Comprehensive analysis of lncRNA-miRNA-mRNA ceRNA network in ischemic stroke.

Objective: Competitive endogenous RNA (ceRNA) networks have uncovered a novel mode of RNA interaction, and are implicated in various biological processes and the pathogenesis of IS. This study aimed to explore the potential mechanisms underlying the ceRNA network in IS. Methods: Four public datasets containing lncRNA and mRNA (GSE22255 and GSE16561) and miRNA (GSE55937 and GSE43618) expression profiles from the GEO database were systematically analyzed to explore the role of RNAs in ischemic stroke (IS). Differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs), and miRNAs (DEmiRNAs) between IS and normal control samples were identified. LncRNA-miRNA and miRNA-mRNA interactions were predicted, and the competing endogenous RNA (ceRNA) regulatory network was constructed using the Cytoscape software. The correlation between the RNAs in the ceRNA network and the clinical features of the samples was evaluated. Finally, principal component analysis was performed on the RNAs that constitute the ceRNA regulatory network, and their differential expression and principal component relationships among different types of samples were observed. Results: A total of 224 DEmRNAs, 7 DEmiRNAs, and four DElncRNAs related to IS in four datasets were identified. Then, through target gene prediction, a lncRNA-miRNA-mRNA ceRNA network that contained 3 DElncRNAs, 2 DEmiRNAs, and 24 DEmRNAs was constructed. Correlations of the clinical characteristics showed that PART1 and SERPINH1 were related to clinical diseases, WNK1 was related to lifestyle, and seven RNAs were related to age. PCA results indicate that three principal components of PC1, PC2, and PC3 can clearly distinguish between control and IS samples. Conclusion: Overall, we constructed a ceRNA network in IS, which could offer insights into the molecular mechanism and potential prognostic biomarkers for further research.

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications.

Diabetic vascular complications are prevalent and severe among diabetic patients, profoundly affecting both their quality of life and long-term prospects. These complications can be classified into macrovascular and microvascular complications. Under the impact of risk factors such as elevated blood glucose, blood pressure, and cholesterol lipids, the vascular endothelium undergoes endothelial dysfunction, characterized by increased inflammation and oxidative stress, decreased NO biosynthesis, endothelial-mesenchymal transition, senescence, and even cell death. These processes will ultimately lead to macrovascular and microvascular diseases, with macrovascular diseases mainly characterized by atherosclerosis (AS) and microvascular diseases mainly characterized by thickening of the basement membrane. It further indicates a primary contributor to the elevated morbidity and mortality observed in individuals with diabetes. In this review, we will delve into the intricate mechanisms that drive endothelial dysfunction during diabetes progression and its associated vascular complications. Furthermore, we will outline various pharmacotherapies targeting diabetic endothelial dysfunction in the hope of accelerating effective therapeutic drug discovery for early control of diabetes and its vascular complications.

Effects of electroacupuncture of different intensities and durations on PERK/ATF4/CHOP signaling pathway in liver of non-alcoholic fatty liver disease rats. / ä¸åŒå¼ºåº¦åŠæ—¶ç¨‹ç”µé’ˆå¹²é¢„å¯¹éžé ’ç²¾æ€§è„‚è‚ªè‚ç— å¤§é¼ è‚è„PERK/ATF4/CHOP通路的影响.

OBJECTIVES: To analyze the effects of electroacupuncture (EA) at "Fenglong" (ST40) and "Zusanli" (ST36) of different intensities and durations on rats with non-alcoholic fatty liver disease (NAFLD) based on the protein kinase R-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway, so as to explore its mechanism underlying improvement of NAFLD. METHODS: SD rats were randomly divided into normal diet group, high-fat model group, sham EA group, strong stimulation EA (SEA) group, and weak stimulation EA (WEA) group, with 15 rats in each group. Each group was further divided into 2, 3, and 4-week subgroups. NAFLD rat model was established by feeding a high-fat diet. After successful modeling, rats in the SEA and WEA groups received EA at bilateral ST40 and ST36 with dense and sparse waves (4 Hz/20 Hz) at current intensities of 4 mA (SEA group) and 2 mA (WEA group), lasting for 20 minutes, once a day, 5 days a week with 2 days of rest. The sham EA group only had the EA apparatus connected without electricity. Different duration subgroups were intervened for 2, 3, and 4 weeks. After the intervention, the contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats were detected by an automatic biochemical analyzer；liver morphological changes were observed by Oil Red O staining；real-time fluorescence quantitative PCR and Western blot were used to detect the expression of PERK, ATF4, and CHOP mRNAs and proteins in the rat liver tissue. RESULTS: In the high-fat model group, there was a significant accumulation of red lipid droplets in the liver cells, which was reduced significantly in the SEA group at the 4th week. Compared with the normal diet group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.01) in the high-fat model group . Compared with the high-fat model group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, CHOP mRNAs and proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups. Compared with the sham EA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were decreased (P<0.01, P<0.05) in the SEA and WEA groups, the expression of PERK, ATF4, and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at the 2nd, 3rd, and 4th week, the expression of PERK and CHOP proteins at the 2nd, 3rd, 4th week and ATF4 protein at 2nd week in the liver tissue were decreased (P<0.01, P<0.05) in the WEA group. Compared with the SEA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated (P<0.05, P<0.01) in the WEA group. Compared with the 2-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and PERK proteins in the liver tissue were decreased (P<0.01, P<0.05) in the SEA and WEA groups at 3rd and 4th week, the expression of ATF4 proteins in the liver tissue was decreased (P<0.01) in the SEA group at 3rd and 4th week, and the expression of CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA group at 4th week and in the WEA group at 3rd and 4th week. Compared with the 3-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were significantly decreased (P<0.05, P<0.01) in the SEA and WEA groups at 4th week, the expression of PERK and CHOP proteins in the liver tissue was decreased (P<0.01) in the SEA and WEA groups at 4th week, and the expression of ATF4 protein in the liver tissue was decreased (P<0.05) in the SEA group at 4th week. CONCLUSIONS: EA at ST40 and ST36 can significantly improve liver function in NAFLD rats, and its mechanism of action may involve inhibiting PERK expression thereby targeting the downstream ATF4/CHOP signaling pathway to suppress endoplasmic reticulum stress, exerting a liver protective effect；the optimal effect was observed with EA intensity of 4 mA for 4 weeks.

Hyperbranched Vitrimer for Ultrahigh Energy Dissipation.

Polymers are ideally utilized as damping materials due to the high internal friction of molecular chains, enabling effective suppression of vibrations and noises in various fields. Current strategies rely on broadening the glass transition region or introducing additional relaxation components to enhance the energy dissipation capacity of polymeric damping materials. However, it remains a significant challenge to achieve high damping efficiency through structural control while maintaining dynamic characteristics.  In this work, we propose a new strategy to develop hyperbranched vitrimers (HBVs) containing dense pendant chains and loose dynamic crosslinked networks. A novel yet weak dynamic transesterification between the carboxyl and boronic acid ester was confirmed and used to prepare HBVs based on poly (hexyl methacrylate-2-(4-ethenylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane) P(HMA-co-ViCL) copolymers. The ABn-type of macromonomers, the crosslinking points formed by the dynamic covalent connection via the associative exchange, and the weak yet dynamic exchange reaction are the three keys to developing high-performance HBV damping materials. We found that P(HMA-co-ViCL) 20k-40-60 HBV exhibited ultrahigh energy-dissipation performance over a broad frequency and temperature range, attributed to the synergistic effect of dense pendant chains and weak dynamic covalent crosslinks. This unique design concept will provide a general approach to developing advanced damping materials.

DSCAM-AS1 promotes the development of prostate cancer.

PURPOSE: The purpose of this study was to investigate the role of lncRNA DSCAM-AS1 in prostate cancer to find new therapeutic targets and promote the research progress of prostate cancer. METHODS: RT-qPCR was used to detect DSCAM-AS1 expression in prostate cancer tissues, normal tissues, human normal prostate epithelial cells (RWPE), and four prostate cancer cell lines. The clinical and prognostic role of DSCAM-AS1 was evaluated by the Kaplan-Meier curve and chi-square test. Secondly, a dual luciferase reporter gene assay was used to study the regulatory mechanism between miR-338-3p and DSCAM-AS1. Finally, the roles of DSCAM-AS1 and miR-338-3p in prostate cancer cell proliferation and metastasis were explored by CCK-8 and Transwell assays. RESULTS: It was found that DSCAM-AS1 upregulation could serve as a warning of deterioration and poor prognosis in prostate cancer patients, and that knockdown of DSCAM-AS1 expression inhibited the progression of prostate cancer cells. In addition, miR-338-3p, a target of DSCAM-AS1, was found to be down-regulated in prostate cancer cells and miR-338-3p knockdown could reverse the inhibitory effect of DSCAM-AS1 silencing on prostate cancer. CONCLUSION: DSCAM-AS1 is up-regulated in prostate cancer and regulates the progression of prostate cancer cells by targeting miR-338-3p.

Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20.

Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays. Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14. Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression. Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children's families.

Light-induced photoluminescence enhancement in chiral CdSe quantum dot films.

Chiral quantum dots (QDs) are promising materials applied in many areas, such as chiral molecular recognition and spin selective filter for charge transport, and can be prepared by facile ligand exchange approaches. However, ligand exchange leads to an increase in surface defects and reduces the efficiencies of radiative recombination and charge transport, which restricts further applications. Here, we investigate the light-induced photoluminescence (PL) enhancement in chiral L- and D-cysteine CdSe QD thin films, providing a strategy to increase the PL. The PL intensity of chiral CdSe QD films can be significantly enhanced over 100 times by continuous UV laser irradiation, indicating a strong passivation of surface defects upon laser irradiation. From the comparative measurements of the PL intensity evolutions in vacuum, dry oxygen, air, and humid nitrogen atmospheres, we conclude that the mechanism of PL enhancement is photo-induced surface passivation with the assistance of water molecules.

A web-based dynamic predictive model for postoperative nausea and vomiting in patient receiving gynecological laparoscopic surgery.

OBJECTIVE: The aim of this study was to develop a web-based dynamic prediction model for postoperative nausea and vomiting (PONV) in patients undergoing gynecologic laparoscopic surgery. METHODS: The patients (N = 647) undergoing gynecologic laparoscopic surgery were included in this observational study. The candidate risk-factors related to PONV were included through literature search. Lasso regression was utilized to screen candidate risk-factors, and the variables with statistical significance were selected in multivariable logistic model building. The web-based dynamic Nomogram was used for model exhibition. Accuracy and validity of the experimental model (EM) were evaluated by generating receiver operating characteristic (ROC) curves and calibration curves. Hosmer-Lemeshow test was used to evaluate the goodness of fit of the model. Decision curve analysis (DCA) was used to evaluate the clinical practicability of the risk prediction model. RESULTS: Ultimately, a total of five predictors including patient-controlled analgesia (odds ratio [OR], 4.78; 95% confidence interval [CI], 1.98-12.44), motion sickness (OR, 4.80; 95% CI, 2.71-8.65), variation of blood pressure (OR, 4.30; 95% CI, 2.41-7.91), pregnancy vomiting history (OR, 2.21; 95% CI, 1.44-3.43), and pain response (OR, 1.64; 95% CI, 1.48-1.83) were selected in model building. Assessment of the model indicates the discriminating power of EM was adequate (ROC-areas under the curve, 93.0%; 95% CI, 90.7%-95.3%). EM showed better accuracy and goodness of fit based on the results of the calibration curve. The DCA curve of EM showed favorable clinical benefits. CONCLUSIONS: This dynamic prediction model can determine the PONV risk in patients undergoing gynecologic laparoscopic surgery.

Anion-Coordination Foldamer-Based Polymer Network: from Molecular Spring to Elastomer.

Foldamer is a scaled-down version of coil spring, which can absorb and release energy by conformational change. Here, polymer networks with high-density of molecular springs were developed by employing anion-coordination-based foldamers as the monomer. The coiling of the foldamer is controlled by oligourea ligands coordinating to chloride ions; subsequently, the folding and unfolding of foldamer conformations endow the polymer network with excellent energy dissipation and toughness. The mechanical performance of the corresponding polymer network shows a dramatic increase from P-L2UCl (non-folding), P-L4UCl (a full turn) to P-L6UCl (1.5 turns), in terms of strength (2.62 MPa; 14.26 Mpa; 22.93 Mpa), elongation at break (70%; 325%; 352%), Young's modulus (2.69 MPa; 63.61 Mpa; 141.50 Mpa), and toughness (1.12 MJ/m3; 21.39 MJ/m3; 49.62 MJ/m3), respectively, which are also better than those without anion centers and the non-foldamer based counterparts. Moreover, P-L6UCl shows enhanced strength and toughness than most of the molecular-spring based polymer networks.Moreover, P-L6UCl shows enhanced strength and toughness than most of the molecular-spring based polymer networks. Thus, an effective strategy for designing high-performance anion-coordination-based materials is presented in this study.

Physiological and biochemical characteristics of the carbon ion beam irradiation-generated mutant strain Clostridium butyricum FZM 240 in vitro and in vivo.

Clostridium butyricum (C. butyricum) represents a new generation of probiotics, which is beneficial because of its good tolerance and ability to produce beneficial metabolites, such as short-chain fatty acids and enzymes; however, its low enzyme activity limits its probiotic efficacy. In this study, a mutant strain, C. butyricum FZM 240 was obtained using carbon ion beam irradiation, which exhibited greatly improved enzyme production and tolerance. The highest filter paper, endoglucanase, and amylase activities produced by C. butyricum FZM 240 were 125.69 U/mL, 225.82 U/ mL, and 252.28 U/mL, which were 2.58, 1.95, and 2.21-fold higher, respectively, than those of the original strain. The survival rate of the strain increased by 11.40 % and 5.60 % after incubation at 90 °C for 5 min and with simulated gastric fluid at pH 2.5 for 2 h, respectively, compared with that of the original strain. Whole-genome resequencing and quantitative real-time PCR(qRT-PCR) analysis showed that the expression of genes related to enzyme synthesis (GE000348, GE001963 and GE003123) and tolerance (GE001114) was significantly up-regulated, while that of genes related to acid metabolism (GE003450) was significantly down-regulated. On this basis, homology modeling and functional prediction of the proteins encoded by the mutated genes were performed. According to the results, the properties related to the efficacy of C. butyricum as a probiotic were significantly enhanced by carbon ion beam irradiation, which is a novel strategy for the application of Clostridium spp. as feed additives.

Host proteins interact with viral elements and affect the life cycle of highly pathogenic avian influenza A virus H7N9.

Host-virus interactions can significantly impact the viral life cycle and pathogenesis; however, our understanding of the specific host factors involved in highly pathogenic avian influenza A virus H7N9 (HPAI H7N9) infection is currently restricted. Herein, we designed and synthesized 65 small interfering RNAs targeting host genes potentially associated with various aspects of RNA virus life cycles. Afterward, HPAI H7N9 viruses were isolated and RNA interference was used to screen for host factors likely to be involved in the life cycle of HPAI H7N9. Moreover, the research entailed assessing the associations between host proteins and HPAI H7N9 proteins. Twelve key host proteins were identified: Annexin A (ANXA)2, ANXA5, adaptor related protein complex 2 subunit sigma 1 (AP2S1), adaptor related protein complex 3 subunit sigma 1 (AP3S1), ATP synthase F1 subunit alpha (ATP5A1), COPI coat complex subunit alpha (COP)A, COPG1, heat shock protein family A (Hsp70) member 1A (HSPA)1A, HSPA8, heat shock protein 90 alpha family class A member 1 (HSP90AA1), RAB11B, and RAB18. Co-immunoprecipitation revealed intricate interactions between viral proteins (hemagglutinin, matrix 1 protein, neuraminidase, nucleoprotein, polymerase basic 1, and polymerase basic 2) and these host proteins, presumably playing a crucial role in modulating the life cycle of HPAI H7N9. Notably, ANXA5, AP2S1, AP3S1, ATP5A1, HSP90A1, and RAB18, were identified as novel interactors with HPAI H7N9 proteins rather than other influenza A viruses (IAVs). These findings underscore the significance of host-viral protein interactions in shaping the dynamics of HPAI H7N9 infection, while highlighting subtle variations compared with other IAVs. Deeper understanding of these interactions holds promise to advance disease treatment and prevention strategies.

Mesenchymal stem cell-derived exosomes as new drug carrier for the treatment of spinal cord injury: A review.

Spinal cord injury (SCI) is a devastating traumatic disease seriously impairing the quality of life in patients. Expectations to allow the hopeless central nervous system to repair itself after injury are unfeasible. Developing new approaches to regenerate the central nervous system is still the priority. Exosomes derived from mesenchymal stem cells (MSC-Exo) have been proven to robustly quench the inflammatory response or oxidative stress and curb neuronal apoptosis and autophagy following SCI, which are the key processes to rescue damaged spinal cord neurons and restore their functions. Nonetheless, MSC-Exo in SCI received scant attention. In this review, we reviewed our previous work and other studies to summarize the roles of MSC-Exo in SCI and its underlying mechanisms. Furthermore, we also focus on the application of exosomes as drug carriers in SCI. In particular, it combs the advantages of exosomes as drug carriers for SCI, imaging advantages, drug types, loading methods, etc., which provides the latest progress for exosomes in the treatment of SCI, especially drug carriers.

The genetic association between hyperthyroidism and heart failure: a Mendelian randomization study.

Background and aims: Hyperthyroidism is an endocrine disease with multiple etiologies and manifestations. Heart failure (HF) is a common, costly, and deadly medical condition in clinical practice. Numerous studies have suggested that abnormal thyroid function can induce or aggravate the development of heart disease. However, no study has demonstrated a causal relationship between hyperthyroidism and heart failure. Therefore, the purpose of this study was to explore the causal link between hyperthyroidism and HF. Methods: Summary data for genetically predicted hyperthyroidism were obtained from a genetic association study. The data examined for genetically determined all-cause heart failure came from 218,208 individuals from the FinnGen Consortium. Two-sample Mendelian randomization (MR) analysis was used to estimate the causal link between hyperthyroidism and heart failure. Statistical analyses were conducted using the inverse variance-weighted, weighted median, simple median, weighted mode, MR-PRESSO (number of distribution = 5000), MR-Egger, and leave-one-out. Results: The results of the inverse-variance weighted analysis indicated a causal association between hyperthyroidism and an increased risk of all-cause heart failure (IVW: ß=0.048, OR=1.049, 95%CI: [1.013 to 1.087], P=0.007). Similarly, the weighted median approach demonstrated a positive correlation between hyperthyroidism and all-cause heart failure (OR=1.049, [95% CI, 1.001-1.100]; P=0.044). Additionally, no horizontal pleiotropy or heterogeneity was observed. The leave-one-out analysis revealed that the majority of the SNP-driven associations were not influenced by a single genetic marker. Conclusion: Our study observed a causal relationship between hyperthyroidism and all-cause heart failure. Hyperthyroidism may associate with heart failure genetically.

The design of a linear voltage divider based on metal oxide arresters.

In recent years, linearization technology for nonlinear devices has become a hot topic in many fields. In this study, a linear voltage divider based on metal oxide arresters was designed by combining linearization technology and electrical measurement technology to solve the objective problems of online voltage monitoring. These problems include high difficulty in equipment installation, low measurement accuracy, and poor economic benefits. Based on a summary of linearization theory, the sufficient and necessary conditions for the linearization of the voltage divider were deduced in detail. The relevant circuit simulations were conducted, along with voltage divider experiments under power frequency AC voltage, operating overvoltage, and lightning overvoltage. The results revealed that the voltage divider was able to realize linearized measurements and meet the relevant standards of online voltage monitoring. The measurement errors were concentrated in the transition region between the pre-breakdown region (small current region) and the breakdown region (nonlinear region) in the volt-ampere characteristic curve. The main influencing factor of errors was the consistency of the nonlinear characteristics of the high- and low-voltage arms of the voltage divider. The voltage divider designed in this study can be applied in many scenarios, such as power plants, substations, high-voltage electrical equipment manufacturing plants, and high-voltage laboratories.

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer.

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs.

Dopamine promotes Klebsiella quasivariicola proliferation and inflammatory response in the presence of macrophages.

Background: Dopamine, a frequently used therapeutic agent for critically ill patients, has been shown to be implicated in clinical infections recently, however, the precise mechanisms underlying this association remain elusive. Klebsiella quasivariicola, a novel strain belonging to the Klebsiella species, exhibits potential pathogenic attributes. The impact of dopamine on K. quasivariicola infection has aroused our interest. Objective: Considering the contribution of host immune factors during infection, this study aimed to investigate the intricate interactions between K. quasivariicola, dopamine, and macrophages were explored. Methods: RAW264.7 cells and C57/BL6 mice were infected with K. quasivariicola, and the bacterial growth within macrophage, the production of inflammatory cytokines and the pathological changes in mice lungs were detected, in the absence or presence of dopamine. Results: Dopamine inhibited the growth of K. quasivariicola in the medium, but promoted bacterial growth when co-cultured with macrophages. The expression of proinflammatory cytokines increased in RAW 264.7 cells infected with K. quasivariicola, and a significant rise was observed upon the addition of dopamine. The infection of K. quasivariicola in mice induced an inflammatory response and lung injury, which were exacerbated by the administration of dopamine. Conclusions: Our findings suggest that dopamine may be one of the potential risk factors associated with K. quasivariicola infection. This empirical insight provides solid references for clinical precision medicine. Furthermore, an in vitro model of microbes-drugs-host immune cells for inhibitor screening was proposed to more accurately replicate the complex in vivo environment. This fundamental work had contributed to the present understanding of the crosstalk between pathogen, dopamine and host immune cells.

The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

Genetic interactions reveal distinct biological and therapeutic implications in breast cancer.

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53mut-AURKAamp and endocrine therapy resistance, germline BRCA1mut-MYCamp and improved sensitivity to PARP inhibitors, and TP53mut-MYBamp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations.

A Review: Cytochrome P450 in Alcoholic and Non-Alcoholic Fatty Liver Disease.

Alcoholic fatty liver disease (FALD) and non-alcoholic fatty liver disease (NAFLD) have similar pathological spectra, both of which are associated with a series of symptoms, including steatosis, inflammation, and fibrosis. These clinical manifestations are caused by hepatic lipid synthesis and metabolism dysregulation and affect human health. Despite having been studied extensively, targeted therapies remain elusive. The Cytochrome P450 (CYP450) family is the most important drug-metabolising enzyme in the body, primarily in the liver. It is responsible for the metabolism of endogenous and exogenous compounds, completing biological transformation. This process is relevant to the occurrence and development of AFLD and NAFLD. In this review, the correlation between CYP450 and liver lipid metabolic diseases is summarised, providing new insights for the treatment of AFLD and NAFLD.

Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness.

BACKGROUND: To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii, which was named Trx4. METHODS: We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4. RESULTS: Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice. CONCLUSIONS: Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment.