Crosstalk of disulfidptosis-related subtypes identifying a prognostic signature to improve prognosis and immunotherapy responses of clear cell renal cell carcinoma patients.

BACKGROUND: Disulfidptosis is a novel form of programmed cell death induced by high SLC7A11 expression under glucose starvation conditions, unlike other known forms of cell death. However, the roles of disulfidptosis in cancers have yet to be comprehensively well-studied, particularly in ccRCC. METHODS: The expression profiles and somatic mutation of DGs from the TCGA database were investigated. Two DGs clusters were identified by unsupervised consensus clustering analysis, and a disulfidptosis-related prognostic signature (DR score) was constructed. Furthermore, the predictive capacity of the DR score in prognosis was validated by several clinical cohorts. We also developed a nomogram based on the DR score and clinical features. Then, we investigated the differences in the clinicopathological information, TMB, tumor immune landscapes, and biological characteristics between the high- and low-risk groups. We evaluated whether the DR score is a robust tool for predicting immunotherapy response by the TIDE algorithm, immune checkpoint genes, submap analysis, and CheckMate immunotherapy cohort. RESULTS: We identified two DGs clusters with significant differences in prognosis, tumor immune landscapes, and clinical features. The DR score has been demonstrated as an independent risk factor by several clinical cohorts. The high-risk group patients had a more complicated tumor immune microenvironment and suffered from more tumor immune evasion in immunotherapy. Moreover, patients in the low-risk group had better prognosis and response to immunotherapy, particularly in anti-PD1 and anti-CTLA-4 inhibitors, which were verified in the CheckMate immunotherapy cohort. CONCLUSION: The DR score can accurately predict the prognosis and immunotherapy response and assist clinicians in providing a personalized treatment regime for ccRCC patients.

COVID-19 acts like a stress test, uncovering the vulnerable part of the human body: a retrospective study of 1640 cases in China.

BACKGROUND: Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection exhibits multi-organ damage with diverse complications, the correlation between age, gender, medical history and clinical manifestations of novel coronavirus disease 2019 (COVID-19) patients was investigated. METHODS: 1640 patients who were infected with SARS-CoV-2 and hospitalized at the First Affiliated Hospital of Ningbo University from 22 December 2022 to 1 March 2023 were categorized and analysed. Normal distribution test and variance homogeneity test were performed. Based on the test results, one-way analysis of variance, Pearson's chi-squared test and logistic regression analysis were conducted in the study. RESULTS: According to the ANOVA, there was a significant difference in the age distribution (P = .001) between different clinical presentations, while gender did not (P = .06). And regression analysis showed that age, hypertension, atherosclerosis and cancer were significant hazard factors for the development of predominant clinical manifestations in patients hospitalized with novel COVID-19. Additionally, infection with SARS-CoV-2 has the potential to exacerbate the burden on specific diseased or related organs. CONCLUSION: The elderly who are infected with SARS-CoV-2 ought to be treated with emphasis not only on antiviral therapy but also on individualized treatment that takes their medical history and comorbidities into account.

Effect of online parent training in promoting language development of children with language delay in Hubei province, China.

BACKGROUND: Training parents to implement language and communication intervention strategies is an effective approach to promote language development for children with language delay. AIMS: This study introduces an online parent training program conducted in Hubei province, China, which was designed to help parents of language-delayed children with a diagnosis of autism spectrum disorder (ASD), developmental language disorder (DLD) or global developmental delay (GDD) apply language intervention strategies into daily interactions and promote their children's language development at home. METHODS & PROCEDURES: The Bethel Hearing and Speaking Training Center Family Training for Early Communication & Language Development (Bethel Family Training Program, BFT) (Bethel HSTC, 2020) was designed to improve the language and communication skills for children with language delay in a naturalistic way. The caregivers (including parents, grandparents and other main caregivers) participated in an 8-h online program, including lectures on milestones in child language development, common misunderstandings of child language development, and three basic family language intervention strategies ('Looking together, playing together, and talking together') incorporating active learning through video analysis and discussion. Tongji Hospital in Hubei then continued with 3 months of online home intervention monitoring to all the caregivers via weekly online Q&As led by BFT certified speech therapists' team. The Gesell Developmental Schedules (GDS) was carried out before the online parent training program and after the 3-month online home intervention monitoring. OUTCOMES & RESULTS: 146 families whose children aged 12-68 months with language delay participated in the online training program. The results of the GDS assessments conducted before and after the program showed that not only did the developmental quotient (DQ) of language improve, but so did the DQ of social behaviour and adaptive behaviour (p < 0.001). There is no between-group difference in the application of three strategies between the ASD group and the DLD or GDD group (p > 0.05). Furthermore, both caregivers' ability to apply 'looking together, playing together, talking together' strategies and the effective interaction time played important roles in improving the child's language abilities. CONCLUSION & IMPLICATIONS: The online parent training focusing on improving daily interaction with children through speech-language stimulation strategies promoted the development of language skills. It is an economic and practical approach for children with language delay who have limited access to local language intervention programs. WHAT THIS PAPER ADDS: What is already known on the subject Parent-implemented language intervention is an effective approach at improving children's language development. Telepractice is an appropriate model of service delivery for audiologists and speech-language therapists and may be the primary mode of service delivery or may supplement in-person services. What this paper adds to the existing knowledge This paper explores the effectiveness of an online parent training program and provides new evidence that online training on language support strategies (looking together, playing together, talking together) followed by home intervention monitoring works for Mandarin-speaking children and it is equally effective for children with ASD and non-ASD diagnosis. What are the potential or actual clinical implications of this work? Developmental behavioural paediatricians and speech-language therapists in countries and areas that lack sufficient training resource for every child will have the option to deliver parent training and home intervention monitoring online, which will save time and cost considerably while offering convenience.

Combined application of biochar and sulfur alleviates cadmium toxicity in rice by affecting root gene expression and iron plaque accumulation.

Biochar and sulfur are considered useful amendments for soil cadmium (Cd) contamination remediation. However, there is still a gap in the understanding of how combined biochar and sulfur application affects Cd resistance in rice, and the role of the accumulation of iron plaque and the expression of Cd efflux transporter-related genes are still unclear in this type of treatment. In this study, we screened an effective combination of biochar and sulfur (0.75 % biochar, 60 mg/kg sulfur) that significantly reduced the Cd content of rice roots (32.9 %) and shoots (12.3 %); significantly reduced the accumulation of amino acids and their derivatives, organic acids and their derivatives and flavonoids in rice roots; and altered secondary metabolite production and release. This combined biochar and sulfur application alleviated the toxicity of Cd to rice, in which the enhancement of iron plaque (24.8 %) formation and upregulated expression of heavy metal effector genes (NRAMP3, MTP3, ZIP1) were important factors. These findings show that iron plaque and heavy metal transport genes are involved in the detoxification of rice under the combined application of biochar and sulfur, which provides useful information for the combined treatment of soil Cd pollution.

[Clinical and genetic analysis of a child with maternal uniparental disomy of chromosome 20].

OBJECTIVE: To explore the clinical and genetic characteristics of a boy with isolated maternal uniparental disomy of chromosome 20 [UPD(20)mat]. METHODS: A child who was admitted to the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology on April 8,2021. was selected as the study subject. Phenotypic and endocrinological findings of the child were retrospectively analyzed. Whole exome sequencing (WES) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were carried out for detecting the UPD sequences and copy number variations. Both of his parents were verified by Sanger sequencing. Relevant literature was systematically reviewed. RESULTS: The child, a 3-year-and-8-month-old boy born to a 41-year-old mother by Cesarean delivery at 36+2 gestational weeks due to oligohydramia, had a birth weight of 2 300 g and length of 46 cm. He was admitted to the NICU for feeding difficulties which had persisted despite of clinical management. At the age of 3.75, he had a height of 92.5 cm (< 3rd percentile; 25th ~ 50th percentile at 2.5 years) and a weight of 10.8 kg (< 3rd percentile; 50th percentile at 15 months). He had also presented with growth retardation, short stature, attention deficit and hyperactivity disorder (ADHD), mild mental retardation, and speech and language development disorders. He had simian creases in both hands but no additional dysmorphic signs, and his motor development was normal. Serum insulin, thyroid-stimulating hormone, and insulin growth factor binding protein 3 levels were within the normal ranges, though insulin growth factor-1 (IGF-1) was slightly decreased. Since that time he had continuously used atomoxetine hydrochloride capsules to control his ADHD. WES and MS-MLPA revealed the existence of UPD (20)mat. CONCLUSION: The UPD(20)mat syndrome is characterized by feeding difficulties, growth retardation and short stature. The child in our case has been accompanied by ADHD and speech and language development disorders, which required long-term treatment. For women with advanced maternal age and suggestive phenotypes, genetic testing and counseling should be conducted.

Brain-Heart Axis and Biomarkers of Cardiac Damage and Dysfunction after Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Cardiac complications after a stroke are the second leading cause of death worldwide, affecting the treatment and outcomes of stroke patients. Cardiac biomarkers such as cardiac troponin (cTn), brain natriuretic peptide (BNP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) have been frequently reported in patients undergoing a stroke. The aim of the present study is to meta-analyze the relationship between changes in such cardiac biomarkers and stroke and to present a systematic review of the previous literature, so as to explore the brain-heart axis. METHODS: We searched four online databases pertinent to the literature, including PubMed, Embase, the Cochrane Library, and the Web of Science. Then, we performed a meta-analysis to investigate changes in cTn, BNP, and NT-proBNP associated with different types of stroke. RESULTS AND CONCLUSIONS: A significant increase in cTnI concentration was found in patients exhibiting a brain hemorrhage. BNP increased in cases of brain infarction, while the NT-proBNP concentration was significantly elevated in patients suffering an acute ischemic stroke and brain hemorrhage, indicating cardiac damage and dysfunction after a stroke. Our analysis suggests that several potential mechanisms may be involved in the brain-heart axis. Finally, clinicians should pay careful attention to monitoring cardiac function in the treatment of cerebrovascular diseases in order to provide a timely and more accurate treatment.

Dehydroalkylative Activation of CNN- and PNN-Pincer Ruthenium Catalysts for Ester Hydrogenation.

Ruthenium-pincer complexes bearing CNN- and PNN-pincer ligands with diethyl- or diisopropylamino side groups, which have previously been reported to be active precatalysts for ester hydrogenation, undergo dehydroalkylation on heating in the presence of tricyclohexylphosphine to release ethane or propane, giving five-coordinate ruthenium(0) complexes containing a nascent imine functional group. Ethane or propane is also released under the conditions of catalytic ester hydrogenation, and time-course studies show that this release is concomitant with the onset of catalysis. A new PNN-pincer ruthenium(0)-imine complex is a highly active catalyst for ester hydrogenation at room temperature, giving up to 15 500 turnovers with no added base. This complex was shown to react reversibly at room temperature with two equivalents of hydrogen to give a ruthenium(II)-dihydride complex, where the imine functionality has been hydrogenated to give a protic amine side group. These observations have potentially broad implications for the identities of catalytic intermediates in ester hydrogenation and related transformations.

PINK1-Parkin alleviates metabolic stress induced by obesity in adipose tissue and in 3T3-L1 preadipocytes.

Mitochondria play an important role in cellular metabolism and are closely related with metabolic stress. Recently, several studies have shown that mitophagy mediated by PTEN-induced putative kinase 1 (PINK1) and Parkin may play a critical role in clearing the damaged mitochondria and maintaining the overall balance of intracellular mitochondria in quality and quantity. A previous study showed that PINK1 and Parkin were overexpressed in adipose tissue in obese subjects. However, it is still unclear whether a direct relationship exists between obesity and mitophagy. In this study, we created a high-fat-diet (HFD)-induced obese mouse model and examined the expression of PINK1 and Parkin in adipose tissue using western blot and real-time quantitative PCR. After we confirmed that there is an interesting difference between regular-chow-fed mice and HFD-induced obese mice in the expression of PINK1 and Parkin in vivo, we further tested the expression of PINK1 and Parkin in 3T3-L1 preadipocytes in vitro by treating cells with palmitic acid (PA) to induce metabolic stress. To better understand the role of PINK1 and Parkin in metabolic stress, 3T3-L1 preadipocytes were transfected with small interfering RNA (siRNA) of PINK1 and Parkin followed by PA treatment. Our results showed that under lower concentrations of PA, PINK1 and Parkin can be activated and play a protective role in resisting the harmful effects of PA, including protecting the mitochondrial function and resisting cellular death, while under higher concentrations of PA, the expression of PINK1 and Parkin can be inhibited. These results suggest that PINK1-Parkin can protect mitochondrial function against metabolic stress induced by obesity or PA to a certain degree.

Increased peripheral proinflammatory T helper subsets contribute to cardiovascular complications in diabetic patients.

BACKGROUND: Coronary atherosclerotic heart disease (CHD) is one of the major concerns in type 2 diabetes (T2D). The systemic chronic inflammation has been postulated to bridge the increased risk of cardiovascular disease and T2D. We formulated that increased peripheral proinflammatory T helper subsets contributed to the development of cardiovascular complications in diabetic patients. METHODS: The frequencies of peripheral total CD4+ T helper cells, proinflammatory Th1, Th17, and Th22 subsets were determined by flow cytometry in diabetic patients with or without CHD (n = 42 and 67, resp.). RESULTS: Both peripheral frequencies and total numbers of Th1, Th17, and Th22 cells were further increased in diabetic patients with CHD. Logistic regression and categorical cross-table analysis further confirmed that increased proinflammatory Th subsets, especially Th22, were independent risk factors of cardiovascular complication in diabetes. Elevated Th subsets also correlated with increased CRP levels and the atherogenic index of plasma. Moreover, Th1 frequency and Th22 numbers demonstrated remarkable potential in predicting CHD in diabetes. CONCLUSIONS: Increased peripheral proinflammatory T helper subsets act in concert and contribute to the increased prevalence of diabetic cardiovasculopathy. The recently identified Th22 cells might play an independent role in CHD and represent a novel proxy for cardiovascular risks in diabetes.

Association of prenatal and postnatal exposure to air pollution with clinically diagnosed attention deficit hyperactivity disorder: a systematic review.

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder in children, originates from a multifaceted interplay of genetic, neurological, and environmental factors. Recent studies have increasingly concentrated on environmental determinants, notably air pollution, and their impact on the risk of developing ADHD. Additionally, previous research has often conflated clinically diagnosed ADHD cases with instances of mere ADHD-like symptoms, a methodology that can introduce bias and obscure the true relationship between environmental factors and ADHD. To address this oversight, our systematic review meticulously investigates the relationship between both prenatal and postnatal exposures to particular air pollutants and strictly clinically diagnosed ADHD. Our comprehensive review encompassed 801 studies from PubMed, Cochrane Library, Web of Science, and Embase databases, out of which eight met our rigorous inclusion criteria. The Newcastle-Ottawa Scale (NOS) was utilized to gauge quality and bias. Our review found substantiated the connection between prenatal exposure to PM2.5 and NOx and a heightened risk of ADHD, while exposure to PM10 during the prenatal stage was not associated with ADHD. These findings hint at varied health impacts from different particulate matters and the prospect of gender-specific susceptibilities to such exposures. We also identified an association between postnatal exposure to PM2.5, PM10, and NO2 and an increased ADHD risk, underlining the potential neurodevelopmental harms from early exposure to these pollutants. These relationships, seemingly intricate and potentially dose-dependent, underscore the need for more detailed scrutiny. The unique value of our review is in its detailed exploration of the association between specific air pollution exposures and clinically diagnosed ADHD. Our findings offer much-needed clarity in this complex domain and emphasize the importance of future research to standardize exposure and outcome metrics, probe potential mechanisms, and reduce bias and heterogeneity.

Lipid metabolism: the potential targets for toxoplasmosis treatment.

Toxoplasmosis is a zoonosis caused by Toxoplasma gondii (T. gondii). The current treatment for toxoplasmosis remains constrained due to the absence of pharmaceutical interventions. Thus, the pursuit of more efficient targets is of great importance. Lipid metabolism in T. gondii, including fatty acid metabolism, phospholipid metabolism, and neutral lipid metabolism, assumes a crucial function in T. gondii because those pathways are largely involved in the formation of the membranous structure and cellular processes such as division, invasion, egress, replication, and apoptosis. The inhibitors of T. gondii's lipid metabolism can directly lead to the disturbance of various lipid component levels and serious destruction of membrane structure, ultimately leading to the death of the parasites. In this review, the specific lipid metabolism pathways, correlative enzymes, and inhibitors of lipid metabolism of T. gondii are elaborated in detail to generate novel ideas for the development of anti-T. gondii drugs that target the parasites' lipid metabolism.

Targeted Integration of siRNA against Porcine Cytomegalovirus (PCMV) Enhances the Resistance of Porcine Cells to PCMV.

In the world's first pig-to-human cardiac cytomegalovirus (PCMV), xenotransplant and elevated levels of porcine key factors contributing to patient mortality were considered. This has renewed attention on PCMV, a virus widely prevalent in pigs. Currently, there are no effective drugs or vaccines targeting PCMV, and its high detection difficulty poses challenges for prevention and control research. In this study, antiviral small hairpin RNA (shRNA) was selected and inserted into the Rosa26 and miR-17-92 loci of pigs via a CRISPR/Cas9-mediated knock-in strategy. Further in vitro viral challenge experiments demonstrated that these genetically edited pig cells could effectively limit PCMV replication. Through this process, we constructed a PCMV-infected cell model, validated partial viral interference sites, enhanced gene knock-in efficiency, performed gene editing at two different gene loci, and ultimately demonstrated that RNA interference (RNAi) technology combined with CRISPR/Cas9 has the potential to generate pig cells with enhanced antiviral infection capabilities. This opens up possibilities for the future production of pig populations with antiviral functionalities.

Protective effect and mechanism of Qingfei Paidu decoction on myocardial damage mediated by influenza viruses.

Introduction: Significant attention has been paid to myocardial damage mediated by the single-stranded RNA virus. Qingfei Paidu decoction (QFPDD) has been proved to protect the damage caused by the influenza virus A/PR/8/1934 (PR8), but its specific mechanism is unclear. Methods: Molecular biological methods, together with network pharmacology, were used to analyze the effects and underlying mechanism of QFPDD treatment on PR8-induced myocardial damage to obtain insights into the treatment of COVID-19-mediated myocardial damage. Results: Increased apoptosis and subcellular damage were observed in myocardial cells of mice infected by PR8. QFPDD treatment significantly inhibited the apoptosis and subcellular damage induced by the PR8 virus. The inflammatory factors IFN-ß, TNF-α, and IL-18 were statistically increased in the myocardia of the mice infected by PR8, and the increase in inflammatory factors was prevented by QFPDD treatment. Furthermore, the expression levels or phosphorylation of necroptosis-related proteins RIPK1, RIPK3, and MLKL were abnormally elevated in the group of infected mice, while QFPDD restored the levels or phosphorylation of these proteins. Our study demonstrated that HIF-1α is a key target of QFPDD in the treatment of influenza virus-mediated injury. The HIF-α level was significantly increased by PR8 infection. Both the knockdown of HIF-1α and treatment of the myocardial cell with QFPDD significantly reversed the increased inflammatory factors during infection. Overexpression of HIF-1α reversed the inhibition effects of QFPDD on cytokine expression. Meanwhile, seven compounds from QFPDD may target HIF-1α. Conclusion: QFPDD can ameliorate influenza virus-mediated myocardial damage by reducing the degree of cell necroptosis and apoptosis, inhibiting inflammatory response and the expression of HIF-1α. Thus, our results provide new insights into the treatment of respiratory virus-mediated myocardial damage.

Some evidence supporting the use of optically pure R-(-)-diniconazole: Toxicokinetics and configuration conversion on chiral diniconazole.

Diniconazole is a chiral pesticide that exists in two enantiomers, R-(-)-diniconazole and S-(+)-diniconazole, with the R-enantiomer being much more active than the S-enantiomer. Previous enantioselective toxicology studies of diniconazole focused mostly on simple environmental model organisms. In this study, we evaluated the toxicokinetics of the two diniconazole enantiomers in rats and mice to provide a more comprehensive risk assessment. The two enantiomers displayed clear differences in their stereoselective contents in vivo. The t1/2 of R-(-)-diniconazole was 7.06 ± 3.35 h, whereas that of S-(+)-diniconazole was 9.14 ± 4.60 h, indicating that R-(-)-diniconazole was eliminated faster in vivo. The excretion rates of R-(-)-diniconazole and S-(+)-diniconazole were 4.08 ± 0.50 % and 2.68 ± 0.58 %, respectively, indicating more excretion of R-(-)-diniconazole. S-(+)-diniconazole had a higher bioavailability than R-(-)-diniconazole (52.19 % vs. 42.44 %). S-(+)-Diniconazole was also found in relatively high abundance in tissues such as the stomach, large intestine, small intestine, cecum, liver, kidney, brain, and testes, with the abundance being 1.71-2.48-fold that of R-(-)-diniconazole. The selective degradation of both enantiomers in the tissues and their mutual conversion in vivo were not observed, and this could indicate that configuration conversion did not contribute to the differences in the content of enantiomers in the tissues. Instead, such differences were mainly caused by the differences in affinity of each enantiomer for the tissues. Furthermore, investigation of the interconversion between optically pure R-(-)-diniconazole and S-(+)-diniconazole monomers in soil revealed no interconversion. All of the above results indicated no interconversion between R-(-)-diniconazole and S-(+)-diniconazole in vivo and in the soil, and that S-(+)-diniconazole tends to have a greater potential to accumulate in vivo. Thus, if only R-(-)-diniconazole is used as a pesticide, the negative impact on mammals and the environment will be reduced, suggesting that in agriculture, the application of optically pure R-(-)-diniconazole may be a better strategy.

Disentangling the impact of straw incorporation on soil microbial communities: Enhanced network complexity and ecological stochasticity.

Straw incorporation is typically employed to enhance the nutrient content of soil and promote crop growth in intensive agricultural systems. Despite studies regarding the effects of straw incorporation on soil microbial communities, the underlying mechanisms of its effect on community co-occurrence interactions and assembly processes remain poorly understood. Herein, soil samples with or without straw incorporation were collected across a latitudinal gradient from north to central China. We found that straw incorporation considerably altered the structure of soil microbial community. The relative abundance of bacterial Latescibacterota and fungal Mortierellomycota were higher in straw-amended soils owing to their ability to decompose straw residues. The co-occurrence network in straw-amended soil exhibited greater complexity, including more network connectivity and keystone species, and higher average degrees and clustering coefficients compared with the control sample network. The network robustness and vulnerability indices suggested that straw incorporation increased the microbial network stability. Normalized stochastic ratios demonstrated that the stochastic process was the dominant mechanisms shaping the assembly of microbial communities in straw-amended soils. Concurrently, null model analysis revealed that straw increased the contribution of dispersal limitation to the assembly of bacterial and fungal communities. The migration rate of the microbial community, obtained from Sloan neutral community model, was relatively low in straw-amended soil at all the sample sites, potentially indicating the great importance of dispersal limitation. These findings would enhance our understanding of the ecological patterns and interactions of soil microbial communities in response to straw incorporation.

Correlation between preoperative frailty and postoperative delirium in elderly patients undergoing hip arthroplasty.

BACKGROUND: Postoperative delirium (POD) refers to acute brain dysfunction occurring within 7 days after operation or before discharge. Frailty refers to the state that the body's physiological reserve is insufficient, so that the compensative capacity to endogenous and exogenous stress stimuli decreases. The purpose of this study is to explore the association of preoperative frailty (PF) with POD in elderly patients undergoing hip arthroplasty. METHODS: Totally 228 elderly patients (age ≥ 65 years) who received elective hip arthroplasty in the Ningbo No. 6 Hospital between December 2021 and June 2022 were enrolled. One day before surgery, the frailty phenotype scale was adopted for evaluation of patients' frailty. On the 1st-3rd day after operation, the confusion assessment method was adopted for evaluation of delirium, and the patients were grouped into a POD group and non-POD group. Logistic regression was conducted to analyze the correlation between PF and POD. RESULTS: Among the patients, the incidence of PF was 30.70% (70/228), and the incidence of delirium within 3 days after operation was 25.88% (59/228). According to binary logistic regression analysis, PF, age, hypertension, diabetes mellitus, and preoperative sleep disorder were independent risk factors for POD in elderly patients undergoing hip arthroplasty (all P < .05). CONCLUSION: PF is a crucial risk factor for POD in elderly patients undergoing hip arthroplasty.

Resveratrol Improves Paclitaxel-Induced Cognitive Impairment in Mice by Activating SIRT1/PGC-1α Pathway to Regulate Neuronal State and Microglia Cell Polarization.

Objective: This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms. Methods: Morris Water Maze (MWM) test was used to evaluate the mice's spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1ß, IL-4, and IL-10. Results: PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527. Conclusion: Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.

PROS1, a clinical prognostic biomarker and tumor suppressor, is associated with immune cell infiltration in breast cancer: A bioinformatics analysis combined with experimental verification.

BACKGROUND: PROS1 is an encoding gene that can generate protein S. This protein is a glycoprotein found in plasma that conducts physiological functions with vitamin K. However, the impact of its expression remains absent in the progression and prognosis of breast cancer (BC). METHODS: In this study, we comprehensively explored the expression of PROS1 in BC and its relationship with BC patient survival, prognosis, and other clinicopathological features. We investigated how PROS1 influenced the malignant biological behavior of BC cells. A series of enrichment analyses were conducted, and the immune landscape was explored in BC affected by PROS1. We also determined correlations between PROS1 and common drug sensitivities used for BC treatments. RESULTS: PROS1 had low expression in BC, which tended to result in poor survival of BC patients. Overexpressed PROS1 inhibited the migration and invasion of BC cells as well as the epithelial-mesenchymal transition process by downregulating SNAIL. Functional enrichment analyses revealed that PROS1 was more active in extracellular matrix (ECM) organization and structural constituent, ECM-receptor interaction, and other pathways with its related genes. PROS1 was also found to affect immune activity, including various immune cells infiltrating BC. BC patients with high PROS1 expression tended to have lower IC50 values of three common medications and obtained better efficacy. CONCLUSIONS: PROS1 can become a promising prognostic factor and a possible therapeutic target in BC patients and suppress BC cell metastatic potential. In addition, PROS1 is a crucial factor in immune infiltration in BC.

Fecal microbiota transplantation in a child with severe ASD comorbidities of gastrointestinal dysfunctions-a case report.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by social communication impairments and restricted, repetitive behaviors. In addition to behavioral interventions and psychotherapies, and pharmacological interventions, in-depth studies of intestinal microbiota in ASD has obvious abnormalities which may effectively influenced in ASD. Several attempts have been made to indicate that microbiota can reduce the occurrence of ASD effectively. Fecal microbiota transplantation (FMT) is a type of biological therapy that involves the transplant of intestinal microbiota from healthy donors into the patient's gastrointestinal tract to improve the gut microenvironment. In this case report, we describe a case of child ASD treated by FMT. The patient have poor response to long-term behavioral interventions. After five rounds of FMT, clinical core symptoms of ASD and gastrointestinal(GI) symptoms were significantly altered. Moreover, the multiple levels of functional development of child were also significantly ameliorated. We found that FMT changed the composition of the intestinal microbiota as well as the metabolites, intestinal inflammatory manifestations, and these changes were consistent with the patient's symptoms. This report suggests further FMT studies in ASD could be worth pursuing, and more studies are needed to validate the effectiveness of FMT in ASD and its mechanisms.

Biochar-extracted liquor stimulates nitrogen related gene expression on improving nitrogen utilization in rice seedling.

Introduction: Biochar has been shown to be an effective soil amendment for promoting plant growth and improving nitrogen (N) utilization. However, the physiological and molecular mechanisms behind such stimulation remain unclear. Methods: In this study, we investigated whether biochar-extracted liquor including 21 organic molecules enhance the nitrogen use efficiency (NUE) of rice plants using two N forms (NH4 +-N and NO3 --N). A hydroponic experiment was conducted, and biochar-extracted liquor (between 1 and 3% by weight) was applied to rice seedlings. Results: The results showed that biochar-extracted liquor significantly improved phenotypic and physiological traits of rice seedlings. Biochar-extracted liquor dramatically upregulated the expression of rice N metabolism-related genes such as OsAMT1.1, OsGS1.1, and OsGS2. Rice seedlings preferentially absorbed NH4 +-N than NO3 --N (p < 0.05), and the uptake of NH4 +-N by rice seedlings was significantly increased by 33.60% under the treatment of biochar-extracted liquor. The results from molecular docking showed that OsAMT1.1protein can theoretically interact with 2-Acetyl-5-methylfuran, trans-2,4-Dimethylthiane, S, S-dioxide, 2,2-Diethylacetamide, and 1,2-Dimethylaziridine in the biochar-extracted liquor. These four organic compounds have similar biological function as the OsAMT1.1 protein ligand in driving NH4 +-N uptakes by rice plants. Discussion: This study highlights the importance of biochar-extracted liquor in promoting plant growth and NUE. The use of low doses of biochar-extracted liquor could be an important way to reduce N input in order to achieve the purpose of reducing fertilizer use and increasing efficiency in agricultural production.