into the mechanism of damage caused by avermectin on bone development, thus helping demonstrate its toxicity.

Epstein-Barr virus-associated B-cell lymphoproliferative disorder meeting the definition of CAEBV B cell disease: a case report.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD) considered to be associated with a genetic immunological abnormality, although its cause is still unclear. EBV is usually detected in T cells or NK cells in CAEBV patients with only a few cases involving B cells described in East Asia, which may be due to differences in genetic and environmental factors. CASE DESCRIPTION: A 16-year-old boy who seemed to be diagnosed as CAEBV of B cell type was studied. The patient had IM-like symptoms persisting for more than 3 months, high levels of EBV DNA in the PB, and positive EBER in situ hybridization in B cells. In addition, to exclude underlying genetic disorders, we performed next-generation sequencing (NGS) and whole-exome sequencing (WES), which identified the missense mutation in PIK3CD (E1021K), ADA (S85L) and CD3D (Q140K) in the patient while no same genetic mutation was detected in his parents and sister. However, there is no diagnosis of CAEBV of B cell type in the most recent World Health Organization classification of tumors of hematopoietic and lymphoid tissues, therefore we finally diagnosed this patient as EBV-B-LPD. CONCLUSIONS: This study shows a rare case of a patient meeting the definition of CAEBV B-cell disease in East Asia. Meanwhile, the case indicates that the missense mutation and the disease are related.

Osteophilic and Dual-Regulated Alendronate-Gene Lipoplexes for Reversing Bone Loss.

The pathogenesis of postmenopausal osteoporosis (PMOP) is mainly determined by the adhesion of osteoclasts to the bone matrix and the involvement of various molecules in bone resorption. The dual regulation strategy of the physical barriers of bone matrix and intracellular gene regulation generated by advanced biomaterials is a decent alternative for the treatment of PMOP. Herein, for the first time, it is identified that hsa-miR-378i/mmu-miR-378a-3p are closely associated with PMOP. Then, an osteophilic and dual-regulated alendronate-gene lipoplex (antagomir@Aln-Lipo), composed of medicative alendronate-functionalized liposomal vehicle and encapsulated specific microRNAs is engineered, for bone-targeting delivery of genes to achieve combined mitigation of bone loss. Alendronate targets hydroxyapatite in the bone matrix and occupies the adhesion site of osteoclasts, thus providing the "physical barriers". Antagomir is coupled precisely to specific endogenous microRNAs, thus providing the "genetic signals". These functionalized lipoplexes exhibited long-term stability and good transfection efficiency. It is proven that antagomir@Aln-Lipo could synergistically regulate osteoclastogenesis and bone resorption in vitro and in vivo. Furthermore, intravenous injection of antagomir@Aln-Lipo efficiently reverses bone loss through a dual mechanism driven by alendronate and antagomir-378a-3p. In conclusion, the osteophilic and dual-regulated antagomir@Aln-Lipo offers a brand-new bifunctional strategy for the precise treatment of PMOP.