Pharmacogenetic intervention improves treatment outcomes in Chinese adult men with schizophrenia.

To investigate the clinical application value of pharmacogenetic testing in individualized drug therapy for adult male patients with schizophrenia. A total of 186 adult patients with schizophrenia were enrolled and randomised into the pharmacogenetic (PGx) intervention group and the standard care group. In the PGx intervention group, PGx testing was performed, and the medication regimen was adjusted according to the results of the pharmacogenomic analysis. In contrast, in the standard care group, patients were treated according to the physician's medication experience. Differences in the primary indicator of schizophrenia, the Positive and Negative Symptom Scale (PANSS), and the secondary efficacy measures, the Clinical Global Impressions-Severity of Illness scale (CGI-SI) and Clinical Global Impressions-Global Improvement (CGI-GI) scale, were compared between the intervention and standard care groups. At baseline, the PGx intervention group consisted of 109 individuals, while the standard care group had 77 participants. After 12 weeks of treatment, 49 individuals withdrew from the PGx group (a dropout rate of 45.0%), and 34 withdrew from the standard care group (a dropout rate of 44.2%), with no significant difference in dropout rates between the two groups. The PANSS score reduction rate in the PGx intervention group significantly exceeded that of the standard care group during weeks 3, 6, and 12 of follow-up (P < 0.05). At the 12th week, the PGx intervention group achieved a treatment response rate of 81.7%, significantly surpassing the 48.8% of the standard care group (odds ratio of 4.67, 95% confidence interval of 1.96-11.41; P = 0.001). Furthermore, the PGx intervention was significantly more effective than standard care regardless of whether the patient had a first episode or a relapse (P < 0.05). Furthermore, the Global Assessment of Functioning (GAF) scores and the Personal and Social Performance Scale (PSP) score changes in the PGx intervention group were both significantly different from those in the standard care group (P < 0.05). It is noteworthy that the PGx intervention similarly improves the prognostic outcomes for patients with and without a family history of mental disorders. In conclusion, the application of a PGx intervention treatment model based on PGx testing can significantly improve medication efficacy and shorten the time to achieve the effects of medication in schizophrenia.

Identifying gray matter alterations in Cushing's disease using machine learning: An interpretable approach.

BACKGROUND: Cushing's Disease (CD) is a rare clinical syndrome characterized by excessive secretion of adrenocorticotrophic hormone, leading to significant functional and structural brain alterations as observed in Magnetic Resonance Imaging (MRI). While traditional statistical analysis has been widely employed to investigate these MRI changes in CD, it has lacked the ability to predict individual-level outcomes. PURPOSE: To address this problem, this paper has proposed an interpretable machine learning (ML) framework, including model-level assessment, feature-level assessment, and biology-level assessment to ensure a comprehensive analysis based on structural MRI of CD. METHODS: The ML framework has effectively identified the changes in brain regions in the stage of model-level assessment, verified the effectiveness of these altered brain regions to predict CD from normal controls in the stage of feature-level assessment, and carried out a correlation analysis between altered brain regions and clinical symptoms in the stage of biology-level assessment. RESULTS: The experimental results of this study have demonstrated that the Insula, Fusiform gyrus, Superior frontal gyrus, Precuneus, and the opercular portion of the Inferior frontal gyrus of CD showed significant alterations in brain regions. Furthermore, our study has revealed significant correlations between clinical symptoms and the frontotemporal lobes, insulin, and olfactory cortex, which also have been confirmed by previous studies. CONCLUSIONS: The ML framework proposed in this study exhibits exceptional potential in uncovering the intricate pathophysiological mechanisms underlying CD, with potential applicability in diagnosing other diseases.

Medium-temperature calcination and acid pressure leaching extract the Al2O3 from coal gangue: activation mechanism and kinetic analysis.

Bauxite is an important strategic resource, and it is facing with the problem of balance between high demand of bauxite ore and low resource of bauxite reserves in China. This research takes the Fuxin coal gangue as the object and extracts Al2O3 by medium-temperature calcination and acid pressure leaching process. The results show that at a calcination temperature of 650 °C, calcination time of 2 h, acid pressure leaching temperature of 160 °C and acid pressure leaching time of 6 h, the extraction ratio of Al2O3 reaches 80.19%. Furthermore, the research finding that the complete activation temperatures of kaolinite and muscovite are 650 °C and 850 °C, respectively, and the decomposition reactions of active Si, active Al, and metakaolinite occur above 800 °C, which leads to a low extraction ratio of Al2O3. The acid pressure leaching process can directly destroy the muscovite structure at a calcination temperature of 650 °C. The acid pressure leaching kinetic equations are studied by three kinetic models, and the apparent activation energies of the reactions are calculated by the Arrhenius formula. The results show that acid pressure leaching is subject to solid residue in-layer diffusion control, and the kinetic equation is "". The apparent activation energy is 13.48 kJ mol-1.

Compliant Iontronic Triboelectric Gels with Phase-Locked Structure Enabled by Competitive Hydrogen Bonding.

Rapid advancements in flexible electronics technology propel soft tactile sensing devices toward high-level biointegration, even attaining tactile perception capabilities surpassing human skin. However, the inherent mechanical mismatch resulting from deficient biomimetic mechanical properties of sensing materials poses a challenge to the application of wearable tactile sensing devices in human-machine interaction. Inspired by the innate biphasic structure of human subcutaneous tissue, this study discloses a skin-compliant wearable iontronic triboelectric gel via phase separation induced by competitive hydrogen bonding. Solvent-nonsolvent interactions are used to construct competitive hydrogen bonding systems to trigger phase separation, and the resulting soft-hard alternating phase-locked structure confers the iontronic triboelectric gel with Young's modulus (6.8-281.9 kPa) and high tensile properties (880%) compatible with human skin. The abundance of reactive hydroxyl groups gives the gel excellent tribopositive and self-adhesive properties (peel strength > 70 N m-1). The self-powered tactile sensing skin based on this gel maintains favorable interface and mechanical stability with the working object, which greatly ensures the high fidelity and reliability of soft tactile sensing signals. This strategy, enabling skin-compliant design and broad dynamic tunability of the mechanical properties of sensing materials, presents a universal platform for broad applications from soft robots to wearable electronics.

Matrine reduced intestinal stem cell damage in eimeria necatrix-infected chicks via blocking hyperactivation of Wnt signaling.

BACKGROUND: Coccidiosis is a rapidly spreading and acute parasitic disease that seriously threatening the intestinal health of poultry. Matrine from leguminous plants has anthelmintic and anti-inflammatory properties. PURPOSE: This assay was conducted to explore the protective effects of Matrine and the AntiC (a Matrine compound) on Eimeria necatrix (EN)-infected chick small intestines and to provide a nutritional intervention strategy for EN injury. STUDY DESIGN: The in vivo (chick) experiment: A total of 392 one-day-old yellow-feathered broilers were randomly assigned to six groups in a 21-day study: control group, 350 mg/kg Matrine group, 500 mg/kg AntiC group, EN group, and EN + 350 mg/kg Matrine group, EN + 500 mg/kg AntiC group. The in vitro (chick intestinal organoids, IOs): The IOs were treated with PBS, Matrine, AntiC, 3 µM CHIR99021, EN (15,000 EN sporozoites), EN + Matrine, EN + AntiC, EN + Matrine + CHIR99021, EN + AntiC + CHIR99021. METHODS: The structural integrity of chicks jejunal crypt-villus axis was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). And the activity of intestinal stem cells (ISCs) located in crypts was assessed by in vitro expansion advantages of a primary in IOs model. Then, the changes of Wnt/ß-catenin signaling in jejunal tissues and IOs were detected by Real-Time qPCR,Western blotting and immunohistochemistry. RESULTS: The results showed that dietary supplementation with Matrine or AntiC rescued the jejunal injury caused by EN, as indicated by increased villus height, reduced crypt hyperplasia, and enhanced expression of tight junction proteins. Moreover, there was less budding efficiency of the IOs expanded from jejunal crypts of chicks in the EN group than that in the Matrine and AntiC group, respectively. Further investigation showed that AntiC and Matrine inhibited EN-stimulated Wnt/ß-catenin signaling. The fact that Wnt/ß-catenin activation via CHIR99021 led to the failure of Matrine and AntiC to rescue damaged ISCs confirmed the dominance of this signaling. CONCLUSION: Our results suggest that Matrine and AntiC inhibit ISC proliferation and promote ISC differentiation into absorptive cells by preventing the hyperactivation of Wnt/ß-catenin signaling, thereby standardizing the function of ISC proliferation and differentiation, which provides new insights into mitigating EN injury by Matrine and AntiC.

The Phase Control of Transition Metallic Elements via Facile Chemical and Physical Syntheses.

The crystal phases of metals are important factors to tune the properties of metals, and therefore received extensive attention. Traditionally, phase control is performed within limited numbers of elements by harsh conditions, such as face-centered cubic Fe by high temperature. This review summarizes most reports in metal phase control area, including elements of Fe, Co, Ni, Cu, Ru, Pd, Rh, Os and Au. For every metallic element, the facile phase control methods are systematically introduced, such as epitaxial growth, ball milling, chemical reduction, etc. Their corresponding applications and the mechanisms for phase control are thoroughly discussed.

Comparative Analysis of Sucrose-Regulatory Genes in High- and Low-Sucrose Sister Clones of Sugarcane.

Sugarcane is a significant primitive source of sugar and energy worldwide. The progress in enhancing the sugar content in sugarcane cultivars remains limited due to an insufficient understanding of specific genes related to sucrose production. The present investigation examined the enzyme activities, levels of reducing and non-reducing sugars, and transcript expression using RT-qPCR to assess the gene expression associated with sucrose metabolism in a high-sucrose sugarcane clone (GXB9) in comparison to a low-sucrose sister clone (B9). Sucrose phosphate synthase (SPS), sucrose phosphate phosphatase (SPP), sucrose synthase (SuSy), cell wall invertase (CWI), soluble acid invertase (SAI), and neutral invertase (NI) are essential enzymes involved in sucrose metabolism in sugarcane. The activities of these enzymes were comparatively quantified and analyzed in immature and maturing internodes of the high- and low-sucrose clones. The results showed that the higher-sucrose-accumulating clone had greater sucrose concentrations than the low-sucrose-accumulating clone; however, maturing internodes had higher sucrose levels than immature internodes in both clones. Hexose concentrations were higher in immature internodes than in maturing internodes for both clones. The SPS and SPP enzymes activities were higher in the high-sucrose-storing clone than in the low-sucrose clone. SuSy activity was higher in the low-sucrose clone than in the high-sucrose clone; further, the degree of SuSy activity was higher in immature internodes than in maturing internodes for both clones. The SPS gene expression was considerably higher in mature internodes of the high-sucrose clones than the low-sucrose clone. Conversely, the SuSy gene exhibited up-regulated expression in the low-sucrose clone. The enhanced expression of SPS in the high-sucrose clone compared to the low-sucrose clone suggests that SPS plays a major role in the increased accumulation of sucrose. These findings provide the opportunity to improve sugarcane cultivars by regulating the activity of genes related to sucrose metabolism using transgenic techniques.

Molecular mechanism of endophytic bacteria DX120E regulating polyamine metabolism and promoting plant growth in sugarcane.

Introduction: Sugarcane endophytic nitrogen-fixing bacterium Klebsiella variícola DX120E displayed broad impact on growth, but the exact biological mechanism, especially polyamines (PAs) role, is still meager. Methods: To reveal this relationship, the content of polyamine oxidase (PAO), PAs, reactive oxygen species (ROS)-scavenging antioxidative enzymes, phytohormones, 1-aminocyclopropane-1-carboxylic synthase (ACS), chlorophyll content, and biomass were determined in sugarcane incubated with the DX120E strain. In addition, expression levels of the genes associated with polyamine metabolism were measured by transcriptomic analysis. Results: Genomic analysis of Klebsiella variícola DX120E revealed that 39 genes were involved in polyamine metabolism, transport, and the strain secrete PAs in vitro. Following a 7-day inoculation period, DX120E stimulated an increase in the polyamine oxidase (PAO) enzyme in sugarcane leaves, however, the overall PAs content was reduced. At 15 days, the levels of PAs, ROS-scavenging antioxidative enzymes, and phytohormones showed an upward trend, especially spermidine (Spd), putrescine (Put), catalase (CAT), auxin (IAA), gibberellin (GA), and ACS showed a significant up-regulation. The GO and KEGG enrichment analysis found a total of 73 differentially expressed genes, involving in the cell wall (9), stimulus response (13), peroxidase activity (33), hormone (14) and polyamine metabolism (4). Discussion: This study demonstrated that endophytic nitrogen-fixing bacteria stimulated polyamine metabolism and phytohormones production in sugarcane plant tissues, resulting in enhanced growth. Dual RNA-seq analyses provided insight into the early-stage interaction between sugarcane seedlings and endophytic bacteria at the transcriptional level. It showed how diverse metabolic processes selectively use distinct molecules to complete the cell functions under present circumstances.

Mitochondrial calcium uniporter promotes mitophagy by regulating the PINK1/Parkin pathway in caerulein­treated pancreatic ductal epithelial cells in vitro.

The mitochondrial calcium uniporter (MCU) is a major protein for the uptake of mitochondrial calcium to regulate intracellular energy metabolism, including processes such as mitophagy. The present study investigated the effect of the MCU on mitophagy in pancreatic ductal epithelial cells (PDECs) in acute pancreatitis (AP) in vitro. The normal human PDECs (HPDE6-C7) were treated with caerulein (CAE) to induce AP-like changes, with or without ruthenium red to inhibit the MCU. The mitochondrial membrane potentials (MMPs) and mitochondrial Ca2+ levels were analyzed by fluorescence. The expression levels of MCU, LC3, p62, and translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), putative kinase 1 (PINK1), and Parkin were measured by western blotting and immunofluorescence. Mitophagy was observed by confocal fluorescence microscopy and transmission electron microscopy. The results showed that CAE increased the MCU protein expression, mitochondrial Ca2+ levels, MMP depolarization and the protein expression of mitophagy markers including the LC3II/I ratio, PINK1, and Parkin. CAE decreased the protein expression of p62 and TOMM20, and promoted the formation of mitophagosomes in HPDE6-C7 cells. Notably, changes in these markers were reversed by inhibiting the MCU. In conclusion, an activated MCU may promote mitophagy by regulating the PINK1/Parkin pathway in PDECs in AP.

Latent and incubation periods of Delta, BA.1, and BA.2 variant cases and associated factors: a cross-sectional study in China.

BACKGROUND: The latent and incubation periods characterize the transmission of infectious viruses and are the basis for the development of outbreak prevention and control strategies. However, systematic studies on the latent period and associated factors with the incubation period for SAS-CoV-2 variants are still lacking. We inferred the two durations of Delta, BA.1, and BA.2 cases and analyzed the associated factors. METHODS: The Delta, BA.1, and BA.2 (and its lineages BA.2.2 and BA.2.76) cases with clear transmission chains and infectors from 10 local SAS-CoV-2 epidemics in China were enrolled. The latent and incubation periods were fitted by the Gamma distribution, and associated factors were analyzed using the accelerated failure time model. RESULTS: The mean latent period for 672 Delta, 208 BA.1, and 677 BA.2 cases was 4.40 (95%CI: 4.24 ~ 4.63), 2.50 (95%CI: 2.27 ~ 2.76), and 2.58 (95%CI: 2.48 ~ 2.69) days, respectively, with 85.65% (95%CI: 83.40 ~ 87.77%), 97.80% (95%CI: 96.35 ~ 98.89%), and 98.87% (95%CI: 98.40 ~ 99.27%) of them starting to shed viruses within 7 days after exposure. In 405 Delta, 75 BA.1, and 345 BA.2 symptomatic cases, the mean latent period was 0.76, 1.07, and 0.79 days shorter than the mean incubation period [5.04 (95%CI: 4.83 ~ 5.33), 3.42 (95%CI: 3.00 ~ 3.89), and 3.39 (95%CI: 3.24 ~ 3.55) days], respectively. No significant difference was observed in the two durations between BA.1 and BA.2 cases. After controlling for the sex, clinical severity, vaccination history, number of infectors, the length of exposure window and shedding window, the latent period [Delta: exp(ß) = 0.81, 95%CI: 0.66 ~ 0.98, p = 0.034; Omicron: exp(ß) = 0.82, 95%CI: 0.71 ~ 0.94, p = 0.004] and incubation period [Delta: exp(ß) = 0.69, 95%CI: 0.55 ~ 0.86, p < 0.001; Omicron: exp(ß) = 0.83, 95%CI: 0.72 ~ 0.96, p = 0.013] were significantly shorter in 18 ~ 49 years but did not change significantly in ≥ 50 years compared with 0 ~ 17 years. CONCLUSION: Pre-symptomatic transmission can occur in Delta, BA.1, and BA.2 cases. The latent and incubation periods between BA.1 and BA.2 were similar but shorter compared with Delta. Age may be associated with the latent and incubation periods of SARS-CoV-2.

Research on the evaluation method of English textbook readability based on the TextCNN model and its application in teaching design.

English is a world language, and the ability to use English plays an important role in the improvement of college students' comprehensive quality and career development. However, quite a lot of Chinese college students feel that English learning is difficult; it is difficult to understand the learning materials, and they cannot effectively improve their English ability. This study uses a convolutional neural network to evaluate the readability of English reading materials. It provides students with English reading materials of suitable difficulty based on their English reading ability so as to improve the effect of English learning. Aiming at the high dispersion of students' English reading level, a text readability evaluation model for English reading textbooks based on deep learning is designed. First, the legibility dataset is constructed based on college English textbooks; second, the TextCNN text legibility evaluation model is constructed; finally, the model training is completed through parameter adjustment and optimization, and the evaluation accuracy rate on the self-built dataset reaches 90%. We use the text readability method based on TextCNN model to conduct experimental teaching, and divided the two groups into comparative experiments. The experimental results showed that the reading level and reading interest of students in the experimental group were significantly improved, which proved that the text readability evaluation method based on deep learning was scientific and effective. In addition, we will further expand the capacity of the English legibility dataset and invite more university classes and students to participate in comparative experiments to improve the generality of the model.

Association of HTR1A Gene Polymorphisms with Efficacy and Plasma Concentrations of Atypical Antipsychotics in the Treatment of Male Patients with Schizophrenia.

Purpose: We investigate the association of HTR1A rs10042486 and rs6295 with efficacy and plasma concentrations of atypical antipsychotics in the treatment of male patients with schizophrenia. Patients and Methods: A total of 140 male patients diagnosed with schizophrenia who were treated with any single atypical antipsychotic between May 2020 and May 2022 were retrospectively included. Clinical symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). All SNPs were typed using Agena Bioscience MassARRAY DNA mass spectrometry. Plasma concentrations of antipsychotics at week 3, 6 and 12 after treatment commence were analyzed using mass spectrometry. Results: For efficacy of atypical antipsychotics, we observed no significant difference between HTR1A rs10042486, rs6295 and positive symptom improvement, where the patients with heterozygous mutant at the rs10042486 and rs6295 locus were superior to those with wild-type or homozygous mutant genotypes on negative symptom improvement, especially at 12 weeks of follow-up when the difference between genotypes at the rs6295 locus have statistical significance (P = 0.037). For plasma concentration, we found that quetiapine plasma concentrations were significantly lower in patients with mutation-heterozygous types than in wild-type and homozygous mutation genotypes at week 6. In contrast, higher plasma concentrations were found for mutant heterozygous than wild genotypes in the risperidone monotherapy analysis, and the difference among genotypes at the rs6295 locus was statistically significant at 6 weeks of follow-up. Conclusion: The assessment of the correlation of genetic polymorphisms of HTR1A rs6295 and rs10042486 in male patients with schizophrenia with the monitoring of therapeutic drug concentrations and therapeutic efficacy provides a constructive foundation for the clinical individualization of antipsychotics, such as quetiapine and risperidone, which is important in selecting the dose of the medication and improving the improvement of negative symptoms.

Intrapulmonary migration of a fractured acupuncture needle: a case report.

BACKGROUND: Acupuncture, a traditional Chinese medical treatment, has been gaining popularity over the years. However, it also presents certain risks. We report a case of a patient who discovered a foreign body in their lung several years after undergoing acupuncture. CASE PRESENTATION: A middle-aged woman presented to our hospital with chest pain. An X-ray revealed a needle-like foreign body in the middle lobe of her right lung. The patient had previously undergone acupuncture treatment for local pain in her lower back and lower extremities many years prior. Based on the imaging findings and her medical history, we hypothesized that the foreign body in her lung was a result of a dislodged acupuncture needle. Through preoperative 3-dimensional reconstruction and indocyanine green localization, we were able to locate the foreign body in the lateral segment of the right middle lobe. We successfully removed the foreign body via wedge resection, and the patient made a smooth recovery post-surgery. CONCLUSION: Acupuncturists and surgeons should remain vigilant about the potential risks associated with acupuncture.

Gabapentin attenuates cardiac remodeling after myocardial infarction by inhibiting M1 macrophage polarization through the peroxisome proliferator-activated receptor-γ pathway.

OBJECTIVES: Inflammation regulates ventricular remodeling after myocardial infarction (MI), and gabapentin exerts anti-inflammatory effects. We investigated the anti-inflammatory role and mechanism of gabapentin after MI. METHODS: Rats were divided into the sham group (n = 12), MI group (n = 20), and MI + gabapentin group (n = 16). MI was induced by left coronary artery ligation. The effects of gabapentin on THP-1-derived macrophages were examined in vitro. RESULTS: In vivo, 1 week after MI, gabapentin significantly reduced inducible nitric oxide synthase (iNOS; M1 macrophage marker) expression and decreased pro-inflammatory factors (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß). Gabapentin upregulated the M2 macrophage marker arginase-1, as well as CD163 expression, and increased the expression of anti-inflammatory factors, including chitinase-like 3, IL-10, and transforming growth factor-ß. Four weeks after MI, cardiac function, infarct size, and cardiac fibrosis improved after gabapentin treatment. Gabapentin inhibited sympathetic nerve activity and decreased ventricular electrical instability in rats after MI. Tyrosine hydroxylase and growth-associated protein 43 were suppressed after gabapentin treatment. Gabapentin downregulated nerve growth factor (NGF) and reduced pro-inflammatory factors (iNOS, TNF-α, and IL-1ß). In vitro, gabapentin reduced NGF, iNOS, TNF-α, and IL-1ß expression in lipopolysaccharide-stimulated macrophages. Mechanistic studies revealed that the peroxisome proliferator-activated receptor-γ antagonist GW9662 attenuated the effects of gabapentin. Moreover, gabapentin reduced α2δ1 expression in the macrophage plasma membrane and reduced the calcium content of macrophages. CONCLUSION: Gabapentin attenuates cardiac remodeling by inhibiting inflammation via peroxisome proliferator-activated receptor-γ activation and preventing calcium overload.

Harmonizing Enzyme-like Cofactors to Boost Nanozyme Catalysis.

Engineering isolated metal sites resembling the primary coordination sphere of metallocofactors enables atomically dispersed materials as promising nanozymes. However, most existing nanozymes primarily focus on replicating specific metallocofactors while neglecting other supporting cofactors within active pockets, leading to reduced electron transfer (ET) efficiency and thus inferior catalytic performances. Herein, we report a metal-organic framework UiO-67 nanozyme with atomically dispersed iron sites, which involves multiple tailored enzyme-like nanocofactors that synergistically drive the ET process for enhanced peroxidase-like catalysis. Among them, the linker-coupled atomic iron site plays a critical role in substrate activation, while bare linkers and zirconia nodes facilitate the ET efficiency of intermediates. The synergy of three nanocofactors results in a 4.29-fold enhancement compared with the single effort of isolated metal site-based nanocofactor, holding promise in immunoassay for sensitive detection of chlorpyrifos. This finding opens a new way for designing high-performance nanozymes by harmonizing various nanocofactors at the atomic and molecular scale.

Physiological and Transcriptomic Analyses Reveal Commonalities and Specificities in Wheat in Response to Aluminum and Manganese.

Aluminum (Al) and manganese (Mn) toxicity are the top two constraints of crop production in acid soil. Crops have evolved common and specific mechanisms to tolerate the two stresses. In the present study, the responses (toxicity and tolerance) of near-isogenic wheat lines (ET8 and ES8) and their parents (Carazinho and Egret) to Al and Mn were compared by determining the physiological parameters and conducting transcriptome profiling of the roots. The results showed the following: (1) Carazinho and ET8 exhibited dual tolerance to Al and Mn compared to Egret and ES8, indicated by higher relative root elongation and SPAD. (2) After entering the roots, Al was mainly distributed in the roots and fixed in the cell wall, while Mn was mainly distributed in the cell sap and then transported to the leaves. Both Al and Mn stresses decreased the contents of Ca, Mg, and Zn; Mn stress also inhibited the accumulation of Fe, while Al showed an opposite effect. (3) A transcriptomic analysis identified 5581 differentially expressed genes (DEGs) under Al stress and 4165 DEGs under Mn stress. Among these, 2774 DEGs were regulated by both Al and Mn stresses, while 2280 and 1957 DEGs were exclusively regulated by Al stress and Mn stress, respectively. GO and KEGG analyses indicated that cell wall metabolism responds exclusively to Al, while nicotianamine synthesis exclusively responds to Mn. Pathways such as signaling, phenylpropanoid metabolism, and metal ion transport showed commonality and specificity to Al and Mn. Transcription factors (TFs), such as MYB, WRKY, and AP2 families, were also regulated by Al and Mn, and a weighted gene co-expression network analysis (WGCNA) identified PODP7, VATB2, and ABCC3 as the hub genes for Al tolerance and NAS for Mn tolerance. The identified genes and pathways can be used as targets for pyramiding genes and breeding multi-tolerant varieties.

Efficacy and feasibility of aerobic exercise interventions as an adjunctive treatment for patients with schizophrenia: a meta-Analysis.

Schizophrenia is a chronic mental disorder primarily treated with antipsychotics, which have limited efficacy for negative symptoms. This study aims to evaluate the effectiveness and feasibility of exercise interventions as adjuncts to pharmacotherapy through a meta-analysis, providing valuable insights for rational intervention design. Four databases were searched, and randomized controlled trials with no language restrictions published up to March 27, 2023, were included. The primary outcome indicator was the Positive and Negative Symptom Scale (PANSS) total score along with its three sub-scales. Secondary outcomes included the Scale for Assessment of Negative Symptoms (SANS) and Body Mass Index (BMI), which were used to assess the efficacy of aerobic exercise interventions in patients with schizophrenia. Subgroup analyses were conducted to explore the impact of intervention duration and total weekly exercise time, while treatment feasibility was assessed through adherence rates. A total of 17 publications involving 973 patients with schizophrenia were deemed eligible and included in the analysis. Compared to other forms of adjunctive interventions, the network meta-analysis of 12 PANSS-based studies revealed that adjunctive aerobic exercise interventions were the most effective in reducing overall PANSS scores in patients with schizophrenia, with statistically significant pooled results (MD = -4.84, 95% CI: -5.72, -3.96). Both the PANSS negative symptom subscale (MD = -2.11, 95% CI: -3.26, -0.95) and SANS (MD = -9.11, 95% CI: -11.94, -6.27) indicated that adjunctive aerobic exercise interventions effectively alleviate negative symptoms. Subgroup meta-analysis indicated that 2-3 month interventions involving 100-220 min of exercise per week were the most effective. Additionally, adherence to the adjunctive aerobic exercise regimen was found to be comparable to that of conventional treatment alone. Aerobic exercise interventions, as adjunctive therapy, are an effective measure for reducing PANSS scores in patients with schizophrenia, contributing to the alleviation of both the positive and negative symptoms, and patients demonstrated strong adherence to aerobic exercise.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Cannabinoids improve mitochondrial function in skeletal muscle of exhaustive exercise training rats by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathways.

Cannabidiol (CBD) is a pure natural phytocannabinoid derived from cannabis that has anti-inflammatory, antiapoptotic and antioxidative stress abilities. In recent years, an increasing number of studies have reported the regulatory effect of CBD on skeletal muscle injury induced by exercise, but its mechanism is still unclear. Mitochondria are the main organelles responsible for the energy supply within eukaryotic cells, and their function has been closely linked to cellular health. Moderate exercise improves mitochondrial function, but the excessive exercise has a negative impact on mitochondria. Therefore, we speculate that CBD may promote exercise induced skeletal muscle cell damage by improving mitochondrial function. In this study, by establishing an animal model of exhaustive exercise training in rats, the protective effect of CBD on skeletal muscle mitochondrial structure and function was elaborated, and the possible molecular mechanism was discussed based on transcriptomics. Our results indicate that skeletal muscle mitochondrial structure and function were improved after CBD intervention. GO and KEGG pathway enrichment analysis showed that exhaustive exercise training induced mitochondrial dysfunction in skeletal muscle is associated with excessive autophagy/mitophagy, the signaling pathways involved in FOXO3 and GABARAPL1 may play important roles. After CBD intervention, the protein expression of PINK1, PARKIN and BNIP3 was down-regulated, indicating that CBD may improve the mitochondrial function by inhibiting mitophagy through the PINK1/PARKIN and BNIP3 pathway.