IRX3 promotes adipose tissue browning and inhibits fibrosis in obesity-resistant mice.

Obesity is one of the threats to human health and survival. High fat diet (HFD)-induced obesity leads to adipose tissue fibrosis and a series of metabolic diseases. There are some people still thin under HFD, a phenomenon known as the "obesity resistance (OR) phenotype". It was found that Iroquois homeobox 3 (IRX3) is considered as a regulator in obesity, but the regulatory mechanism between OR and IRX3 is still unclear. In this study, we investigated obesity resistance (OR) on a high-fat diet (HFD) and the role of the Iroquois homeobox 3 (IRX3) gene. Using mice, we observed that OR mice had lower body weights, reduced liver lipid synthesis, and increased white adipose tissue (WAT) lipolysis compared to obesity-prone (OP) mice. Additionally, OR mice exhibited spontaneous WAT browning and less fibrosis, correlating with higher Irx3 expression. Utilizing 3T3-L1 differentiated adipocytes, our study demonstrated that overexpression of Irx3 promoted thermogenesis-related gene expression and reduced adipocyte fibrosis. Therefore, Irx3 promotes WAT browning and inhibits fibrosis in OR mice. These results provide insight into the differences between obesity and OR, new perspectives on obesity treatment, and guidance for lessening adipose tissue fibrosis.

Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration.

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Metal π-Lewis base activation in palladium(0)-catalyzed trans-alkylative cyclization of alkynals.

The Pd(0)-mediated umpolung reaction of an alkyne to achieve trans-difunctionalization is a potential synthetic methodology, but its insightful activation mechanism of Pd(0)-alkyne interaction has yet to be established. Here, a Pd(0)-π-Lewis base activation mode is proposed and investigated by combining theoretical and experimental studies. In this activation mode, the Pd(0) coordinates to the alkyne group and enhances its nucleophilicity through π-back-donation, facilitating the nucleophilic attack on the aldehyde to generate a trans-Pd(ii)-vinyl complex. Ligand-effect studies reveal that the more electron-donating one would accelerate the reaction, and the cyclization of the challenging flexible C- or O-tethered substrates has been realized. The origin of regioselectivities is also explicated by the newly proposed metal π-Lewis base activation mode.

[Biomanufacturing of propionic acid].

Propionic acid as an important C3 platform chemical has been widely used in food, pharmaceutical, and chemical fields. The chemical synthesis of propionic acid from petroleum and other chemical products has serious environmental pollution and is not sustainable. In recent years, the production of propionic acid by microbial transformation of renewable resources has received extensive attention. Focusing on the biomanufacturing of propionic acid, this paper firstly reviews the studies about the metabolic engineering of Propionibacterium and the pathway reconstruction in heterogeneous hosts such as Escherichia coli and Saccharomyces cerevisiae. Secondly, this paper reviews the recent progress in the synthesis of high-purity propionic acid from L-threonine or bio-based 1, 2-propanediol by the design and modification of the pathway of Pseudomonas putida KT2440 based on synthetic biology.

Simultaneously activating molecular oxygen and surface lattice oxygen on Pt/TiO2 for low-temperature CO oxidation.

Developing high-performance Pt-based catalysts with low Pt loading is crucial but challenging for CO oxidation at temperatures below 100 °C. Herein, we report a Pt-based catalyst with only a 0.15 wt% Pt loading, which consists of Pt-Ti intermetallic single-atom alloy (ISAA) and Pt nanoparticles (NP) co-supported on a defective TiO2 support, achieving a record high turnover frequency of 11.59 s-1 at 80 °C and complete conversion of CO at 120 °C. This is because the coexistence of Pt-Ti ISAA and Pt NP significantly alleviates the competitive adsorption of CO and O2, enhancing the activation of O2. Furthermore, Pt single atom sites are stabilized by Pt-Ti ISAA, resulting in distortion of the TiO2 lattice within Pt-Ti ISAA. This distortion activates the neighboring surface lattice oxygen, allowing for the simultaneous occurrence of the Mars-van Krevelen and Langmuir-Hinshelwood reaction paths at low temperatures.

Ammonia monooxygenase-mediated cometabolic biotransformation of volatile 4-chlorophenol in nitrifying counter-diffused biofilms: A combined molecular dynamics simulation, DFT calculation and experimental study.

Ammonia monooxygenase (AMO)-mediated cometabolism of organic pollutants has been widely observed in biological nitrogen removal process. However, its molecular mechanism remains unclear, hindering its practical application. Furthermore, conventional nitrification systems encounter significant challenges such as air pollution and the loss of ammonia-oxidizing bacteria, when dealing with wastewater containing volatile organic pollutants. This study developed a nitrifying membrane-aerated biofilm reactor (MABR) to enhance the biodegradation of volatile 4-chlorophenol (4-CP). Results showed that 4-CP was primarily removed via Nitrosomonas nitrosa-mediated cometabolism in the presence of NH4+-N, supported by the increased nicotinamide adenine dinucleotide (NADH) and adenosine triphosphate (ATP) content, AMO activity and the related genes abundance. Hydroquinone, detected for the first time and produced via oxidative dechlorination, as well as 4-chlorocatechol was primary transformation products of 4-CP. Nitrosomonas nitrosa AMO structural model was constructed for the first time using homology modeling. Molecular dynamics simulation suggested that the ortho-carbon in the benzene ring of 4-CP was more prone to metabolismcompared to the ipso-carbon. Density functional theory calculation revealed that 4-CP was metabolized by AMO via H-abstraction-OH-rebound reaction, with a significantly higher rebound barrier at the ipso-carbon (16.37 kcal·mol-1) as compared to the ortho-carbon (6.7 kcal·mol-1). This study fills the knowledge gap on the molecular mechanism of AMO-mediated cometabolism of organic pollutants, providing practical and theoretical foundations for improving volatile organic pollutants removal through nitrifying MABR.

Comprehensive Analysis of the Yield and Leaf Quality of Fresh Tea (Camellia sinensis cv. Jin Xuan) under Different Nitrogen Fertilization Levels.

Reasonable application of nitrogen fertilizer can improve the yield and quality of tea. This study used Jin Xuan as the tested variety and applied nitrogen fertilizer at rates of 0 kg/ha (N0), 150 kg/ha (N150), 300 kg/ha (N300), and 450 kg/ha (N450) in the summer and autumn seasons to analyze the effects of nitrogen application on the quality components and gene expression of tea leaves. The results showed that the N150 treatment significantly increased total polyphenols (TP), total catechins (TC), and caffeine contents, with the most significant increase observed in the content of six monomers of catechins (EGCG, ECG, EGC, GCG, GC, and EC) in the summer. The N300 treatment significantly increased TP and AA contents in the autumn while decreasing TC content. Additionally, the N300 treatment significantly increased caffeine and theanine contents in the autumn. Notably, the N300 treatment significantly increased both summer and autumn tea yields. Multivariate statistical analysis showed that TPs, AAs, TCs, EGC, and caffeine were key factors affecting the quality of Jin Xuan. Furthermore, the N150 treatment upregulated the expression of the phenylalanine ammonia-lyase (PAL) gene, which may increase the accumulation of catechins. In conclusion, it is recommended to apply 150 kg/ha of nitrogen fertilizer in the summer and 300 kg/ha of nitrogen fertilizer in the autumn. This recommendation provides a theoretical basis for improving the quality and yield of tea leaves in summer and autumn.

A viroid-derived small interfering RNA targets bHLH transcription factor MdPIF1 to regulate anthocyanin biosynthesis in Malus domestica.

Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.

Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression.

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

Quantitative Proteomics Reveal the Mechanism of MiR-138-5p Suppressing Cervical Cancer via Targeting ZNF385A.

MicroRNAs are short, noncoding RNA molecules that exert pivotal roles in cancer development and progression by modulating various target genes. There is growing evidence that miR-138-5p is significantly involved in cervical cancer (CC). However, its precise molecular mechanism has yet to be fully understood. In the current investigation, a quantitative proteomics approach was utilized to detect possible miR-138-5p targets in HeLa cells systematically. In total, 364 proteins were downregulated, and 150 were upregulated after miR-138-5p overexpression. Bioinformatic analysis of these differentially expressed proteins (DEPs) revealed significant enrichment in several cancer-related pathways. Zinc finger protein 385A (ZNF385A) was determined as a novel direct target of miR-138-5p and discovered to facilitate the proliferation, migration, and cell cycle progression of HeLa cells. SFN and Fas cell surface death receptor(FAS) were then identified as functional downstream effectors of ZNF385A and miR-138-5p. Moreover, a tumor xenograft experiment was conducted to validate the association of miR-138-5p-ZNF385A-SFN/FAS axis with the development of CC in vivo. Our findings have collectively established a catalog of proteins mediated by miR-138-5p and have provided an in-depth comprehension of the molecular mechanisms responsible for the inhibitory effect of miR-138-5p on CC. The miR-138-5p-ZNF385A-SFN/FAS axis could also be beneficial to the identification of new therapeutic targets.

Baicalin Prevents Colon Cancer by Suppressing CDKN2A Protein Expression.

OBJECTIVE: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. METHODS: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. RESULTS: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). CONCLUSION: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer.

Mechanism Involved in Polyvinyl Chloride Nanoplastics Induced Anaerobic Granular Sludge Disintegration: Microbial Interaction Energy, EPS Molecular Structure, and Metabolism Functions.

Nanoplastics (NPs) are emerging pollutants and have been reported to cause the disintegration of anaerobic granular sludge (AnGS). However, the mechanism involved in AnGS disintegration was not clear. In this study, polyvinyl chloride nanoplastics (PVC-NPs) were chosen as target NPs and their long-term impact on AnGS structure was investigated. Results showed that increasing PVC-NPs concentration resulted in the inhibition of acetoclastic methanogens, syntrophic propionate, and butyrate degradation, as well as AnGS disintegration. At the presence of 50 µg·L-1 PVC-NPs, the hydrophobic interaction was weakened with a higher energy barrier due to the relatively higher hydrophilic functional groups in extracellular polymeric substances (EPS). PVC-NPs-induced ROS inhibited quorum sensing, significantly downregulated hydrophobic amino acid synthesis, whereas it highly upregulated the genes related to the synthesis of four hydrophilic amino acids (Cys, Glu, Gly, and Lys), resulting in a higher hydrophily degree of protein secondary structure in EPS. The differential expression of genes involved in EPS biosynthesis and the resulting protein secondary structure contributed to the greater hydrophilic interaction, reducing microbial aggregation ability. The findings provided new insight into the long-term impact of PVC-NPs on AnGS when treating wastewater containing NPs and filled the knowledge gap on the mechanism involved in AnGS disintegration by PVC-NPs.

Microplastics in tea from planting to the final tea product: Traceability, characteristics and dietary exposure risk analysis.

Tea, sold as tea bags or loose tea, is a popular drink worldwide. We quantified microplastics in loose tea during various stages of production, from planting to processing and brewing. The quantity of microplastics in tea ranged from (70-3472 pcs/kg), with the highest abundance detected during processing, mainly in the rolling stage (2266 ± 1206 pcs/kg tea). Scanning electron microcopy revealed scratches and pits on the surface of microplastics fibers from tea plantation soil and processed tea, and their degradation was characterized by cracks and fractures. Exposure risks, based on an estimated dietary intake of 0.0538-0.0967 and 0.0101-0.0181 pcs /kg body weight /day for children and adults, respectively, are considered very low. This study not only evaluates the extent of research on microplastics pollution in tea, but also assess the risk of people's exposure to microplastics through drinking tea.

Machine learning-based model development for predicting risk factors of prolonged intra-aortic balloon pump therapy in patients with coronary artery bypass grafting.

Machine learning algorithms are frequently used to clinical risk prediction. Our study was designed to predict risk factors of prolonged intra-aortic balloon pump (IABP) use in patients with coronary artery bypass grafting (CABG) through developing machine learning-based models. Patients who received perioperative IABP therapy were divided into two groups based on their length of IABP implantation longer than the 75th percentile for the whole cohort: normal (≤ 10 days) and prolonged (> 10 days) groups. Seven machine learning-based models were created and evaluated, and then the Shapley Additive exPlanations (SHAP) method was employed to further illustrate the influence of the features on model. In our study, a total of 143 patients were included, comprising 56 cases (38.16%) in the prolonged group. The logistic regression model was considered the final prediction model according to its most excellent performance. Furthermore, feature important analysis identified left ventricular end-systolic or diastolic diameter, preoperative IABP use, diabetes, and cardiac troponin T as the top five risk variables for prolonged IABP implantation in patients. The SHAP analysis further explained the features attributed to the model. Machine learning models were successfully developed and used to predict risk variables of prolonged IABP implantation in patients with CABG. This may help early identification for prolonged IABP use and initiate clinical interventions.

Association Between Early Sexual Debut and New HIV Infections Among Adolescents and Young Adults in 11 African Countries.

We investigated the association between early sexual debut and HIV infection among adolescents and young adults. Analyzing data from nationally representative Population-Based HIV Impact Assessment (PHIA) surveys in 11 African countries, the research employed a multivariate logistic regression model to assess the relationship between the early sexual debut and new HIV infections in the age group of 10-24 years. The results revealed a significant and robust association, indicating that young individuals who experienced early sexual debut were approximately 2.65 times more likely to contract HIV than those who did not, even after accounting for other variables. These findings align with prior research suggesting that early initiation of sexual activity may increase vulnerability to HIV infection due to factors such as biological susceptibility and risky behaviors like low condom use and multiple sexual partners. The implications of these findings for HIV prevention strategies are substantial, suggesting that interventions aimed at delaying sexual debut could be an effective component in reducing HIV risk for this population. Targeted sex education programs that address the risks of early sexual debut may play a pivotal role in these prevention efforts. By employing a comprehensive approach, there is a possibility to advance efforts towards ending AIDS by 2030.

Cost-effectiveness of interventions for HIV/AIDS, malaria, syphilis, and tuberculosis in 128 countries: a meta-regression analysis.

BACKGROUND: Cost-effectiveness analyses have been conducted for many interventions for HIV/AIDS, malaria, syphilis, and tuberculosis, but they have not been conducted for all interventions that are currently recommended in all countries. To support national decision makers in the effective allocation of resources, we conducted a meta-regression analysis of published incremental cost-effectiveness ratios (ICERs) for interventions for these causes, and predicted ICERs for 14 recommended interventions for Global Fund-eligible countries. METHODS: In the meta-regression analysis, we used data from the Tufts University Center for the Evaluation of Value and Risk in Health (Boston, MA, USA) Cost-Effectiveness Registries (the CEA Registry beginning in 1976 and the Global Health CEA registry beginning in 1995) up to Jan 1, 2018. To create analysis files, we standardised and mapped the data, extracted additional data from published articles, and added variables from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Then we selected ratios for interventions with a minimum of two published articles and three published ICERs that mapped to one of five GBD causes (HIV/AIDS, malaria, syphilis, drug-susceptible tuberculosis, or multi-drug resistant tuberculosis), and to a GBD country; reported a currency year during or after 1990; and for which the comparator intervention was defined as no intervention, standard of care, or placebo. Our meta-regression analysis used all available data on 25 eligible interventions, and quantified the association between ICERs and factors at country level and intervention level. We used a five-stage statistical model that was developed to synthesise evidence on cost-effectiveness analyses, and we adapted it for smaller sample sizes by grouping interventions by cause and type (ie, prevention, diagnostics, and treatment). Using the meta-regression parameters we predicted country-specific median ICERs, IQRs, and 95% uncertainty intervals in 2019 US$ per disability-adjusted life-year (DALY) for 14 currently recommended interventions. We report ICERs in league tables with gross domestic product (GDP) per capita and country-specific thresholds. FINDINGS: The sample for the analysis was 1273 ratios from 144 articles, of which we included 612 ICERs from 106 articles in our meta-regression analysis. We predicted ICERs for antiretroviral therapy for prevention for two age groups and pregnant women, pre-exposure prophylaxis against HIV for two risk groups, four malaria prevention interventions, antenatal syphilis screening, two tuberculosis prevention interventions, the Xpert tuberculosis test, and chemotherapy for drug-sensitive tuberculosis. At the country level, ranking of interventions and number of interventions with a predicted median ICER below the country-specific threshold varied greatly. For instance, median ICERs for six of 14 interventions were below the country-specific threshold in Sudan, whereas 12 of 14 were below the country-specific threshold in Peru. Antenatal syphilis screening had the lowest median ICER among all 14 interventions in 81 (63%) of 128 countries, ranging from $3 (IQR 2-4) per DALY averted in Equatorial Guinea to $3473 (2244-5222) in Ukraine. Pre-exposure prophylaxis for HIV/AIDS for men who have sex with men had the highest median ICER among all interventions in 116 (91%) countries, ranging from $2326 (1077-4567) per DALY averted in Lesotho to $53 559 (23 841-108 534) in Maldives. INTERPRETATION: Country-specific league tables highlight the interventions that offer better value per DALY averted, and can support decision making at a country level that is more tailored to available resources than GDP per capita and country-specific thresholds. Meta-regression is a promising method to synthesise cost-effectiveness analysis results and transfer them across settings. FUNDING: Bill & Melinda Gates Foundation.

Adipocyte-specific FAK deletion promotes pancreatic ß-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus.

BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. METHODS AND RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic ß-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases ß cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic ß cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves. CONCLUSION: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.

Effects of radial extracorporeal shock wave therapy on flexor spasticity of the upper limb in post-stroke patients: A randomized controlled trial.

OBJECTIVE: This study aimed to assess the efficacy of radial extracorporeal shock wave therapy in treating upper limb spasticity after a stroke. DESIGN: Randomized controlled trial. SETTING: Zhujiang Hospital of Southern Medical University. SUBJECTS: This study included 95 people with stroke. INTERVENTION: The active (n = 47) and sham-placebo (n = 48) radial extracorporeal shockwave therapy groups received three treatment sessions (every third day). MAIN MEASURES: The Modified Ashworth Scale, Hmax/Mmax ratio, root mean square, co-contraction ratio, mechanical parameters of the muscle and temperature were measured at baseline and days 2, 5 and 8. RESULTS: Among the 135 potential participants screened, 100 were enrolled and allocated randomly, with 95 participants ultimately being included in the intent-to-treat analysis dataset. The active group showed significantly better improvements in upper limb spasticity and muscle function than did the sham-placebo group. Greater improvements in the Modified Ashworth Scale were observed in the active group than in the sham-placebo group (difference, -0.45; 95% CI, -0.69 to -0.22; P < 0.001). Moreover, significant differences in root mean square, co-contraction ratio and Hmax/Mmax ratio were observed between the two groups (all P < 0.001). The mechanical parameters of the biceps muscle were significantly better in the active group than in the sham-placebo group (P < 0.001). The active group had a higher temperature than the sham-placebo group, although the difference was not significant (P = 0.070). CONCLUSIONS: This study revealed that the treatment with extracorporeal shockwave therapy can relieve upper limb spasticity in people with stroke.

Polymorphic Heterogeneous Polar Structure Enabled Superior Capacitive Energy Storage in Lead-Free Relaxor Ferroelectrics at Low Electric Field.

High-performance energy storage dielectrics capable of low/moderate field operation are vital in advanced electrical and electronic systems. However, in contrast to achievements in enhancing recoverable energy density (Wrec), the active realization of superior Wrec and energy efficiency (η) with giant energy-storage coefficient (Wrec/E) in low/moderate electric field (E) regions is much more challenging for dielectric materials. Herein, lead-free relaxor ferroelectrics are reported with giant Wrec/E designed with polymorphic heterogeneous polar structure. Following the guidance of Landau phenomenological theory and rational composition construction, the conceived (Bi0.5Na0.5)TiO3-based ternary solid solution that delivers giant Wrec/E of ≈0.0168 µC cm-2, high Wrec of ≈4.71 J cm-3 and high η of ≈93% under low E of 280 kV cm-1, accompanied by great stabilities against temperature/frequency/cycling number and excellent charging-discharging properties, which is ahead of most currently reported lead-free energy storage bulk ceramics measured at same E range. Atomistic observations reveal that the correlated coexisting local rhombohedral-tetragonal polar nanoregions embedded in the cubic matrix are constructed, which enables high polarization, minimized hysteresis, and significantly delayed polarization saturation concurrently, endowing giant Wrec/E along with high Wrec and η. These findings advance the superiority and feasibility of polymorphic nanodomains in designing highly efficient capacitors for low/moderate field-region practical applications.

Histamine-related genes participate in the establishment of an immunosuppressive microenvironment and impact the immunotherapy response in hepatocellular carcinoma.

Chronic inflammation is pivotal in the pathogenesis of hepatocellular carcinoma (HCC). Histamine is a biologically active substance that amplifies the inflammatory and immune response and serves as a neurotransmitter. However, knowledge of histamine's role in HCC and its effects on immunotherapy remains lacking. We focused on histamine-related genes to investigate their potential role in HCC. The RNA-seq data and clinical information regarding HCC were obtained from The Cancer Genome Atlas (TCGA). After identifying the differentially expressed genes, we constructed a signature using the univariate Cox proportional hazard regression and least absolute shrinkage and selection operator (LASSO) analyses. The signature's predictive performance was evaluated using a receiver operating characteristic curve (ROC) analysis. Furthermore, drug sensitivity, immunotherapy effects, and enrichment analyses were conducted. Histamine-related gene expression in HCC was confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). A histamine-related gene prognostic signature (HRGPS) was developed in TCGA. Time-dependent ROC and Kaplan-Meier survival analyses demonstrated the signature's strong predictive power. Importantly, patients in high-risk groups exhibited a higher frequency of TP53 mutations, elevated immune checkpoint-related gene expression, and increased infiltration of immunosuppressive cells-indicating a potentially favorable response to immunotherapy. In addition, drug sensitivity analysis revealed that the signature could effectively predict chemotherapy efficacy and sensitivity. qRT-PCR results validated histamine-related gene overexpression in HCC. Our findings demonstrate that inhibiting histamine-related genes and signaling pathways can impact the therapeutic effect of anti-PD-1/PD-L1. The precise predictive ability of our signature in determining the response to different therapeutic options highlights its potential clinical significance.