Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer.

BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

Regulation of the growth performance and the gastrointestinal microbiota community by the addition of defective pear fermentation to feed of small-tailed Han sheep.

This study investigated the effects of defective pear fermentation (DPF) diets on growth performance and gastrointestinal microbial communities in 60 healthy male small-tailed Han sheep, aged 90 days. The sheep were randomly divided into four groups, each consisting of three replicates with five sheep per replicate. Initially, all groups received a basal diet for seven days during the adaptation stage. Subsequently, for 60 days, group C (control) was fed a basal diet, group X received a basal diet with 2% DPF, group Y had a basal diet with 4% DPF, and group Z was fed a basal diet with 6% DPF. The results indicated that group Y experienced a significant increase in average daily gain (ADG) and average daily feed intake (ADFI). The addition of DPF significantly elevated the levels of GSH-Px and notably reduced MDA content compared to group C. Analysis of gastrointestinal microbiota showed that groups receiving DPF had increased relative abundances of Lachnospiraceae_NK3A20_group, norank_f p-2534-18B5_gut_group, Acetitomaculum, Actinobacteriota, Bacteroidota and Ruminococcus_gauvreauii_group, and decreased abundances of Proteobacteria, Prevotella, Staphylococcus, and Psychrobacter compared to group C. Group X exhibited the highest relative abundance of Olsenella, while group Y showed a significant increase in unclassified_f Lachnospiraceae compared to the other groups. Bacterial function prediction indicated that pathways related to energy metabolism were more prevalent in group X and Y. This study preliminarily confirms the feasibility of using DPF as feed additives, providing a foundation for further research and evaluation of DPF's application in animal production.

Network analysis of suicide ideation and depression-anxiety symptoms among Chinese adolescents.

Background: The co-occurrence of depression and anxiety among adolescents is typically associated with suicide ideation. Aims: The study aimed to investigate the symptom-level relationship between suicide ideation and the comorbidity of depression and anxiety. Methods: 1501 adolescents aged 12-19 years were assessed using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Scale, and 716 adolescents who scored ≥5 on both scales were selected as participants. Network analysis was used to identify the network structure of depressive symptoms and anxiety symptoms. Participants were categorised into either the suicide ideation or non-suicide ideation groups based on their scoring on the suicide-related item in PHQ-9. A comparison was made between the depression-anxiety symptom networks of the two groups. Results: 'Restlessness', 'sad mood' and 'trouble relaxing' were the most prominent central symptoms in the depression-anxiety symptom network, and 'restlessness', 'nervousness' and 'reduced movement' were the bridge symptoms in this network. 'Sad mood' was found to be directly related to 'suicide ideation' with the highest variance. The network structure was significantly different in properties between the suicide ideation group and the non-suicide ideation group, with 'restlessness' and 'sad mood' exhibiting significantly higher influence in the network of the suicide ideation group than that in the non-suicide ideation group. Conclusion: Restlessness and sad mood could be targeted for the intervention of depression-anxiety symptoms among adolescents with suicide ideation.

Application of Oral Retractor for Lip Injury Protection in Oral and Maxillofacial Surgeries: A Randomized Controlled Trial.

PURPOSE: Iatrogenic lip injury may occur during oral and maxillofacial surgical procedures. This study aimed to evaluate the effect of oral retractors on iatrogenic lip injury prevention during intraoral procedures of oral and maxillofacial surgery. METHODS: We conducted a randomized controlled trial and included patients who underwent intraoral procedures of oral and maxillofacial surgery. Patients were randomly allocated to receive oral retractor (intervention group) or traditional procedure without lip protection (control group). The incidence of lip injury was the outcome variable. Other study variables included surgical time and satisfaction of patients and surgeons with treatment experience evaluated by visual analog scale (VAS). Student t test and χ2 test were used to compare both groups' variables and measure the relationship between the predictor variable and the outcome variable. P<0.05 was considered significant for all analyses. RESULTS: A total of 114 patients were included, with 56 allocated to intervention group and 58 to control group. The results showed that the application of an oral retractor did not significantly increase surgical time (P=0.318). A total of 12 patients had lip injury, with 1 in the intervention group and 11 in the control group (P=0.003). For the assessment of satisfaction with treatment experience, the intervention group had significantly higher VAS scores for doctors and patients (P<0.05). CONCLUSIONS: We found that the oral retractor was a good tool for iatrogenic lip injury prevention in oral and maxillofacial surgical procedures and could be considered in clinical treatment.

A cubic DNA nanocage probe for in situ analysis of miRNA-10b in tumor-derived extracellular vesicles.

A cubic DNA nanocage probe is able to enter EVs derived from MDA-MB-231 cells and react with miRNA-10b. The probe-loaded EVs were employed to monitor the process of entry of miRNA-10b into MCF-10A cells, allowing visualization of EV-mediated intercellular communication of miRNA-10b between the cancer cells.

A molecularly imprinted photoelectrochemical sensor based on an rGO/MoSSe heterojunction for the detection of chlortetracycline.

A reduced graphene oxide/molybdenum selenosulfide (rGO/MoSSe) heterojunction was synthesized, and a molecularly imprinted photoelectrochemical sensor for the detection of chlortetracycline was prepared. MoSSe was grown in situ on rGO by a hydrothermal method to form an rGO/MoSSe heterojunction, which acts as the sensitive film of the sensor. Since rGO can promote electron transfer and effectively inhibit electron-hole recombination, it effectively reduces the recombination probability of electrons and holes and improves the photoelectric efficiency, thus enhancing the detection sensitivity of the PEC sensor. The rGO/MoSSe was immobilized on an FTO electrode, and molecularly imprinted polymers (MIPs) were prepared by electropolymerization on the rGO/MoSSe-modified FTO electrode with chlortetracycline as the template molecule and o-phenylenediamine as the functional monomer, so as to construct a molecularly imprinted photoelectrochemical (MIP-PEC) sensor. The determination of chlortetracycline was realized by the strategy of a "gate-controlled effect", and the detection range of the chlortetracycline concentration was 5.0 × 10-13-5 × 10-9 mol L-1 with a detection limit of 1.57 × 10-13 mol L-1. The sensor has been applied to the determination of chlortetracycline in animal-derived food samples.

A Shear-Stiffening Mouthguard with Excellent Shock Absorption Capability and Remoldability via a Dynamic Dual Network.

Mouthguards are used to reduce injuries and the probability of them to orofacial tissues when impacted during sports. However, the usage of a mouthguard is low due to the discomfort caused by the thickness of the mouthguard. Herein, we have constructed a dynamic dual network to fabricate a shear-stiffening mouthguard with remoldability, which are called remoldable shear-stiffening mouthguards (RSSMs). Based on diboron/oxygen dative bonds, RSSMs show a shear-stiffening effect and excellent shock absorption ability, which can absorb more than 90% of the energy of a blank. Even reducing the thickness to half, RSSMs can reduce approximately 25% of the transmitted force and elongate by about 1.6-fold the buffer time compared to commercial mouthguard materials (Erkoflex and Erkoloc-pro). What is more, owing to the dynamic dual network, RSSMs show good remolding performance with unchanged shear-stiffening behavior and impact resistance, which conforms to the existing vacuum thermoforming mode. In addition, RSSMs exhibit stability in artificial saliva and biocompatibility. In conclusion, this work will broaden the range of mouthguard materials and offer a platform to apply shear-stiffening materials to biomedical applications and soft safeguarding devices.

Associations between maternal urinary kisspeptin in late pregnancy and decreased fetal growth: a pregnancy-birth cohort study.

Background: Kisspeptin has been indicated to be a biomarker of fetal growth. Although some evidence suggested that maternal kisspeptin concentrations in early pregnancy were associated with increased fetal growth, studies are still limited and the effect of kisspeptin in late pregnancy remains unknown. This study aimed to investigate the associations between maternal kisspeptin in late pregnancy and fetal growth. Methods: Based on the Shanghai-Minhang Birth Cohort study, 724 mother-neonate pairs were included in this study. We measured maternal kisspeptin concentrations in the urine samples collected in late pregnancy and neonatal anthropometric indices at birth. The associations between maternal kisspeptin and neonatal anthropometry were investigated using multiple linear regression models. Results: Higher maternal urinary kisspeptin concentrations were associated with lower neonatal birth weight, head circumference, upper arm circumference, abdominal skinfold thickness, triceps skinfold thickness, and back skinfold thickness. The inverse associations were more pronounced for the highest kisspeptin levels versus the lowest. These patterns were consistent in analyses stratified by neonatal sex, with notably stable associations between maternal kisspeptin concentrations and skinfold thickness. Conclusion: The present study suggested that maternal kisspeptin concentrations in late pregnancy might be inversely associated with fetal growth. The physiological mechanisms of maternal kisspeptin might differ from those in early pregnancy. Further studies are required to assess associations between maternal kisspeptin and energy homeostasis and explore the physiological roles of kisspeptin in late pregnancy.

Achieving Cross Time-Domain Multiplexed Signal Cascade and Cancer Exosomes Identification by Bridging Long Lifetime Phosphor to NIR-II Lanthanide Energy Transfer.

Designing lanthanide luminescence lifetime sensors in the second near-infrared (NIR-II) window holds great potentials for physiological studies. However, the single lifetime signal is confined to one or two orders of magnitude of signal variation, which limits the sensitivity of lifetime probes. In this study, a lifetime cascade system, i.e., ZGO:Mn, Eu-DNA-1/TCPP-PEI70K @Yb-AptEpCAM , with a variety of signals (τm , τn , τµ , τm /τn and τm /τµ ) is constructed for exosome identification using time-domain multiplexing. The sensitized ligand TCPP acts as both target-modulated switch and a bridge for connecting long lifetime ZGO:Mn, Eu-DNA-1 emitter to lanthanide Yb3+ . This drives successive dual-path energy transfer and forms two D(donor) -A(acceptor) pairs. The lifetime variation is dominantly modulated by arranging TCPP as energy intermediate relay to covert milliseconds to nanoseconds to microseconds. It enables a broad lifetime range of six orders of magnitude. The presence of exosome specifically recognizes aptamers on TCPP-PEI70K @Yb-AptEpCAM to impede D-A pairs and reverse multiplexed response signals of the lifetime cascade system. The ratio lifetime signals τm /τn and τm /τµ achieve prominent exosome quantification and exosome type differentiation attributed to signal amplification. The cascade system relying on lifetime criteria can realize precise quantization and provide an effective strategy for subsequent physiological study.

Low frequency/high frequency ratio is a predictor of hospitalization and death in patients on maintenance hemodialysis: A prospective study.

INTRODUCTION: This study aims to evaluate the predictive value of the low frequency/high frequency (LF/HF) ratio in all causes of death and hospitalizations in maintenance hemodialysis (MHD) patients. METHODS: This is a single-center prospective study with a 48-h electrocardiograph (ECG) recording. A total of 110 patients were enrolled in the study from October 1, 2021, to September 30, 2022. ECG recordings started before initiation of the hemodialysis (HD) session and lasted for 48 h, covering the intra- as well as inter- HD period. We divided our participants into two groups based on the median value of LF/HF, one of the frequency domain parameters of heart rate variability (HRV). Patients with LF/HF < 1.33 were categorized as group A and those with LF/HF≥1.33 were group B. The endpoint of the study was a composite event of death or hospitalization. We followed all patients until the composite endpoint or the end of the study on February 28, 2023. Multivariate Cox regression was used to assess the adjusted effect of LF/HF on the composite endpoint. RESULTS: Patients in group A were older and the number of patients with diabetes was more than that of group B. With regards to the laboratory data, group A had lower serum creatinine and uric acid and higher ferritin and NT-ProBNP. In the index hemodialysis session, systolic blood pressure was higher but diastolic blood pressure was significantly lower in group A. During the median follow-up period of 8.8 (7.6-9.8) months, 27 hospitalizations and 10 deaths were documented. Increased LF/HF ratio was an independent protective factor of composite endpoint events (HR = 0.357, 95% CI 0.162-0.790, P = 0.011). CONCLUSION: Risks of mortality and hospitalizations are higher among hemodialysis patients having decreased LF/HF ratios. LF/HF in the 48-h recording can be considered as a prognostic factor for risk stratification in HD patients.

Persistence of antibodies 5 years after hepatitis B vaccination in preterm birth children: A retrospective cohort study using real-world data.

Previous studies did not provide substantial evidence for long-term immune persistence after the hepatitis B vaccine (HepB) in preterm birth (PTB) children. Consequently, there is ongoing controversy surrounding the booster immunization strategy for these children. Therefore, we conducted a retrospective cohort study to evaluate the disparities in immune persistence between PTB children and full-term children. A total of 1027 participants were enrolled in this study, including 505 PTB children in the exposure group and 522 full-term children in the control group. The negative rate of hepatitis B surface antibody (HBsAb) in the PTB group was significantly lower than that in the control group (47.9% vs. 41.4%, p = .035). The risk of HBsAb-negative in the exposure group was 1.5 times higher than that in the control group (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI]: 1.1-2.0). The geometric mean concentration (GMC) of HBsAb was much lower for participants in the exposure group compared to participants in the control group (9.3 vs. 12.4 mIU/mL, p = .029). Subgroup analysis showed that the very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) had relatively low GMC levels of 3.2 mIU/mL (95% CI: 0.9-11.1) and 7.9 mIU/mL (95% CI: 4.2-14.8), respectively. Our findings demonstrated that PTB had a significant impact on the long-term persistence of HBsAb after HepB vaccination. The very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) may be special populations that should be given priority for HepB booster vaccination.

Global research trends in prediabetes over the past decade: Bibliometric and visualized analysis.

OBJECT: This study aimed to investigate global research advances and hot trends in prediabetes in the last decade based on a bibliometric analysis of publications. Publications from 2013 to 2022 were retrieved from the Web of Science Core Collection database through a topic search. With the use of CiteSpace, VOS viewer, and Bibliometrix R software packages, the number of publications, production categories, countries/regions, institutions, authors, journals, references, and keywords were comprehensively analyzed to sort out the hot spots and directions of prediabetes and predict the future research directions. A total of 13,223 papers were recruited for this study by the end of March 3, 2023. A generally increasing trend was observed in the number of annual publications. PLOS ONE (journal), USA (national), and the University of Copenhagen (institutional) published the most papers in this research area. The top 3 contributor authors were Tuomilehto Jaakko, Rathmann Wolfgang, and Peters Annette. "Intestinal microbiota" (2020-2022) was the most populated keyword in terms of intensity, and "biomarkers," "gut microbiota," and "metabolomics" were the most populated keywords in the last 3 years. "Prediabetes: a high-risk state for diabetes development-2012" was the strongest burst reference. This study summarized the research hotspots and trends in prediabetes research in the last decade. Frontier research can be found in the journal Diabetes Care and Journal of Clinical Endocrinology Metabolism. Prediabetes research focuses on preventing risk factors to reduce the prevalence of prediabetes, and current research hotspots focus on gut microbes and metabolism-related biomarkers.

Risk factors associated with depression and anxiety among the Chinese general population after retracting the dynamic zero-COVID policy: A network analysis.

BACKGROUND: Recent studies have evidenced the negative psychological consequences of the COVID-19 pandemic and sociodemographic vulnerability among the general population, while limited information was available on which factors make the greatest contribution to psychological distress when these factors were considered concurrently. Herein, we aimed to investigate the pathways that underlie psychological distress in the context of retracting dynamic zero-COVID policy. METHODS: We employed the mixed graphical model to construct the network of depression (PHQ-9), anxiety (GAD-7), and pandemic-related factors in a general population sample (N = 1610). Then, we re-examined the network by adding sociodemographic variables to further explore the influence of sociodemographic factors. Additionally, we repeated the analyses in the second sample (N = 620) collected in the same period to assess the replicability. RESULTS: The relationships between the pandemic factors and anxiety and depressive symptoms exhibited a tendency to decrease after adding demographic variables, and income became the most important node and shared edge weights with all anxiety and depressive symptoms. These findings were replicable with the second sample. No significant difference in the network properties was detected between the two samples. LIMITATIONS: The cross-sectional design limits the ability to observe longitudinal changes in these risk factors and their relationship with psychological distress. CONCLUSIONS: Income level, rather than the pandemic-related factors, acted as a vital role in the psychological distress of the general population, implying that livelihood issues may be the critical intervention targets for mental health during the post-pandemic period.

Impact of perioperative red blood cell transfusion on the prognosis of patients with epithelial ovarian cancer.

Background: Surgery for advanced ovarian cancer tends to be extensive. We performed an analysis to determine whether perioperative red blood cell transfusion (PRBCT) is associated with a poor prognosis in women with epithelial ovarian cancer (EOC). Methods: Our retrospective analysis included 314 women. The Mann-Whitney rank-sum test and chi-square test were used to analyze the clinical characteristics of the PRBCT and non-PRBCT groups, and Cox proportional hazard models were used for the multivariate analysis. Results: PRBCT was associated with higher relapse and mortality rates in 121 (38.54 %) patients. After multivariate analysis, transfused patients were 1.59 times at risk of death (hazard ratio [HR] = 1.59; 95%CI, 1.12-2.25) and 1.63 times at risk of recurrence (HR = 1.63; 95%CI, 1.22-2.18) than non-transfused patients. Conclusions: PRBCT could prolong hospital stay, and increased hospital costs were significantly associated with increased cancer recurrence and overall mortality in patients with EOC.

The accuracy of Fiber-Optic Raman Spectroscopy in the detection and diagnosis of head and neck neoplasm in vivo: a systematic review and meta-analysis.

Purpose: The aim of this article was to review and collectively assess the published studies of fiber-optic Raman spectroscopy (RS) of the in vivo detection and diagnosis of head and neck carcinomas, and to derive a consensus average of the accuracy, sensitivity and specificity. Methods: The authors searched four databases, including Ovid-Medline, Ovid-Embase, Cochrane Library, and the China National Knowledge Infrastructure (CNKI), up to February 2023 for all published studies that assessed the diagnostic accuracy of fiber-optic RS in the in vivo detection of head and neck carcinomas. Nonqualifying studies were screened out in accordance with the specified exclusion criteria, and relevant information about the diagnostic performance of fiber-optic RS was excluded. Publication bias was estimated by Deeks' funnel plot asymmetry test. A random effects model was adopted to calculate the pooled sensitivity, specificity and diagnostic odds ratio (DOR). Additionally, the authors conducted a summary receiver operating characteristic (SROC) curve analysis and threshold analysis, reporting the area under the curve (AUC) to evaluate the overall performance of fiber-optic RS in vivo. Results: Ten studies (including 16 groups of data) were included in this article, and a total of 5365 in vivo Raman spectra (cancer = 1,746; normal = 3,619) were acquired from 877 patients. The pooled sensitivity and specificity of fiber-optic RS of head and neck carcinomas were 0.88 and 0.94, respectively. SROC curves were generated to estimate the overall diagnostic accuracy, and the AUC was 0.96 (95% CI [0.94-0.97]). No significant publication bias was found in this meta-analysis by Deeks' funnel plot asymmetry test. The heterogeneity of these studies was significant; the Q test values of the sensitivity and specificity were 106.23 (P = 0.00) and 64.21 (P = 0.00), respectively, and the I2 index of the sensitivity and specificity were 85.88 (95% CI [79.99-91.77]) and 76.64 (95% CI [65.45-87.83]), respectively. Conclusion: Fiber-optic RS was demonstrated to be a reliable technique for the in vivo detection of head and neck carcinoma with high accuracy. However, considering the high heterogeneity of these studies, more clinical studies are needed to reduce the heterogeneity, and further confirm the utility of fiber-optic Raman spectroscopy in vivo.

Arginine Biosynthesis Pathway Found to Play a Key Role in the Neuroprotective Effect of Liu-Wei-Luo-Bi (LWLB) Granules in Diabetic db/db Mice with Peripheral Neuropathy Using an Untargeted Metabolomics Strategy.

Aim: Liu-Wei-Luo-Bi (LWLB) granules was a Chinese compound prescription for treating diabetic peripheral neuropathy (DPN). The aim of this study was to investigate the effect of LWLB granules on diabetic mice with peripheral neuropathy and to elucidate the potential mechanism based on an untargeted metabolomics approach. Methods: One hundred forty db/db mice were randomly divided into seven groups: the Control group, DPN group, Mudan (MD) granules group, Epalrestat (Epa) group, and the LWLB low, medium, or high dose (LW-l, LW-m, or LW-h) group. After 12 weeks of treatment, body weight, blood glucose, mechanical pain threshold, motor conduction velocity (MCV), sensory conduction velocity (SCV), and Pathological Organization of the Sciatic and Caudal Nerves in mice were measured. Serum samples were collected for untargeted metabolomics analysis using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and multivariate statistics. Disease-related pathways were screened out with function enrichment analyses of candidate biomarkers. Results: LWLB granules can improve the peripheral neuropathy of type 2 diabetic mice with peripheral nerve conduction disorders, mainly through significantly improving the nerve conduction velocity (P < 0.05) and lowering the mechanical pain threshold (P < 0.05). A total of 43 metabolites were identified as potential biomarkers related to the therapeutic effect of LWLB granules. Fifty, 4, and 26; 23, 4, and 22; and 24, 1, and 16 biomarkers were discovered in the LW-l, LW-m, and LW-h groups at the 4th, 6th, and 12th weeks, respectively. Five, three, seven, five, and four metabolic pathways were found in MD, Epa, LW-l, LW-m, and LW-h groups, respectively. The arginine biosynthesis pathway is the overlapping pathway in LW-l, LW-m, and LW-h groups. Conclusion: LWLB granules have an obvious neuroprotective effect on diabetic peripheral neuropathy, and the metabolism mechanism of LWLB is mainly related to the arginine biosynthesis pathway on diabetic db/db mice with peripheral neuropathy.

Bridge symptoms between parenting styles and proximal psychological risk factors associated with adolescent suicidal thoughts: a network analysis.

BACKGROUND: Parenting styles and the associated proximal psychological factors are suggested to increase suicidal risks in adolescents. However, how the two factors interact and confer risks on the emergence of adolescent suicidal thoughts remains unclear. Herein, we used a network approach to investigate their interrelationship and explore whether the network properties predict adolescent suicidal thoughts. METHODS: Self-report questionnaires were completed by 1171 students aged 12-16. Network analyses were performed by Gaussian graphical models estimating the adolescent psychosocial network structure of parenting styles and psychological variables including depression, anxiety, affective lability, rumination, and resilience. Furthermore, we re-examined the network by adding a variable measuring active suicidal thoughts. Moreover, we conducted linear regressions to examine the predictive utility of bridge symptoms for adolescent suicidal thoughts. RESULTS: Resilience, Afraid, Rumination, Concentration, and affective lability (Anger) had the highest bridge strengths in the adolescent psychosocial network. Among the identified bridge symptoms, Resilience was negatively correlated with active suicidal thoughts (regularized edge weights = -0.181, bootstrapped 95% CIs: [-0.043, -0.155]), whereas affective lability (from Anxiety to Depression, Anger), Rumination, and Afraid were positively correlated with active suicidal thoughts, with edge weights (bootstrapped 95% CIs) ranging from 0.057 (0.001, 0.112) to 0.081(0.026, 0.136). Regression analysis showed that bridge strength was significantly correlated with active suicidal thoughts (R2 = 0.432, P = 0.001). CONCLUSION: Negative parenting styles may drive and maintain suicidal thoughts by modifying the key proximal psychological variables. Our findings highlight the important role of bridge symptoms, which may serve as vital targets for triggering adolescent suicide.

Effect of cell settlement on the electrochemical collision behaviors of single microbes.

Electrochemical collision technique has emerged as a powerful approach to detect the intrinsic properties of single entities. The diffusion model, together with migration and convection processes are generally used to describe the transport and collision processes of single entities. However, things become more complicated concerning microbes because of their relatively large size, inherent motility and biological activities. In this work, the electrochemical collision behaviors of four different microorganisms: Escherichia coli (Gram-negative bacteria), Staphylococcus aureus, Bacillus subtilis (Gram-positive bacteria) and Saccharomyces cerevisiae (fungus) were systematically detected and compared using a blocking strategy. By using K4Fe(CN)6 as redox probe, the downwards step-like signals were recorded in the collision process of all the three bacteria, whereas the collision of S. cerevisiae was rarely detected. To further investigate the underlying reason for the abnormal collision behavior of S. cerevisiae, the effect of cell settlement was discussed. The results indicated that ellipsoidal S. cerevisiae with a cell size larger than 2 µm exhibited a cell sedimentation rate of 261.759 nm s-1, which is dozens of times higher than the other three bacteria. By further enhanced convection near the microelectrode or positioned the microelectrode at the bottom of electrochemical cell, the collision signals of S. cerevisiae were successfully detected, indicating cell sedimentation is a nonnegligible force in large cell transport. This study fully addressed the effect of cell settlement on the transport of microbial cells and provided two strategies to counteract this effect, which benefit for the deeper understanding and further application of electrochemical collision technique in single-cell detection.

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.

OBJECTIVE: Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc- , a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC). METHODS: qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+ /NADPH dynamics were measured using a NADP+ /NADPH kit. RESULTS: In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis. CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.

Inhibitory effect of daidzein on the calcium-activated chloride channel TMEM16A and its anti-lung adenocarcinoma activity.

TMEM16A is highly expressed in a variety of tumor cells and is involved in the growth and metastasis of malignancies. It has been established that down-regulation of TMEM16A expression or functional activity can inhibit tumor cells growth. However, there is a lack of targeted inhibitors with high efficiency and low toxicity. Here, we identified a novel inhibitor daidzein from dozens of natural product molecules. Whole-cell patch clamp data indicated that daidzein inhibits TMEM16A channel in a dose-dependent manner, with IC50 of 1.39 ± 0.59 µM. Western blot result showed that daidzein can also reduce the expression of TMEM16A protein in LA795 cells. These results indicated that the inhibitory effects of daidzein exert on TMEM16A in two ways, both inhibiting TMEM16A current and decreasing its protein expression. In addition, the putative binding sites of daidzein on TMEM16A are G608, G628, and K839 through molecular docking. Moreover, daidzein concentration-dependently reduced cell viability and cell migration, causing G1/S cell cycle arrest in vitro. It was also confirmed that daidzein can effectively inhibit the growth of LA795 lung adenocarcinoma cells implanted nude mice in vivo. In conclusion, daidzein can be used as a lead compound for the development of therapeutic drugs for lung adenocarcinoma.