Investigation of multiple nosocomial infections using a semi-Markov multi-state model.

BACKGROUND: The prevalence of multiple nosocomial infections (MNIs) is on the rise, however, there remains a limited comprehension regarding the associated risk factors, cumulative risk, probability of occurrence, and impact on length of stay (LOS). METHOD: This multicenter study includes all hospitalized patients from 2020 to July 2023 in two sub-hospitals of a tertiary hospital in Guangming District, Shenzhen. The semi-Markov multi-state model (MSM) was utilized to analyze risk factors and cumulative risk of MNI, predict its occurrence probability, and calculate the extra LOS of nosocomial infection (NI). RESULTS: The risk factors for MNI include age, community infection at admission, surgery, and combined use of antibiotics. However, the cumulative risk of MNI is lower than that of single nosocomial infection (SNI). MNI is most likely to occur within 14 days after admission. Additionally, SNI prolongs LOS by an average of 7.48 days (95% Confidence Interval, CI: 6.06-8.68 days), while MNI prolongs LOS by an average of 15.94 days (95% CI: 14.03-18.17 days). Furthermore, the more sites of infection there are, the longer the extra LOS will be. CONCLUSION: The longer LOS and increased treatment difficulty of MNI result in a heavier disease burden for patients, necessitating targeted prevention and control measures.

Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice.

Enteroendocrine cells (EECs) and vagal afferent neurons constitute functional sensory units of the gut, which have been implicated in bottom-up modulation of brain functions. Sodium oligomannate (GV-971) has been shown to improve cognitive functions in murine models of Alzheimer's disease (AD) and recently approved for the treatment of AD patients in China. In this study, we explored whether activation of the EECs-vagal afferent pathways was involved in the therapeutic effects of GV-971. We found that an enteroendocrine cell line RIN-14B displayed spontaneous calcium oscillations due to TRPA1-mediated calcium entry; perfusion of GV-971 (50, 100 mg/L) concentration-dependently enhanced the calcium oscillations in EECs. In ex vivo murine jejunum preparation, intraluminal infusion of GV-971 (500 mg/L) significantly increased the spontaneous and distension-induced discharge rate of the vagal afferent nerves. In wild-type mice, administration of GV-971 (100 mg· kg-1 ·d-1, i.g. for 7 days) significantly elevated serum serotonin and CCK levels and increased jejunal afferent nerve activity. In 7-month-old APP/PS1 mice, administration of GV-971 for 12 weeks significantly increased jejunal afferent nerve activity and improved the cognitive deficits in behavioral tests. Sweet taste receptor inhibitor Lactisole (0.5 mM) and the TRPA1 channel blocker HC-030031 (10 µM) negated the effects of GV-971 on calcium oscillations in RIN-14B cells as well as on jejunal afferent nerve activity. In APP/PS1 mice, co-administration of Lactisole (30 mg ·kg-1 ·d-1, i.g. for 12 weeks) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors. We conclude that GV-971 activates sweet taste receptors and TRPA1, either directly or indirectly, to enhance calcium entry in enteroendocrine cells, resulting in increased CCK and 5-HT release and consequent increase of vagal afferent activity. GV-971 might activate the EECs-vagal afferent pathways to modulate cognitive functions.

Zr modulated N doping composites for CO2 conversion into carbonates.

Acidic and basic sites of catalysts are essential for CO2 capture and activation. In this work, Zr, N-ZnO/ZnAl-LDH-IL composites in ionic liquid and methanol systems were fabricated, and applied to catalyze the synthesis of ethylene carbonate (EC) from ethylene glycol (EG) and CO2 with about 4.76 mmolEC gCat.-1 h-1. The composites showed more strong basic sites due to the effective induction of reactive groups on the catalyst surface by Zr doping, resulting in an increase of pyridinic-N groups from 5.48% to 22.25%. More C atoms adjacent to pyridinic-N as strong basic sites was conducive to the activation of CO2 and EG. In addition, the possible catalytic pathway and mechanism of the composites for synthesizing EC as well as the doping of La, Fe, Ce, and Cu were also investigated, which provides an effective strategy for regulating the acid-base centers on the catalyst surface through ionic liquids and methanol solvents.

Deep learning system for screening AIDS-related cytomegalovirus retinitis with ultra-wide-field fundus images.

Background: Ophthalmological screening for cytomegalovirus retinitis (CMVR) for HIV/AIDS patients is important to prevent lifelong blindness. Previous studies have shown good properties of automated CMVR screening using digital fundus images. However, the application of a deep learning (DL) system to CMVR with ultra-wide-field (UWF) fundus images has not been studied, and the feasibility and efficiency of this method are uncertain. Methods: In this study, we developed, internally validated, externally validated, and prospectively validated a DL system to detect AIDS-related from UWF fundus images from different clinical datasets. We independently used the InceptionResnetV2 network to develop and internally validate a DL system for identifying active CMVR, inactive CMVR, and non-CMVR in 6960 UWF fundus images from 862 AIDS patients and validated the system in a prospective and an external validation data set using the area under the curve (AUC), accuracy, sensitivity, and specificity. A heat map identified the most important area (lesions) used by the DL system for differentiating CMVR. Results: The DL system showed AUCs of 0.945 (95 % confidence interval [CI]: 0.929, 0.962), 0.964 (95 % CI: 0.870, 0.999) and 0.968 (95 % CI: 0.860, 1.000) for detecting active CMVR from non-CMVR and 0.923 (95 % CI: 0.908, 0.938), 0.902 (0.857, 0.948) and 0.884 (0.851, 0.917) for detecting active CMVR from non-CMVR in the internal cross-validation, external validation, and prospective validation, respectively. Deep learning performed promisingly in screening CMVR. It also showed the ability to differentiate active CMVR from non-CMVR and inactive CMVR as well as to identify active CMVR and inactive CMVR from non-CMVR (all AUCs in the three independent data sets >0.900). The heat maps successfully highlighted lesion locations. Conclusions: Our UWF fundus image-based DL system showed reliable performance for screening AIDS-related CMVR showing its potential for screening CMVR in HIV/AIDS patients, especially in the absence of ophthalmic resources.

High-fidelity single logical qubit encoding scheme assisted by single-sided quantum dot-cavity systems.

We present an encoding scheme of a single logical qubit with single-sided quantum dot (QD)-cavity systems, which is immune to the collective decoherence. By adjusting the Purcell factor to satisfy the balanced reflection condition, the detrimental effects of unbalanced reflection between the coupled and uncoupled QD-cavity systems can be effectively suppressed. Furthermore, the fidelity of each step can be increased to unity regardless of the strong coupling regime and the weak coupling regime of cavity quantum electrodynamics (QED) with the assistance of waveform correctors. The scheme requires QD-cavity systems and simple linear optical elements, which can be implemented with the currently experimental techniques.

Magnesium implantation as a continuous hydrogen production generator for the treatment of myocardial infarction in rats.

Molecular hydrogen is an emerging broad-spectrum antioxidant molecule that can be used to treat myocardial infarction (MI). However, with hydrogen inhalation, the concentration that can be reached within target organs is low and the duration of action is short, which makes it difficult to achieve high dose targeted delivery of hydrogen to the heart, seriously limiting the therapeutic potential of hydrogen for MI. As a result of reactions with the internal environment of the body, subcutaneous implantation of magnesium slices leads to continuous endogenous hydrogen production, leading to a higher hydrogen concentration and a longer duration of action in target organs. In this study, we propose magnesium implant-based hydrogen therapy for MI. After subcutaneous implantation of magnesium slices in the dorsum of rats, we measured hydrogen production and efficiency, and evaluated the safety of this approach. Compared with hydrogen inhalation, it significantly improved cardiac function in rats with MI. Magnesium implantation also cleared free radicals that were released as a result of mitochondrial dysfunction, as well as suppressing cardiomyocyte apoptosis.

Effect of heart rate on poor outcome in stroke patients treated with intra-arterial thrombectomy.

BACKGROUND AND PURPOSE: The relationship between heart rate and the prognosis of patients with large vessel occlusion strokes treated with mechanical thrombectomy (MT) is not well established. This study aimed to evaluate the association of mean heart rate and heart rate variability (HRV) with the clinical outcomes after MT therapy. METHODS: Acute ischemic stroke patients undergoing MT therapy were prospectively recruited from March 2020 to November 2022. Their heart rate was collected every hour for the initial 72 h after MT procedure, and the variability of heart rate was measured by standard deviation (SD) and coefficient of variation (CV). All-cause mortality and worsening of functional outcome (change in modified Rankin Scale (mRS) score) at 3-month were captured. Binary logistic regression was used to evaluate the association between heart rate indicators and all-cause mortality. Ordinal logistic regression was used to evaluate the association between heart rate indicators and worsening of functional outcome. RESULTS: Among 191 MT-treated patients, 51(26.7%) patients died at 3-month after stroke. Increased mean heart rate per 10-bpm, heart rate SD and CV per 5-unit were all associated with the increased risk of mortality (adjusted hazard ratio [aHR] with 95% CI: 1.29 [1.09-1.51], 1.19 [1.07-1.32], 1.14 [1.03-1.27]; respectively). Patients in the highest tertile of heart rate SD had an increased risk of mortality (4.62, 1.70-12.52). After using mRS as a continuous variable, we found increased mean heart rate per 10-bpm, heart rate SD and CV per 5-unit were associated with the worsening of functional outcome (adjusted odds ratio [aOR] with 95% CI: 1.35 [1.11-1.64], 1.27 [1.05-1.53], 1.19 [1.02-1.40]; respectively). A linear relationship was observed between mean heart rate or heart rate SD and mortality; while all of the heart rate measures in this study showed a linear relationship with the worsening of functional outcome. CONCLUSIONS: Higher mean heart rate and HRV were associated with the increased risk of 3-month all-cause mortality and worse functional outcome after MT therapy for AIS patients.

Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines. METHODS: Murine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1-/- KPC (LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry. RESULTS: Double knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function. CONCLUSION: Our results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response.

Longitudinal Relationship between L2 Grit and Motivational Regulation Strategy in University Second Language Learning: An Autoregressive Cross-lagged Model Study.

Despite the significance of grit and motivational regulation strategies (MRS) to language learning, limited research has been conducted on their longitudinal interplay. The present study explores the relationship between these two constructs in an English as a second language (L2) learning context through a longitudinal design. This study utilizes repeated measures of L2 grit and MRS at two time points (T1 and T2) to investigate the direction of influence between them and proposes and evaluates four models: an autoregressive model, two unidirectional models, and a bidirectional model. Using questionnaire data from 205 Chinese university students to evaluate the models, results from model assessment revealed that L2 grit at T1 positively predicted L2 grit at T2 and that MRS at T1 positively predicted MRS at T2. While L2 grit showed stability, MRS developed over time. The unidirectional model with L2 grit at T1 as a predictor of MRS at T2 was identified as the model of best fit, indicating that L2 grit at an earlier time unidirectionally influenced MRS at a later time. Based on these findings, we conclude that there is a unidirectional influence between L2 grit and MRS: the former plays an influential role in shaping MRS in L2 learning over time. Implications and recommendations for future research are discussed. This study contributes to a deeper understanding of the dynamics between the two constructs, which in turn impacts language learning persistence and success, offering valuable insights for educators, policymakers, and researchers striving to optimize language learning environments and interventions.

Effect of Jianpi Shengxue Tablet on Iron Metabolism and Nutritional Status in Patients with Renal Anemia: A Prospective, Randomized, Open, Parallel Controlled and Multicenter Clinical Study.

OBJECTIVE: This study aimed to analyze the clinical efficacy of the Jianpi Shengxue tablet for treating renal anemia. METHODS: A total of 200 patients with renal anemia from December 2020 to December 2022 were enrolled and randomly divided into two groups. Patients in the control group were treated with polysaccharide-iron complex, and those in the experimental group were administered Jianpi Shengxue tablet. After 8 weeks of continuous treatment, the therapeutic outcomes regarding anemia were compared between the two groups. RESULTS: After treatment, the red blood cell (RBC) count, hematocrit (HCT), reticulocyte percentage (RET), ferritin (SF), serum iron (SI), transferrin saturation (TSAT), and serum albumin (ALB) all increased (P<0.01), and the clinical symptom score and total iron binding capacity decreased (P<0.01) in the experimental group. Moreover, the improvements in RBC, HCT, RET, SF, SI, TAST, ALB, and clinical symptoms (fatigue, anorexia, dull skin complexion, numbness of hands and feet) in the experimental group were significantly greater than those in the control group (P<0.05). The total effective rate for treating renal anemia was significantly higher in the experimental group than in the control group (P<0.01). CONCLUSION: The Jianpi Shengxue tablet demonstrates efficacy in treating renal anemia, leading to significant improvements in the laboratory examination results and clinical symptoms of patients with renal anemia.

Coronary Calcium Is Elevated in Patients with Myocardial Infarction without Standard Modifiable Risk Factors.

Objectives: Recent reports have highlighted myocardial infarction (MI) patients without standard modifiable risk factors (SMRF), noting them to be surprisingly common and to have a substantial risk of adverse outcomes. The objective of this study was to address the challenge of identifying at-risk patients without SMRF and providing preventive therapy. Methods: Patients presenting between 2001 and 2021 to Intermountain Health catheterization laboratories with a diagnosis of MI were included if they also had a coronary artery calcium (CAC) scan by computed tomography within 2 years. SMRF were defined as a clinical diagnosis or treatment of hypertension, hyperlipidemia, diabetes, or smoking. The co-primary endpoints in SMRF-less patients were: (1) proportion of patients with an elevated (>50%ile) CAC score, and (2) an indication for statin therapy (i.e., CAC ≥ 100 AU or ≥75%ile). The 60-day and long-term major adverse cardiovascular events were determined. A comparison set included MI patients with SMRF. Results: We identified 429 MI patients with a concurrent CAC scan, of which 60 had no SMRF. SMRF status did not distinguish most risk factors or interventions. No-SMRF patients had a high CAC prevalence and percentile (82% ≥ 50%ile; median, 80%ile), and 77% met criteria for preventive therapy. As expected, patients with SMRF had high CAC scores and percentiles. Outcomes were more favorable for No-SMRF status and for lower CAC scores. Conclusions: Patients without SMRF presenting with an MI have a high prevalence and percentile of CAC. Wider application of CAC scans, including in those without SMRF, is promising as a method to identify an additional at-risk population for MI and to provide primary preventive therapy.

Dietary cholesterol intervention could alleviate the intestinal injury of Oreochromis niloticus induced by plant-based diet via the intestinal barriers.

This study aims to explore the effects of supplementing cholesterol in plant-based feed on intestinal barriers (including physical barrier, chemical barrier, immune barrier, biological barrier) of GIFT strain tilapia (Oreochromis niloticus). Four isonitrogenous and isolipidic diets were prepared as follows: plant-based protein diet (Con group) containing corn protein powder, soybean meal, cottonseed meal, and rapeseed meal, with the addition of cholesterol at a level of 0.6 % (C0.6 % group), 1.2 % (C1.2 % group), and 1.8 % (C1.8 % group), respectively. A total of 360 fish (mean initial weight of (6.08 ± 0.12) g) were divided into 12 tanks with 30 fish per tank, each treatment was set with three tanks and the feeding period lasted 9 weeks. Histological analysis revealed that both the C0.6 % and C1.2 % groups exhibited a more organized intestinal structure, with significantly increased muscle layer thickness compared to the Con group (P < 0.05). Furthermore, in the C1.2 % group, there was a significant up-regulation of tight junction-related genes (claudin-14, occludin, zo-1) compared to the Con group (P < 0.05). 5-ethynyl-2'-deoxyuridine staining results also demonstrated a notable enhancement in intestinal cell proliferation within the C1.2 % group (P < 0.05). Regarding the intestinal chemical barrier, trypsin and lipase activities were significantly elevated in the C1.2 % group (P < 0.05), while hepcidin gene expression was considerably down-regulated in this group but up-regulated in the C1.8 % group (P < 0.05). In terms of the intestinal immune barrier, inflammation-related gene expression levels (tnf-α, il-1ß, caspase 9, ire1, perk, atf6) were markedly reduced in the C1.2 % group (P < 0.05). Regarding the intestinal biological barrier, the composition of the intestinal microbiota indicated that compared to the Con group, both the 0.6 % and 1.2 % groups showed a significant increase in Shannon index (P < 0.05). Additionally, there was a significant increase in the abundance of Firmicutes and Clostridium in the C1.2 % group (P < 0.05). In summary, supplementation of 1.2 % cholesterol in the plant-based diet exhibits the potential to enhance intestinal tight junction function and improve the composition of intestinal microbiota, thereby significantly promoting tilapia's intestinal health.

Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney, and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways.

BACKGROUND: Jianpi Gushen Huayu Decoction (JPGS) has been used to clinically treat diabetic nephropathy (DN) for many years. However, the protective mechanism of JPGS in treating DN remains unclear. AIM: To evaluate the therapeutic effects and the possible mechanism of JPGS on DN. METHODS: We first evaluated the therapeutic potential of JPGS on a DN mouse model. We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics. Furthermore, we examined the effects of JPGS on c-Jun N-terminal kinase (JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3). RESULTS: The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress. Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice. A total of 51 differential metabolites were screened. Pathway analysis results indicated that nine pathways significantly changed between the control and model groups, while six pathways significantly altered between the model and JPGS groups. Pathways related to cysteine and methionine metabolism; alanine, tryptophan metabolism; aspartate and glutamate metabolism; and riboflavin metabolism were identified as the key pathways through which JPGS affects DN. Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors. CONCLUSION: JPGS could markedly treat mice with streptozotocin (STZ)-induced DN, which is possibly related to the regulation of several metabolic pathways found in kidneys. Furthermore, JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathway-mediated apoptosis in DN mice.

Efficacy and safety of precision-guided transjugular extrahepatic portosystemic shunt (TEPS) in the management of cavernous transformation of the portal vein with portal hypertension: a case series.

BACKGROUND AND AIMS: Performing a Transjugular intrahepatic portal system shunt (TIPS) in patients with portal vein cavernous transformation (CTPV) poses significant challenges. As an alternative, transjugular extrahepatic portal vein shunt (TEPS) may offer a potential solution for these patients. Nonetheless, the effectiveness and safety of TEPS remain uncertain. This case series study aimed to evaluate the efficacy and safety of TEPS in treating patients with CTPV portal hypertension complications. METHODS: The study encompassed a cohort of 22 patients diagnosed with CTPV who underwent TEPS procedures. Of these, 13 patients manifested recurrent hemorrhagic episodes subsequent to conventional therapies, 8 patients grappled with recurrent or refractory ascites, and 1 patient experienced acute bleeding but refused endoscopic treatment. Comprehensive postoperative monitoring was conducted for all patients to rigorously evaluate both the technical and clinical efficacy of the intervention, as well as long-term outcomes. RESULTS: The overall procedural success rate among the 22 patients was 95.5% (21/22).During the TEPS procedure, nine patients were guided by percutaneous splenic access, three patients were guided by percutaneous hepatic access, five patients were guided by transmesenteric vein access from the abdomen, and two patients were guided by catheter marking from the hepatic artery. Additionally, guidance for three patients was facilitated by pre-existing TIPS stents. The postoperative portal pressure gradient following TEPS demonstrated a statistically significant decrease compared to preoperative values (24.95 ± 3.19 mmHg vs. 11.48 ± 1.74 mmHg, p < 0.01).Although three patients encountered perioperative complications, their conditions ameliorated following symptomatic treatment, and no procedure-related fatalities occurred. During a median follow-up period of 14 months, spanning a range of 5 to 39 months, we observed four fatalities. Specifically, one death was attributed to hepatocellular carcinoma, while the remaining three were ascribed to chronic liver failure. During the follow-up period, no instances of shunt dysfunction were observed. CONCLUSIONS: Precision-guided TEPS appears to be a safe and efficacious intervention for the management of CTPV.

G6PD maintains the VSMC synthetic phenotype and accelerates vascular neointimal hyperplasia by inhibiting the VDAC1-Bax-mediated mitochondrial apoptosis pathway.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in vascular smooth muscle cell (VSMC) phenotypic switching, which is an early pathogenic event in various vascular remodeling diseases (VRDs). However, the underlying mechanism is not fully understood. METHODS: An IP‒LC‒MS/MS assay was conducted to identify new binding partners of G6PD involved in the regulation of VSMC phenotypic switching under platelet-derived growth factor-BB (PDGF-BB) stimulation. Co-IP, GST pull-down, and immunofluorescence colocalization were employed to clarify the interaction between G6PD and voltage-dependent anion-selective channel protein 1 (VDAC1). The molecular mechanisms involved were elucidated by examining the interaction between VDAC1 and apoptosis-related biomarkers, as well as the oligomerization state of VDAC1. RESULTS: The G6PD level was significantly elevated and positively correlated with the synthetic characteristics of VSMCs induced by PDGF-BB. We identified VDAC1 as a novel G6PD-interacting molecule essential for apoptosis. Specifically, the G6PD-NTD region was found to predominantly contribute to this interaction. G6PD promotes VSMC survival and accelerates vascular neointimal hyperplasia by inhibiting VSMC apoptosis. Mechanistically, G6PD interacts with VDAC1 upon stimulation with PDGF-BB. By competing with Bax for VDAC1 binding, G6PD reduces VDAC1 oligomerization and counteracts VDAC1-Bax-mediated apoptosis, thereby accelerating neointimal hyperplasia. CONCLUSION: Our study showed that the G6PD-VDAC1-Bax axis is a vital switch in VSMC apoptosis and is essential for VSMC phenotypic switching and neointimal hyperplasia, providing mechanistic insight into early VRDs.

The comorbid network characteristics of anxiety and depressive symptoms among Chinese college freshmen.

BACKGROUND: This study aimed to investigate the interplay between anxiety and depressive symptoms in Chinese college freshmen using the causal system perspective (CSP), which differs from the traditional common cause perspective (CCP) by providing an alternative explanation by attributing comorbidity to direct interactions among symptoms. METHODS: A convenience sample of 2,082 Chinese college freshmen (39.51% male, Mage = 18.61) from a normal university completed the Generalized Anxiety Disorder 7-Item Scale (GAD-7) and the Patient Health Questionnaire (PHQ-9). Network analysis was conducted and evaluated as to centrality, stability, node predictability, and bridging features. Moreover, the moderated network model (MNM) was utilized to detect the moderation effects of gender in the comorbidity network. RESULTS: The network of anxiety and depressive symptoms exhibited stability, characterized by the core symptoms of "restlessness", "lack of energy", and "excessive worry about control", as well as the bridging symptoms of "fearfulness", "sad mood", and "irritability". Notably, the nodes representing "uncontrollable worry" and "difficulty in relaxation" demonstrated the highest predictive power. Gender did not exert any moderating effects on the anxiety and depressive symptom network. CONCLUSION: These results reinforce that certain anxiety or depressive symptoms are more central than others, and thus play a more vital role in the comorbid network. These findings highlight underlying potential targeting symptoms to consider in future interventions.

Stem moisture content prediction model for Larix olgensis based on beta regression.

To investigate the longitudinal variation patterns of sapwood, heartwood, bark and stem moisture content along the trunk of artificial Larix olgensis, we constructed mixed effect models of moisture content based on beta regression by combining the effects of sampling plot and sample trees. We used two sampling schemes to calibrate the model, without limiting the relative height (Scheme Ⅰ) and with a limiting height of less than 2 m (Scheme II). The results showed that sapwood and stem moisture content increased gradually along the trunk, heartwood moisture content decreased slightly and then increased along the trunk, and bark moisture content increased along the trunk and then levelled off before increasing. Relative height, height to crown base, stand area at breast height per hectare, age, and stand dominant height were main factors driving moisture content of L. olgensis. Scheme Ⅰ showed the stable prediction accuracy when randomly sampling moisture content measurements from 2-3 discs to calibrate the model, with the mean absolute percentage error (MAPE) of up to 7.2% for stem moisture content (randomly selected 2 discs), and the MAPE of up to 7.4%, 10.5% and 10.5% for sapwood, heartwood and bark moisture content (randomly selected 3 discs), respectively. Scheme Ⅱ was appropriate when sampling moisture content measurements from discs of 1.3 and 2 m height and the MAPE of sapwood, heartwood, bark and stem moisture content reached 7.8%, 11.0%, 10.4% and 7.1%, respectively. The prediction accuracies of all mixed effect beta regression models were better than the base model. The two-level mixed effect beta regression models, considering both plot effect and tree effect, would be suitable for predicting moisture content of each part of L. olgensis well.

Classification of nomophobia among Chinese college students: Evidence from latent profile and ROC analysis.

Background and aims: Nomophobia (NMP) is a contemporary digital ailment referring to the improper utilization of smartphones which can have significant impacts on the physical and mental health of college students. However, as a result of unclear cutoff points, the proportion of people with NMP may be exaggerated. This study therefore aimed to determine the critical value of NMP and assess the extent to which Chinese college students are impacted by NMP using the Nomophobia Questionnaire (NMP-Q). Methods: Latent profile analysis (LPA) and the receiver operating characteristic curve (ROC) were combined to determine the critical value based on NMP-Q scores using a large sample of 3,998 college students (Mage = 20.58; SD = 1.87). Results: Based on latent profile (i.e., at-risk NMP group), ROC revealed an optimal cut-off point of 73 (Sensitivity = 0.965, Specificity = 0.970, Accuracy = 0.968, AUC = 99.60%, Youden's index = 0.935), and the percentage of NMP students being 28.04%, with 1,121 participants identified as positive cases (probable cases). Positive cases were found to exhibit more severe depression and anxiety symptoms, with a higher proportion of females were observed in the positive group (N = 829; 73.95%). Conclusions: These findings provide evidence that the proportion of NMP individuals may have been overestimated in the past. Furthermore, this study helps to validate the NMP-Q as a valid tool to identify NMP in college-aged individuals.

Phloretic acid requires the insulin/IGF-1 pathway and autophagy to enhance stress resistance and extend the lifespan of Caenorhabditis elegans.

Objective: In humans, aging is associated with increased susceptibility to most age-related diseases. Phloretic acid (PA), a naturally occurring compound found in Ginkgo biloba and Asparagus, exhibits has potential as an anti-aging agent and possesses antioxidant, anti-inflammatory, and immunomodulatory properties. This study aimed to investigate the effects of PA on longevity and stress resistance in Caenorhabditis elegans (C.elegans) and the mechanisms that underlie its effects. Methods: First, we examined the effects of PA on lifespan and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, we examined the insulin/insulin-like pathway, mitochondria, autophagy-related proteins, and gene expression to explain the possible mechanism of PA prolonging lifespan. Results: Our findings demonstrated that PA dose-dependently extended the C.elegans lifespan, with 200 µM PA showing the greatest effect and increased the C.elegans lifespan by approximately 16.7%. PA enhanced motility and the pharyngeal pumping rate in senescent C.elegans while reducing the accumulation of aging pigments. Further investigations revealed that daf-16, skn-1, and hsf-1 were required for mediating the lifespan extension effect of PA in C.elegans since its impact was suppressed in mutant strains lacking these genes. This suggests that PA activates these genes, leading to the upregulation of downstream genes involved in stress response and senescence regulation pathways. Furthermore, PA did not extend the lifespan of the RNAi atg-18 and RNAi bec-1 but it attenuated SQST-1 accumulation, augmented autophagosome expression, upregulated autophagy-related gene expression, and downregulated S6K protein levels. These findings suggest that the potential life-extending effect of PA also involves the modulation of the autophagy pathway. Conclusion: These findings results highlight the promising anti-aging effects of PA and warrant further investigation into its pharmacological mechanism and medicinal development prospects.