Methylation synthetic lethality: Exploiting selective drug targets for cancer therapy.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies.

Chinese Healthcare Workers' Knowledge, Attitudes, and Practices in Diabetic Kidney Management: A Multi-Centered Cross-Sectional Study.

Background: Given the importance of diabetic kidney disease (DKD) management, this study aims to explore the knowledge, attitudes, and practices in disease management demonstrated by healthcare workers from the nephrology department. Materials and Methods: This study is a multi-centered cross-sectional study, and adopts snowball sampling, with 530 healthcare workers being recruited to complete a questionnaire covering areas such as demographic characteristics, knowledge, attitude, and practices (KAP) of DKD management. This data was analyzed using descriptive statistics and binary logistics analysis. Results: In this study, 530 healthcare workers were studied, including 94 doctors and 436 nurses. The participants were mainly from general tertiary hospitals in 14 provinces. For Chinese nurse, the results indicate that both poor knowledge level (Odds Ratio (OR) =0.63, 95% Confidence Interval (CI): 0.42-0.94) and having experience in further medical training in nephrology (OR=1.92, 95% CI: 1.20-3.08) are associated with the practice levels. For Chinese doctors, having not experience in further medical training in nephrology (OR=0.36, 95% CI: 0.15-0.83) are associated with their practice levels. Conclusion: In summary, Chinese doctors and nurses in this study showed positive attitudes towards DKD management, but their knowledge and practical skills were lacking. This underscores a notable gap in achieving optimal DKD care. Notably, nurses' knowledge influenced their management practices, and additional nephrology training correlated with better engagement. To improve patient care, enhancing nephrology healthcare professional training and addressing knowledge-practice disparities are recommended.

Molecular insight into the allocation of organic carbon to heterotrophic bacteria: Carbon metabolism and the involvement in nitrogen and phosphorus removal.

Carbon metabolism and nutrient removal are crucial for biological wastewater treatment. This study focuses on analyzing carbon allocation and utilization by heterotrophic bacteria in response to increasing COD concentration in the influent. The study also assesses the effect of denitrification and biological phosphorus removal, particularly in combination with anaerobic ammonia oxidation (anammox). The experiment was conducted in a SBR operating under anaerobic/anoxic/oxic conditions. As COD concentration in the influent increased from 100 to 275 mg/L, intracellular COD accounted for 95.72 % of the COD removed. By regulating the NO3- concentration in the anoxic stage from 10 to 30 mg/L, the nitrite accumulation rate reached 69.46 %, which could serve as an electron acceptor for anammox. Most genes related to the tricarboxylic acid (TCA) cycle declined, while the genes involved in the glyoxylate cycle, gluconeogenesis, PHA synthesis increased. This suggests that glycogen accumulation and carbon storage, rather than direct carbon oxidation, was the dominant pathway for carbon metabolism. However, the genes responsible for the reduction of NO2--N (nirK) and NO (nosB) decreased, contributing to NO2- accumulation. The study also employed metagenomic analysis to reveal microbial interactions. The enrichment of specific bacterial species, including Dechloromonas sp. (D2.bin.10), Ca. Competibacteraceae bacterium (D9.bin.8), Ca. Desulfobacillus denitrificans (D6.bin.17), and Ignavibacteriae bacterium (D3.bin.9), played a collaborative role in facilitating nutrient removal and promoting the combination with anammox.

Characteristics of bacterial community structure in the sediment of Chishui River (China) and the response to environmental factors.

Sediment microorganisms performed an essential function in the biogeochemical cycle of aquatic ecosystems, and their structural composition was closely related to environmental carrying capacity and water quality. In this study, the Chishui River (Renhuai section) was selected as the research area, and the concentrations of environmental factors in the water and sediment were detected. High⁃throughput sequencing was adopted to reveal the characteristics of bacterial community structures in the sediment. In addition, the response of bacteria to environmental factors was explored statistically. Meanwhile, the functional characteristics of bacterial were also analyzed based on the KEGG database. The results showed that the concentration of environmental factors in the water and sediment displayed spatial differences, with the overall trend of midstream > downstream > upstream, which was related to the wastewater discharge from the Moutai town in the midstream directly. Proteobacteria was the most dominant phylum in the sediment, with the relative abundance ranged from 52.06% to 70.53%. The distribution of genus-level bacteria with different metabolic activities varied in the sediment. Upstream was dominated by Massilia, Acinetobacter, and Thermomonas. In the midstream, Acinetobacter, Cloacibacterium and Comamonas were the main genus. Nevertheless, the abundance of Lysobacter, Arenimonas and Thermomonas was higher in the downstream. Redundancy analysis (RDA) showed that total nitrogen (TN) and total phosphorus (TP) were the main environmental factors which affected the structure of bacterial communities in sediment, while total organic carbon (TOC) was the secondary. The bacterial community was primarily associated with six biological pathway categories such as metabolism. Carbohydrate metabolism and amino acid metabolism were the most active functions in the 31 subfunctions. This study could contribute to the understanding of the structural composition and driving forces of bacteria in the sediment, which might benefit for the ecological protection of Chishui River.

Exploring Symptom Clusters in Chinese Patients with Diabetic Kidney Disease: A Network Analysis.

Purpose: The research on symptom management in patients with diabetic kidney disease (DKD) has shifted from separate symptoms to symptom clusters and networks recently. This study aimed to evaluate the unpleasant symptoms of DKD patients, and to investigate how these symptom clusters could affect patients. Methods: 408 DKD patients were recruited in this cross-sectional study. The symptoms of DKD patients were measured using the modified Dialysis Symptom Index. Network analysis was employed to evaluate the symptom network and the characteristics of individual nodes, while factor analysis was utilized to identify symptom clusters. Results: Blurred vision was the most prevalent symptom among DKD patients. The symptoms identified as the most distressing, severe, and frequent were light headache or dizziness, arteriovenous fistula/catheterization pain, and diarrhea, respectively. Five symptom clusters were obtained from factor analysis, and the most central symptom cluster in the entire symptom network was sexual dysfunction. Conclusion: This study identified five symptom clusters in Chinese DKD patients, with sexual dysfunction emerging as the most central cluster. These findings carry significant clinical implications, underscoring the necessity of assessing symptom clusters and their associations to enhance symptom management in DKD patients. Further research is essential to elucidate the underlying mechanisms of symptoms and to clarify the associations among symptoms in DKD patients across different disease trajectories or treatment modalities.

Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury.

AIM: Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS: ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS: We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION: Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

New insights into toxicity reduction and pollutants removal during typical treatment of papermaking wastewater.

Papermaking wastewater contained various of toxic and hazardous pollutants that pose significant threats to both the ecosystem and human health. Despite these risks, limited research has addressed the detoxification efficiency and mechanism involved in the typical process treatment of papermaking wastewater. In this study, the acute toxicity of papermaking wastewater after different treatment processes was assessed using luminousbacteria, zebrafish and Daphnia magna (D. magna). Meanwhile, the pollution parament of the corresponding wastewater were measured, and the transformation of organic pollutant in the wastewater was identified by three-dimensional fluorescence and other techniques. Finally, the possible mechanism of toxicity variation in different treatment processes were explored in combination with correlation analyses. The results showed that raw papermaking wastewater displayed high acute toxicity to luminousbacteria, and exhibited slight acute toxicity and acute toxicity effect to zebrafish and D. magna, respectively. After physical and biochemical processes, not only the toxicity of the wastewater to zebrafish and D. magna was completely eliminated, but also the inhibitory effect on luminousbacteria was significantly reduced (TU value decreased from 11.07 to 1.66). Among them, the order of detoxification efficiency on luminousbacteria was air flotation > hydrolysis acidification > IC > aerobic process. Correlation analyses revealed a direct link between the reduced of Total Organic Carbon (TOC) and Chemical Oxygen Demand (COD) and the detoxification efficiency of the different processes on the wastewater. In particular, the removal of benzene-containing aromatic pollutant correlated positively with decreased toxicity. However, the Fenton process, despite lowering TOC and COD, increased of the acute toxicity of the luminousbacteria (TU value increased from 1.66 to 2.33). This may result from the transformation generation of organic pollutant and oxidant residues during the Fenton process. Hence, oxidation technologies such as the Fenton process, as a deep treatment process, should be more concerned about the ecological risks that may be caused while focusing on their effectiveness in removing pollutant.

Effects of human umbilical cord blood mononuclear cells on ovalbumin-induced asthma in mice.

Background: Umbilical cord blood mononuclear cells (UCMNCs) show broad immune-modulation effects, which may be helpful for treating asthma. Effects of UCMNCs on asthma were investigated with mouse model in present study. Methods: Asthma was induced in BALB/c mice by ovalbumin (OVA) immunization and challenge. Asthmatic mice were then treated on days 7 and 20 with intravenous injections of UCMNCs in doses of 4×105, 2×106, and 107 cells per mouse for the low-dose UCMNC (UCMNCL), medium-dose UCMNC (UCMNCM), and high-dose UCMNC (UCMNCH) groups, respectively. Fetal mouse blood mononuclear cells (FMMNCs) were administered to FMMNC group at a dose of 2×106 cells per mouse as approximate allograft control. Airway hyperresponsiveness (AHR), airway inflammation indexes, and CD4/CD8 T cell subsets were measured at day 25. Results: Compared with the model group, AHR in the UCMNCL group, inflammation score of lung tissue in the UCMNCM group, interleukin (IL)-5 in bronchoalveolar lavage fluid (BALF) in UCMNCL group, IL-5 and IL-13 in BALF in UCMNCM group, and IL-17 in serum in UCMNCH group were significantly inhibited. Compared with the model group, CD4+CD8+ T cells were reduced in the UCMNCL group, while decrease of CD4-CD8- T cells and increase of CD4+CD8- T cells were further strengthened in UCMNCM group. FMMNC treatment significantly reduced the IL-13 and IL-17 in serum, decreased CD4-CD8- and CD4+CD8- T cells, and increased the CD4+CD8+ and CD4-CD8+ T cells in BALF. Conclusions: UCMNCs can modulate AHR, T-helper (Th)2 inflammation, and airway injury in experimental asthma at appropriate dose.

The Rate of Infusion Represents an Important Aspect of Administering Anticancer Agents.

Background: Infusion rate is one of the essential elements that should be included in all intravenous orders. Patients may experience adverse consequences or risks associated with inappropriate infusion. Meanwhile, there is growing pressure on the chemotherapy unit to deliver treatment quickly, efficiently, and safely, and thus it is very necessary to improve the chemotherapy process and service to cancer patients. Clinicians should consider how to further standardize infusion therapy, and innovate new infusion strategies to increase efficacy, reduce toxicity, improve patient satisfaction and save health resource costs. Sporadic studies have evaluated the effects of infusion rates of anticancer agents on clinical outcomes, economic benefits, and administration efficiency. However, an update review has not been available. Methods: Relevant literature was identified by search of PubMed until September 2023. Results: Infusion rates may have significant effect on the efficacy of anticancer agents (e.g., methotrexate, fluorouracil, and arsenic trioxide). Slow infusion is safer for platinum compounds, doxorubicin and carmustine, whereas fast infusion is safer than slow infusion of gemcitabine. Optimal flow rates of paclitaxel and fluorouracil are based on the balance between multiple risks of toxicity. Optimal infusion rate may bring economic benefits. If efficacy and safety are not compromised, shortened infusion may result in higher patient satisfaction, improved institutional efficiency and more nursing time available for other activities (e.g., biosimilar products, endostar). Other concerns about infusion rate include clinical indications (eg, paclitaxel and rituximab, methotrexate), severity and type of hypersensitivity reactions (e.g., platinum compounds), formulation features (e.g., paclitaxel, doxorubicin), and genetic polymorphism (e.g., gemcitabine, methotrexate). Conclusion: The latest knowledge of infusion rate concerns will enhance the appropriateness and accuracy in intravenous administration. Interdisciplinary teams should collaborate and implement relevant risk management and healthcare policy. It is worthwhile to conduct comparative studies of intravenous therapy with different infusion speeds.

Autologous Airway Basal Cell Transplantation Alleviates Airway Epithelium Defect in Recurrent Benign Tracheal Stenosis.

BACKGROUND: Airway epithelium defects are a hallmark of recurrent benign tracheal stenosis (RBTS). Reconstructing an intact airway epithelium is of great importance in airway homeostasis and epithelial wound healing and has great potential for treating tracheal stenosis. METHODS: An experimental study was conducted in canines to explore the therapeutic effect of autologous basal cell transplantation in restoring airway homeostasis. First, airway mucosae from human patients with recurrent tracheal stenosis were analyzed by single-cell RNA sequencing. Canines were then randomly divided into tracheal stenosis, Stent, Stent + Cells, and Stent + Cells + Biogel groups. Autologous airway basal cells of canines in the Stent + Cells and Stent + Cells + Biogel groups were transplanted onto the stenotic airway after modeling. A biogel was coated on the airway prior to basal cell transplantation in the Stent + Cells + Biogel group. After bronchoscopic treatments, canines were followed up for 16 weeks. RESULTS: Single-cell RNA sequencing demonstrated packed airway basal cells and an absence of normal airway epithelial cells in patients with RBTS. Autologous airway basal cell transplantation, together with biogel coating, was successfully performed in the canine model. Follow-up observation indicated that survival time in the Stent + Cells + Biogel group was significantly prolonged, with a higher (100%) survival rate compared with the other groups. In terms of pathological and bronchoscopic findings, canines that received autologous basal cell transplantation showed a reduction in granulation hyperplasia as well as airway re-epithelialization with functionally mature epithelial cells. CONCLUSIONS: Autologous airway basal cell transplantation might serve as a novel regenerative therapy for airway re-epithelialization and inhibit recurrent granulation hyperplasia in benign tracheal stenosis.

Mechanical stretch promotes apoptosis and impedes ciliogenesis of primary human airway basal stem cells.

BACKGROUND: Airway basal stem cells (ABSCs) have self-renewal and differentiation abilities. Although an abnormal mechanical environment related to chronic airway disease (CAD) can cause ABSC dysfunction, it remains unclear how mechanical stretch regulates the behavior and structure of ABSCs. Here, we explored the effect of mechanical stretch on primary human ABSCs. METHODS: Primary human ABSCs were isolated from healthy volunteers. A Flexcell FX-5000 Tension system was used to mimic the pathological airway mechanical stretch conditions of patients with CAD. ABSCs were stretched for 12, 24, or 48 h with 20% elongation. We first performed bulk RNA sequencing to identify the most predominantly changed genes and pathways. Next, apoptosis of stretched ABSCs was detected with Annexin V-FITC/PI staining and a caspase 3 activity assay. Proliferation of stretched ABSCs was assessed by measuring MKI67 mRNA expression and cell cycle dynamics. Immunofluorescence and hematoxylin-eosin staining were used to demonstrate the differentiation state of ABSCs at the air-liquid interface. RESULTS: Compared with unstretched control cells, apoptosis and caspase 3 activation of ABSCs stretched for 48 h were significantly increased (p < 0.0001; p < 0.0001, respectively), and MKI67 mRNA levels were decreased (p < 0.0001). In addition, a significant increase in the G0/G1 population (20.2%, p < 0.001) and a significant decrease in S-phase cells (21.1%, p < 0.0001) were observed. The ratio of Krt5+ ABSCs was significantly higher (32.38% vs. 48.71%, p = 0.0037) following stretching, while the ratio of Ac-tub+ cells was significantly lower (37.64% vs. 21.29%, p < 0.001). Moreover, compared with the control, the expression of NKX2-1 was upregulated significantly after stretching (14.06% vs. 39.51%, p < 0.0001). RNA sequencing showed 285 differentially expressed genes, among which 140 were upregulated and 145 were downregulated, revealing that DDIAS, BIRC5, TGFBI, and NKX2-1 may be involved in the function of primary human ABSCs during mechanical stretch. There was no apparent difference between stretching ABSCs for 24 and 48 h compared with the control. CONCLUSIONS: Pathological stretching induces apoptosis of ABSCs, inhibits their proliferation, and disrupts cilia cell differentiation. These features may be related to abnormal regeneration and repair observed after airway epithelium injury in patients with CAD.

Long-term efficacy and safety of the Dumon stent for treatment of benign airway stenosis.

BACKGROUND: The long-term efficacy of the Dumon stent in the treatment of benign airway stenosis is unclear. OBJECTIVE: The objective of this study was to evaluate the long-term efficacy and safety of the Dumon stent in patients with benign airway stenosis. METHODS: We retrospectively reviewed patients with benign airway stenosis who were treated with a Dumon stent at the First Affiliated Hospital of Guangzhou Medical University between March 2014 and October 2021. We included patients with successful removal of silicone stents after implantation. The clinical data and information on bronchoscopic interventional procedures and related complications were collected and analyzed. RESULTS: Ninety-nine patients with benign airway stenosis were included. The stent was placed mainly in the trachea (44.4%) and left main bronchus (43.4%). The main type of stenosis was post-tuberculosis bronchial stenosis (57.6%). The overall cure rate was 60.6%. Stent-related complications included retention of secretions (70.7%), granuloma formation (67.7%), stent angulation (21.2%), and stent migration (12.1%). The stent was less effective for left main bronchus stenosis (p = 0.012). Multivariate logistic regression analysis identified that stent placement for more than 13 months, a stent-intervention number of ⩽ 1 predicted a favorable outcome. CONCLUSION: The efficacy and safety of the Dumon stent for benign airway stenosis need improvement. The stent is less effective for left main bronchus stenosis; regular follow-up is required in such cases. Stent placement for > 13 months and no more than once stent intervention within a 6-month period were associated with a favorable outcome.

Endoscopy-assisted purely total outer wall excision for pediatric Sylvian arachnoid cysts.

BACKGROUND: To present a novel endoscopy-assisted surgical strategy of Sylvian arachnoid cysts (ACs). CASE PRESENTATION: Endoscopy-assisted surgery was performed on 9 children (May 2019-December 2021). All patients were evaluated with CT and/or MRI and had regular follow-up examinations. The procedure consisted of performing a small temporal craniotomy (2 cm) behind the hairline. After dural opening, the surgery was performed with the assistance of a rigid 30-degree transcranial endoscope, self-irrigating bipolar forceps, and other standard endoscopic instruments. Steps included total excision of the AC outer wall and dissection of arachnoid adhesion around the cystic edge to communicate the residual cyst cavity with subdural space. Compared with the microscopical procedure, a 30-degree transcranial endoscope provides a wider view, especially for the lateral part exposure of the outer wall. The average age of the patients was 27.7 months (range 13-44 months). The Sylvian AC was in the right hemisphere in three patients and six in the left, respectively. 1 patient suffered transient postoperative epilepsy. There was no mortality or additional postoperative neurological deficit in this series. All of the patients achieved significant clinical improvement after surgery. Radiological examination after the operation showed a significant reduction in all cases (100%, 9/9) and disappearance in one case (11.1%, 1/9). Postoperative subdural fluid collection occurred in six cases and completely resolved spontaneously in 9 months. CONCLUSION: The study demonstrated the minimally invasive, safety, and effectivity of the endoscopy-assisted purely total outer wall excision.

Association between DIAPH1 variant and posterior circulation involvement with Moyamoya disease.

Moyamoya disease (MMD) is a chronic and progressive cerebrovascular stenosis or occlusive disease that occurs near Willis blood vessels. The aim of this study was to investigate the mutation of DIAPH1 in Asian population, and to compare the angiographic features of MMD patients with and without the mutation of the DIAPH1 gene. Blood samples of 50 patients with MMD were collected, and DIAPH1 gene mutation was detected. The angiographic involvement of the posterior cerebral artery was compared between the mutant group and the non-mutant group. The independent risk factors of posterior cerebral artery involvement were determined by multivariate logistic regression analysis. DIAPH1 gene mutation was detected in 9 (18%) of 50 patients, including 7 synonymous mutations and 2 missense mutations. However, the incidence of posterior cerebral artery involvement in mutation positive group was very higher than that in mutation negative group (77.8% versus 12%; p = 0.001). There is an association between DIAPH1 mutation and PCA involvement (odds ratio 29.483, 95% confidence interval 3.920-221.736; p = 0.001). DIAPH1 gene mutation is not a major genetic risk gene for Asian patients with moyamoya disease but may play an important role in the involvement of posterior cerebral artery.

Evaluation of the Two Typical Diamide Insecticide-Induced Oxidative Damages and the Molecular Mechanism Underlying Their Toxicity in Triticum aestivum.

As the typical representatives of diamide insecticides, excessive exposure to flubendiamide and chlorantraniliprole for plants may inevitably pose threats to plant growth and food safety. However, the underlying toxic mechanisms remain unclear. Here, glutathione S-transferase Phi1 from Triticum aestivum was employed as the biomarker to assess oxidative damages. First, flubendiamide displayed much stronger binding affinity with TaGSTF1 than chlorantraniliprole in consistent with molecular docking results, and flubendiamide also exerted more evident effects on the structure of TaGSTF1. Then, glutathione S-transferase activities of TaGSTF1 declined after interaction with these two insecticides, especially for flubendiamide with more hazardous influence. At last, the adverse impacts on the germination and growth of wheat seedlings were further evaluated with more apparent inhibition of flubendiamide. Hence, this study may illustrate the detailed binding mechanisms of TaGSTF1 with these two typical insecticides, evaluate the destructive impacts on plant growth, and further assess the threat to agriculture.

Human PARP1 substrates and regulators of its catalytic activity: An updated overview.

Poly (ADP-ribose) polymerase 1 (PARP1) is a key DNA damage sensor that is recruited to damaged sites after DNA strand breaks to initiate DNA repair. This is achieved by catalyzing attachment of ADP-ribose moieties, which are donated from NAD+, on the amino acid residues of itself or other acceptor proteins. PARP inhibitors (PARPi) that inhibit PARP catalytic activity and induce PARP trapping are commonly used for treating BRCA1/2-deficient breast and ovarian cancers through synergistic lethality. Unfortunately, resistance to PARPi frequently occurs. In this review, we present the novel substrates and regulators of the PARP1-catalyzed poly (ADP-ribosyl)ation (PARylatison) that have been identified in the last 3 years. The overall aim is the presentation of protein interactions of potential therapeutic intervention for overcoming the resistance to PARPi.

Salvianolic acid A improve mitochondrial respiration and cardiac function via inhibiting apoptosis pathway through CRYAB in diabetic cardiomyopathy.

Salvianolic acid A (SAA) is a traditional Chinese medicine that has a good therapeutic effect on cardiovascular disease. However, the underlying mechanisms by which SAA improves mitochondrial respiration and cardiac function in diabetic cardiomyopathy (DCM) remain unknown. This study aims to elucidate whether SAA had any cardiovascular protection on the pathophysiology of DCM and explored the potential mechanisms. Diabetes was induced in rats by 30 mg/kg of streptozotocin (STZ) treatment. After a week of stability, 5 mg/kg isoprenaline (ISO) was injected into the rats subcutaneously. 3 mg/kg SAA was orally administered for six weeks and 150 mg/kg Metformin was selected as a positive group. At the end of this period, cardiac function was assessed by ultrasound, electrocardiogram, and relevant cardiac injury biomarkers testing. Treatment with SAA improved cardiac function, glucose, and lipid levels, mitochondrial respiration, and suppressed myocardial inflammation and apoptosis. Furthermore, SAA treatment inhibits the apoptosis pathway through CRYAB in diabetic cardiomyopathy rats. As a result, this study not only provides new insights into the mechanism of SAA against DCM but also provides new therapeutic ideas for the discovery of anti-DCM compounds in the clinic.

Organic matter enrichment mechanism of Youganwo Formation oil shale in the Maoming Basin.

The Youganwo Formation oil shale located in the Maoming Basin represents a large commercially valuable lacustrine oil shale resource and a potential bio-shale gas reservoir in South China. With the aim of deepening the understanding of factors that influence organic matter enrichment, this research conducted a geochemical investigation to reconstruct the depositional paleoenvironment of bioproductivity, preservation and dilution. Youganwo Formation oil shale is mainly deposited in semi-deep to deep-lake environments with relatively warm and humid paleoclimate in the subtropical-temperate zone. The total organic carbon (TOC) content (1.46-11.85%), S2 values (4.79-115.80 mg HC/mg rock) and HI (328-1040 mg HC/mg TOC) indicate that the oil shale has a good oil source rock potential. TOC content, (S1 + S2) values and vitrinite reflectance values show that its marginally mature organic matter (OM) belongs to kerogen type I-III with good oil-generating potential. A 3rd order sequence was identified in the Yougnwo formation. Subsequently, the multiple factors including bioproductivity, preservation and dilution that control the OM enrichment of oil shale within system tracts were discussed. Moderate-quality oil shales (Oy-1) were developed in the transgressive systems tract (TST) in an oxidizing condition with abundant detrital input. High-quality oil shales (Oy-2) were deposited during the high-stand systems tract (HST) with increased accommodation space, improved preservation conditions, warm and humid climate, higher water bioproductivity and minimum detrital matter input. During the regressive systems tract (RST, Oy-3), higher detrital matter input and fresher water led to lower TOC values. Among these multiple factors, dilution condition was the major one that influences OM abundance and variation on the basis of sufficient organic matter input. Thus, OM enrichment models of Oy-1, Oy-2 and Oy-3 sub-members were established. The OM enrichment and quality in oil shale were controlled by the combined effect of bioproductivity, preservation, and dilution.

The correlation between white blood cell count, neutrophil-lymphocyte ratio and depression severity in patients with first episode depression / 中华行为医学与脑科学杂志

Objective:To investigate the relationship between white blood cells, neutrophil-lymphocyte ratio(NLR), platelet-lymphocyte ratio(PLR) and monocyte-lymphocyte ratio(MLR) with patients suffering from first episode depression.Methods:This retrospective study was conducted among inpatients of Hebei General Hospital from January 2021 to December 2021.Ultimately, 193 patients with first-episode depression were enrolled.According to the score of Hamilton depression scale-24 (HAMD-24), the patients were divided into mild-moderate depression group(20≤HAMD-24<35 score, n=98) and severe depression group (HAMD-24 score ≥35, n=95). White blood cells and the counts of each cell subtype were detected and the NLR, MLR and PLR were calculated.SPSS 25.0 statistical software was used to analyze the data.Mann-Whitney U test was used to compare differences in the two groups and Binary Logistic regression analyses were performed to recognize the predictive factors of the severity of first episode depression. Results:(1) The white blood cells and NLR in the severe depression group were significantly higher than those in the mild-moderate depression group (white blood cells: 5.77(2.05)×10 9/L vs 5.11(1.31)×10 9/L; NLR: 1.86 (1.04) vs 1.57(0.55), P<0.05). There were no significant differences in PLR and MLR between the two groups ( P>0.05). (2)Multiple regression analysis of NLR, white blood cells and HAMD-24 score showed that there were significant differences in the effect of different white blood cells and NLR levels on HAMD-24 score( B=1.398, P=0.003; B=2.624, P=0.001). (3)Binary Logistic regression revealed that white blood cell count and NLR were risk factors for the severity of depression patients( OR were 1.612 and 2.336, respectively, P<0.05). Conclusion:The results suggest that white blood cells and NLR may be relate with the severity of first episode depression.