Micro-/nano-plastics as vectors of heavy metals and stress response of ciliates using transcriptomic and metabolomic analyses.

The escalating presence of microplastics and heavy metals in marine environments significantly jeopardizes ecological stability and human health. Despite this, research on the combined effects of microplastics/nanoplastics (MPs/NPs) and heavy metals on marine organisms remains limited. This study evaluated the impact of two sizes of polystyrene beads (approximately 2 µm and 200 nm) combined with cadmium (Cd) on the ciliate species Euplotes vannus. Results demonstrated that co-exposure of MPs/NPs and Cd markedly elevated reactive oxygen species (ROS) levels in ciliates while impairing antioxidant enzyme activities, thus enhancing oxidative damage and significantly reducing carbon biomass in ciliates. Transcriptomic profiling indicated that co-exposure of MPs/NPs and Cd potentially caused severe DNA damage and protein oxidation, as evidenced by numerous differentially expressed genes (DEGs) associated with mismatch repair, DNA replication, and proteasome function. Integrated transcriptomic and metabolomic analysis revealed that DEGs and differentially accumulated metabolites (DAMs) were significantly enriched in the TCA cycle, glycolysis, tryptophan metabolism, and glutathione metabolism. This suggests that co-exposure of MPs/NPs and Cd may reduce ciliate abundance and carbon biomass by inhibiting energy metabolism and antioxidant pathways. Additionally, compared to MPs, the co-exposure of NPs and Cd exhibited more severe negative effects due to the larger specific surface area of NPs, which can carry more Cd. These findings provide novel insights into the toxic effects of MPs/NPs and heavy metals on protozoan ciliates, offering foundational data for assessing the ecological risks of heavy metals exacerbated by MPs/NPs.

Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration.

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Real-time continuous glucose monitoring-guided glucose management in inpatients with diabetes receiving short-term continuous subcutaneous insulin infusion: a randomized clinical trial.

Background: The use of real-time continuous glucose monitoring (rtCGM) technology remains largely investigational in the hospital setting. The current study aimed to evaluate the effectiveness of rtCGM in inpatients with diabetes who were treated with short-term continuous subcutaneous insulin infusion (CSII). Methods: In this randomized, parallel controlled trial conducted on the endocrinology wards in a tertiary hospital located in Shanghai, adults with type 1 and type 2 diabetes who required short-term CSII during hospitalization were randomly assigned (1:1) to receive either rtCGM-based glucose monitoring and management program or point-of-care (POC) standard of care (8 times/day) with blinded CGM. Primary outcome measure was the difference in the percentage of time within the target glucose range of 3.9-10 mmol/L (TIR, %). This study was registered at www.chictr.org.cn (ChiCTR2300068933). Findings: Among the 475 randomized participants (237 in the rtCGM group and 238 in the POC group), the mean age of was 60 ± 13 years, and the mean baseline glycated hemoglobin level was 9.4 ± 1.8%. The CGM-recorded mean TIR was 71.1 ± 15.8% in the rtCGM group and 62.9 ± 18.9% in the POC group, with a mean difference of 8.2% (95% confidence interval [CI]: 5.1-11.4%, P < 0.001). The mean time above range >10 mmol/L was significantly lower in the rtCGM group than in the POC group (28.3 ± 15.8% vs. 36.6 ± 19.0%, P < 0.001), whereas there was no significant between-group difference in the time below range <3.9 mmol/L (P = 0.11). Moreover, the time to reach target glucose was significantly shorter in the rtCGM group than in the POC group (2.0 [1.0-4.0] days vs. 4.0 [2.0-5.0] days, P < 0.001). There were no serious adverse events in both groups. Interpretation: In patients with diabetes who received short-term CSII during hospitalization, the rtCGM program resulted in better glucose control than the POC standard of care, without increasing the risk of hypoglycemia. Funding: The Program of Shanghai Academic Research Leader (22XD1402300), Shanghai Oriental Talent Program (Youth Project) (No. NA), the Shanghai "Rising Stars of Medical Talent" Youth Development Program-Outstanding Youth Medical Talents (SHWSRS(2021)_099), and the Shanghai Research Center for Endocrine and Metabolic Diseases (2022ZZ01002).

Sequential delivery of photosensitizers and checkpoint inhibitors by engineered bacteria for enhanced cancer photodynamic immunotherapy.

Engineered bacteria-based cancer therapy has increasingly been considered to be a promising therapeutic strategy due to the development of synthetic biology. Wherein, engineering bacteria-mediated photodynamic therapy (PDT)-immunotherapy shows greater advantages and potential in treatment efficiency than monotherapy. However, the unsustainable regeneration of photosensitizers (PSs) and weak immune responses limit the therapeutic efficiency. Herein, we developed an engineered bacteria-based delivery system for sequential delivery of PSs and checkpoint inhibitors in cancer PDT-immunotherapy. The biosynthetic pathway of 5-aminolevulinic acid (5-ALA) was introduced into Escherichia coli, yielding a supernatant concentration of 172.19 mg/L after 10 h of growth. And another strain was endowed with the light-controllable releasement of anti-programmed cell death-ligand 1 nanobodies (anti-PD-L1). This system exhibited a collaborative effect, where PDT initiated tumor cell death and the released tumor cell fragments stimulated immunity, followed by the elimination of residual tumor cells. The tumor inhibition rate reached 74.97%, and the portion of activated T cells and inflammatory cytokines were reinforced. The results demonstrated that the engineered bacteria-based collaborative system could sequentially deliver therapeutic substance and checkpoint inhibitors, and achieve good therapeutic therapy. This paper will provide a new perspective for the cancer PDT-immunotherapy.

Prognostic Value of the Advanced Lung Cancer Inflammation Index Ratio in Patients with Acute Myocardial Infarction Complicated by Cardiogenic Shock: A Cohort Study.

Background: Acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) carries a high mortality risk. Inflammation and nutrition are involved in the pathogenesis and prognosis of both AMI and CS. The advanced lung cancer inflammation index ratio (ALI) combines the inflammatory and nutritional status. Our present study aimed to explore the prognostic value of ALI in patients with CS following AMI. Methods: In total, 217 consecutive patients with AMI complicated by CS were divided into two groups based on the ALI admissions cut-off: ≤ 12.69 and > 12.69. The primary endpoint of this study was 30-day all-cause mortality. The secondary endpoints were gastrointestinal hemorrhage and major adverse cardiovascular events (MACEs), including 30-day all-cause mortality, atrioventricular block, ventricular tachycardia/ventricular fibrillation, and nonfatal stroke. The association of ALI with the study endpoints was analyzed by Cox regression analysis. Results: During the 30-day follow-up period after admission, 104 (47.9%) patients died and 150 (69.1%) suffered MACEs. The Kaplan-Meier analysis revealed significantly higher cumulative mortality and lower MACE rates in the low-ALI group compared to the high-ALI group (both log-rank p < 0.001). The 30-day mortality rate was significantly higher in patients with ALI ≤ 12.69 compared to ALI > 12.69 (72.1% vs. 22.6%; p < 0.001). Furthermore, the incidence of MACEs was higher in patients with ALI ≤ 12.69 (85.6% vs. 51.9%; p < 0.001). The receiver operating curve showed that ALI had a modest predictive value (area under the curve [AUC]: 0.789, 95% confidence interval [CI]: 0.729, 0.850). After multivariable adjustment, ALI ≤ 12.69 was an independent predictor for both 30-day all-cause mortality (hazard ratio [HR]: 3.327; 95% CI: 2.053, 5.389; p < 0.001) and 30-day MACEs (HR: 2.250; 95% CI 1.553, 3.260; p < 0.001). Furthermore, the addition of ALI to a base model containing clinical and laboratory data statistically improved the predictive value. Conclusions: Assessing ALI levels upon admission can provide important information for the short-term prognostic assessment of patients with AMI complicated by CS. A lower ALI may serve as an independent predictor of increased 30-day all-cause mortality and MACEs.

Relationship between 1,5-anhydroglucitol and renal function assessed by dynamic renal scintigraphy in type 2 diabetes.

CONTEXT: The reliability of serum 1,5-anhydroglucitol (1,5-AG) in type 2 diabetic patients with renal insufficiency remains controversial. OBJECTIVE: To evaluate the relationship between renal function and serum 1,5-AG, and to assess the extent to which renal function influences 1,5-AG. METHODS: A total of 5337 participants with type 2 diabetes were enrolled. The measured glomerular filtration rate (mGFR) was assayed using 99mTc-DTPA dynamic renal scintigraphy. All subjects were stratified into five groups based on mGFR (≥ 120 [n = 507], 90-120 [n = 2015], 60-90 [n = 2178], 30-60 [n = 604], and < 30 mL/min/1.73 m2 [n = 33]). RESULTS: Overall, the serum 1,5-AG and mGFR levels were 3.3 (1.7-7.0) µg/mL and 88.6 ± 24.1 mL/min/1.73 m2, respectively. mGFR was found to be negatively correlated with 1,5-AG levels (r = -0.189, P < 0.001). Multiple linear regression revealed that mGFR was independently and negatively related to serum 1,5-AG after adjusting for covariates including HbA1c (P < 0.001). In subgroups with mGFR ≥ 30 mL/min/1.73 m2, the correlation coefficients between 1,5-AG and HbA1c, fasting plasma glucose, postprandial plasma glucose, and the differences between postprandial and fasting plasma glucose remained significant (range from -0.126 to -0.743, all P < 0.01). However, the link between 1,5-AG and traditional glycemic markers was attenuated in individuals with mGFR < 30 mL/min/1.73 m2. Sensitivity analysis after excluding anemic patients showed similar results regarding the relationship between serum 1,5-AG and HbA1c across the mGFR subgroups. CONCLUSIONS: Although we observed a weak inverse correlation (r = -0.189) between mGFR and serum 1,5-AG in type 2 diabetes, 1,5-AG remains a valid marker for assessing glucose control in subjects with mild or moderate renal dysfunction.

The effects of laryngeal mask versus endotracheal tube on atelectasis after general anesthesia induction assessed by lung ultrasound: A randomized controlled trial.

STUDY OBJECTIVE: This study aims to evaluate the impact of Supreme™ laryngeal masks versus endotracheal tubes on atelectasis during general anesthesia using lung ultrasound (LUS), and provide evidence for respiratory management. DESIGN: A single-center, double-blind, randomized controlled trial was conducted. SETTING: The study was conducted in both the operating room and the post-anesthesia care unit, with follow-up assessments performed in the ward. PATIENTS: Enrollment included 180 cases undergoing non-laparoscopic surgeries in gynecology, urology, and orthopedic limb surgeries. INTERVENTIONS: Patients were randomly assigned 1:1 to the endotracheal intubation or laryngeal mask group. MEASUREMENTS: LUS scores were recorded across 12 lung regions at baseline, 15 min after airway establishment, at the end of surgery, and 30 min following airway removal. Outcome measures encompassed the oxygenation index, dynamic lung compliance, incidence of postoperative pulmonary complications, throat pain, and other postoperative complications assessed at 24 and 48 h postoperatively. The primary outcome focused on the LUS score in all 12 lung regions at 15 min after airway establishment. MAIN RESULTS: Intention-to-treat analysis of 177 subjects revealed endotracheal intubation led to significantly higher LUS scores at 15 min {P < 0.001, mean difference 4.15 ± 0.60, 95% CI [2.97, 5.33]}, end of surgery (P < 0.001, mean difference 3.37 ± 0.68, 95% CI [2.02, 4.72]), and 30 min post-removal (P < 0.001, mean difference 2.63 ± 0.48, 95% CI [1.68, 3.58]). No major complications occurred in the two groups. CONCLUSIONS: Compared to endotracheal intubation, laryngeal masks effectively reduce atelectasis formation and progression in gynecological, urological non-laparoscopic, and orthopedic limb surgeries. However, caution is warranted when generalizing these findings to surgeries with a higher risk of laryngeal mask leakage or obese patients. Additionally, the efficacy of laryngeal masks in reducing postoperative atelectasis remains uncertain when comprehensive monitoring of muscle relaxation and reversal therapy is employed.

Decreased complexity of glucose time series index associated with adverse pregnancy outcomes in gestational diabetes mellitus.

AIM: We investigated the relationship between the complexity of the glucose time series index (CGI) during pregnancy and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: In this retrospective cohort study, 388 singleton pregnant women with GDM underwent continuous glucose monitoring (CGM) at a median of 26.86 gestational weeks. CGI was calculated using refined composite multiscale entropy based on CGM data. The participants were categorized into tertiles according to their baseline CGI (CGI <2.32, 2.32-3.10, ≥3.10). Logistic regression was used to assess the association between CGI and composite adverse outcomes or large for gestational age (LGA). The discrimination performance of CGI was estimated using receiver operating characteristic analysis. RESULTS: Of the 388 participants, 71 (18.3%) had LGA infants and 63 (16.2%) had composite adverse outcomes. After adjustments were made for confounders, compared with those with a high CGI (CGI ≥3.10), participants with a low CGI (CGI <2.32) had a higher risk of composite adverse outcomes (odds ratio: 12.10, 95% confidence interval: 4.41-33.18) and LGA (odds ratio: 12.68, 95% confidence interval: 4.04-39.75). According to the receiver operating characteristic analysis, CGI was significantly better than glycated haemoglobin and conventional CGM indicators for the prediction of adverse pregnancy outcomes (all p < .05). CONCLUSION: A lower CGI during pregnancy was associated with composite adverse outcomes and LGA. CGI, a novel glucose homeostasis predictor, seems to be superior to conventional glucose indicators for the prediction of adverse pregnancy outcomes in women with GDM.

Association of retinal age gap with chronic kidney disease and subsequent cardiovascular disease sequelae: a cross-sectional and longitudinal study from the UK Biobank.

Background: Chronic kidney disease (CKD) increases the risk of cardiovascular disease (CVD) and is more prevalent in older adults. Retinal age gap, a biomarker of aging based on fundus images, has been previously developed and validated. This study aimed to investigate the association of retinal age gap with CKD and subsequent CVD complications. Methods: A deep learning model was trained to predict the retinal age using 19 200 fundus images of 11 052 participants without any medical history at baseline. Retinal age gap, calculated as retinal age predicted minus chronological age, was calculated for the remaining 35 906 participants. Logistic regression models and Cox proportional hazards regression models were used for the association analysis. Results: A total of 35 906 participants (56.75 ± 8.04 years, 55.68% female) were included in this study. In the cross-sectional analysis, each 1-year increase in retinal age gap was associated with a 2% increase in the risk of CKD prevalence [odds ratio 1.02, 95% confidence interval (CI) 1.01-1.04, P = .012]. A longitudinal analysis of 35 039 participants demonstrated that 2.87% of them developed CKD in follow-up, and each 1-year increase in retinal age gap was associated with a 3% increase in the risk of CKD incidence (hazard ratio 1.03, 95% CI 1.01-1.05, P = .004). In addition, a total of 111 CKD patients (15.81%) developed CVD in follow-up, and each 1-year increase in retinal age gap was associated with a 10% increase in the risk of incident CVD (hazard ratio 1.10, 95% CI 1.03-1.17, P = .005). Conclusions: We found that retinal age gap was independently associated with the prevalence and incidence of CKD, and also associated with CVD complications in CKD patients. This supports the use of this novel biomarker in identifying individuals at high risk of CKD and CKD patients with increased risk of CVD.

Intraoperative application of low-dose dexmedetomidine or lidocaine for postoperative analgesia in pediatric patients following craniotomy: a randomized double-blind placebo-controlled trial.

Background: Postoperative pain is a common occurrence in pediatric patients following craniotomy, often leading to negative outcomes. Intravenous dexmedetomidine and lidocaine are commonly used adjuvant medicines in general anesthesia to reduce perioperative opioid consumption and relieve postoperative pain in adults. While they show promise for use in pediatrics, the evidence of their application in pediatric craniotomy patients is limited. Therefore, we aimed to compare the effects of dexmedetomidine and lidocaine on postoperative pain in pediatric patients following craniotomy. Methods: We conducted a randomized, double-blind, single-center trial on children scheduled for craniotomy. The 255 recruited participants aged 1-12 years were randomly assigned to intraoperatively receive a loading intravenous dose of either dexmedetomidine 1 µg·kg-1 or lidocaine 2 mg·kg-1 or normal saline for 15 min followed by dexmedetomidine 0.5 µg·kg-1·h-1 or lidocaine 1 mg·kg-1·h-1 or normal saline until the sutures of endocranium were completed. The primary outcome was the cumulative sufentanil consumption within 24 h post-surgery. Results: A total of 241 patients were included in the statistical analysis. The primary outcome did not show any significant differences among the three groups (median (IQR) lidocaine group: 3.36 (1.32-5.64) µg vs. dexmedetomidine group: 3.12 (1.36-6.39) µg vs. control group 3.46 (1.77-7.62) µg, p = 0.485). Among the secondary outcomes, there was a statistically significant but small reduction in sufentanil consumption within 2 h, postoperative FLACC/WBFS/NRS pain scores within 4 h after surgery and postoperative Ramsay sedation scores in dexmedetomidine group (p < 0.05). Regarding postoperative complications, the incidence of electrolyte disturbance within 24 and 48 h after surgery was significantly higher in control group compared to the other two groups. There were no significant differences in intraoperative opioid consumption, postoperative frequency of remedy medication, or length of hospitalization among the three groups. No adverse events related to lidocaine or dexmedetomidine were observed. Conclusions: There were no significant differences in the primary outcome among the three groups. Although dexmedetomidine showed some benefits in reducing postoperative opioid consumption within the first 2 h and pain intensity within the first 4 h post-surgery, these findings should be interpreted with caution. Further research is required to comprehensively assess the outcomes and determine the optimal administration strategy. Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR1800019411].

Synergistic solidification and mechanism research of electrolytic manganese residue and coal fly ash based on C-A-S-H gel material.

Electrolytic manganese residue (EMR) is known for high concentrations of Mn2+, NH4+, and heavy metals. Failure to undergo benign treatment and landfill disposal would undeniably lead to negative impacts on the quality of the surrounding ecological environment. This study sought to mitigate the latent environmental risks associated with EMR using a cooperative solidification/stabilization (S/S) method involving coal fly ash (CFA). Leveraging leaching toxicity tests, the leaching behavior of pollutants in electrolytic manganese residue-based geopolymer materials (EMRGM) was determined. At the same time, mechanistic insights into S/S processes were explored utilizing characterization techniques such as XRF, XRD, FT-IR, SEM-EDS, and XPS. Those results confirmed significant reductions in the leaching toxicities of Mn2+ and NH4+ to 4.64 µg/L and 0.99 mg/L, respectively, with all other heavy metal ions falling within the permissible limits set by relevant standards. Further analysis shows that most of NH4+ volatilizes into the air as NH3, and a small part is fixed in the EMRGM in the form of struvite; in addition to being oxidized to MnOOH and MnO2, Mn2+ will also be adsorbed and wrapped by silicon-aluminum gel together with other heavy metal elements in the form of ions or precipitation. This research undeniably provides a solid theoretical foundation for the benign treatment and resourceful utilization of EMR and CFA, two prominent industrial solid wastes.

A bulged-type enzyme-free recognition strategy designed for single nucleotide polymorphisms integrating with label-free electrochemical biosensor.

Compared to conventional nucleic acid detection methods, label-free single nucleotide polymorphism (SNP) detection presents challenging due to the necessity of discerning single base mismatches, especially in the field of enzyme-free detection. In this study, we introduce a novel bulged-type DNA duplex probe designed to significantly amplify single-base differences. This probe is integrated with programmable DNA-based nanostructures to develop a sensitive, label-free biosensor for nonenzymatic SNP detection. The duplex probe with one bulge could selectively identify wild-typed DNA (WT) and mutant-type DNA (MT) based on a competitive strand displacement reaction mechanism. The hyperbranched HCR (HHCR) by incorporating of hairpin DNA into the DNA tetrahedron and surface-tethering on the portable screen printing electrode (SPCE) significantly favor the formation of negatively charged DNA nanostructure. We harnessed strong repulsion of DNA nanostructure towards the electroactive [Fe(CN)6]³â»/4⁻ in combination with electrochemical technique to create a label-free biosensor. This simple, enzyme-free and label-free biosensor could detect MT with a detection limit of 56 aM, even in multiple sequence backgrounds. The study served as the proof-of-concept for the integration of enzyme-free competitive mechanism and label-free strategy, which can be extended as a powerful tool to various fields.

Oxidized LDL regulates efferocytosis through the CD36-PKM2-mtROS pathway.

Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention. SUMMARY: Macrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.

Edible bird's nest improves the premature ovarian failure induced by tripterygium glycosides.

Premature ovarian failure (POF) is a common disease in the field of gynecological endocrinology that seriously affects the physical and mental health of patients. Previous studies found that edible bird's nest (EBN) could improve uterine function. These suggested that EBN might also have an ameliorating effect on POF. Therefore, in this study, tripterygium glycosides (TGs) were used to induce POF in rats, and the effect of EBN on the improvement of POF was investigated. After the administration of EBN for 14 days, ovarian index and uterine index, serum hormone levels, apoptosis rate of ovarian granulosa cells, follicle-stimulating hormone receptor (FSHR) protein expression level, and the histopathological examination of the ovaries were determined. It was found that administration of medium and high EBN dose groups increased the ovarian index and granular layer thickness of rats with POF. Particularly, higher follicle-stimulating hormone levels and lower corpus luteum content were observed in the high EBN dose group. In addition, there were lower luteinizing hormone levels and fewer atretic follicles but higher progesterone levels in the medium EBN dose group. These results indicated that EBN had preventive and curative effects on POF induced by TGs. Its mechanism of action might be related to the reduction of ovarian granulosa cell apoptosis, regulation of hormones and receptors, and inhibition of follicle closure.

Accelerometer-Measured Daily Behaviors That Mediate the Association Between Refractive Status and Depressive Disorders.

Purpose: To identify the accelerometer-measured daily behaviors that mediate the association of refractive status with depressive disorders and enhance the understanding of behavioral differences in depression. Methods: Participants with baseline mean spherical equivalent (MSE) and 7-day accelerometer measurements from the UK Biobank were included in this cohort study. Refractive status was categorized as hyperopia and non-hyperopia. Four daily behaviors, including moderate to vigorous intensity physical activity (MVPA), light physical activity (LPA), sedentary, and sleep were recorded between 2013 and 2015. We also assessed 24-hour behavior patterns. Depression cases were defined through both questionnaires and hospital records over 10 years of follow-up. Results: Among 20,607 individuals, every 0.5-diopter increase in MSE was associated with a 6% higher risk of depressive disorders, with hyperopia participants at a higher risk than non-hyperopia participants (odds ratio, 1.14; 95% confidence interval, 1.05-1.23; P = 0.001). MVPA and sleep time significantly correlated with depressive disorders, with odds ratios of 0.79 and 1.14 (P < 0.05). MSE showed significant correlations with all four behaviors. The effects of MVPA and sleep duration on MSE and depressive disorders varied throughout the day. Mediation analyses showed that MVPA and sleep partially mediated the relationship between MSE and depressive disorders, with 35.2% of the association between moderate to high hyperopia and depression mediated by MVPA. Conclusions: Physical activity and sleep significantly mediate the relationship between MSE and depressive disorders. Translational Relevance: The mediation effect of MVPA highlights its therapeutic potential in reducing the risk of depression among individuals with moderate to severe hyperopia. Interventions aimed at increasing daytime MVPA and decreasing daytime sleep could enhance mental health in this vulnerable group.

Four new species of Russulasubsect.Cyanoxanthinae from China (Russulales, Russulaceae).

Four new species of Russulasubsect.Cyanoxanthinae, viz. Russulaatrochermesina Y.L. Chen & J.F. Liang, R.lavandula Y.L. Chen, B. Chen & J.F. Liang, R.lilaceofusca Y.L. Chen & J.F. Liang and R.perviridis Y.L. Chen, B. Chen & J.F. Liang, from China are proposed, based on morphological and molecular evidence. Russulaatrochermesina can be distinguished by its violet pileus with tuberculate-striate margin, distant lamellae that stain greyish-yellow when bruised, basidiospores ornamented by isolated warts, wide hymenial cystidia on lamellae edges, cystidia content negative reaction in sulphovanillin and branched subterminal cells in pileipellis. Russulalavandula has a purplish-white to violet red pileus with a yellow centre, frequently present lamellulae and furcations, stipe often with pale yellow near the base, isolated basidiospores ornamentation and unbranched cuticular hyphal terminations, while R.lilaceofusca is characterised by its lilac brown to dark brown pileus, crowded lamellae with lamellulae and furcations, stipe often turning reddish-yellow when bruised, subreticulate basidiospores ornamentation and clavate hymenial cystidia often with capitate appendage whose contents that change to reddish-black in sulphovanillin. Russulaperviridis is characterised by its large basidiomata, smooth pileus surface, frequently present lamellulae and furcations, stipe with yellow-brown tinge, globose to broadly ellipsoid basidiospores with subreticulate ornamentation, long hymenial cystidia that turn greyish-black in sulphovanillin and symbiotic with Quercussemecarpifolia. Phylogenetic analyses, based on multi-gene ITS+LSU+mtSSU+rpb2, indicate that R.atrochermesina, R.lavandula, R.lilaceofusca and R.perviridis are closely related to R.pallidirosea and R.purpureorosea, R.banwatchanensis, R.lakhanpalii and R.nigrovirens, respectively.

Nanotherapeutics targeting autophagy regulation for improved cancer therapy.

The clinical efficacy of current cancer therapies falls short, and there is a pressing demand to integrate new targets with conventional therapies. Autophagy, a highly conserved self-degradation process, has received considerable attention as an emerging therapeutic target for cancer. With the rapid development of nanomedicine, nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance. Hence, considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy, we outline the latest advances in autophagy-based nanotherapeutics. Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor progression, the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated. Further, emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways, including modulation of the mammalian target of rapamycin (mTOR) pathway, autophagy-related (ATG) and its complex expression, reactive oxygen species (ROS) and mitophagy, interference with autophagosome-lysosome fusion, and inhibition of hypoxia-mediated autophagy. In addition, combination therapies in which nano-autophagy modulation is combined with chemotherapy, phototherapy, and immunotherapy are also described. Finally, the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.

Habitual use of glucosamine and adverse liver outcomes among patients with type 2 diabetes and MASLD.

BACKGROUND: Glucosamine is a dietary supplement commonly used to support joint health. However, there has been interest in exploring other effects of glucosamine on health outcomes due to its ant-inflammation effect. OBJECTIVE: This study compared the risks of major adverse liver outcomes (MALOs) between regular users and non-users of glucosamine among patients with type 2 diabetes and metabolic dysfunction associated steatotic liver disease (MASLD) using the data from a large prospective cohort study. METHODS: Demographic, anthropometric, laboratory and medication prescription information among 18 753 patients with type 2 diabetes and MASLD was obtained from the UK Biobank. MASLD was identified based on hepatic steatosis defined by fatty liver index ≥60 plus the presence of any clues of metabolic dysregulation and cardio-metabolic risk factors, excluding patients with moderate to severe alcohol consumption. RESULTS: During a mean follow-up of 11.4 years, 826 incident MALOs events were recorded. Patients not regularly using glucosamine compared with patients using glucosamine showed a significantly higher risk of the composite MALOs (HR 1.36, 95% confidence interval [CI] 1.09-1.69) as well as most individual MALOs except for ascites. The multivariable-adjusted HRs of MALOs within 3, 5 and 10 years among non-users of glucosamine compared with regular users were 1.79 (95% CI .69-2.03), 1.88 (95% CI 1.21-2.54) and 1.32 (95% CI 1.05-1.72), respectively. Further subgroup analyses in participants with different baseline characteristics and sensitivity analyses excluding participants who regularly took any other supplements and participants who used self-reports to diagnose diabetes confirmed the findings. CONCLUSIONS: The present study indicated that habitual use of glucosamine was associated with a low risk of individual and composite MALOs among patients with type 2 diabetes and MASLD.

Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells.

Energy metabolism has always been a hot topic in cancer progression and targeted therapy, and exploring the role of genes in energy metabolic pathways in cancer cells has become key to address this issue. Eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) plays regulatory roles in cancer and disorders of energy metabolism. Indeed, the role of EIF2AK2 in energy metabolism has been underestimated. The aim of this study is to reveal the expression specificity of EIF2AK2 in gastric cancer (GC) progression and metastasis, and to demonstrate the role of EIF2AK2 in energy metabolism, cytoskeleton, proliferation, death and metastasis pathways in GC cells. Mechanistically, EIF2AK2 overexpression promoted cytoskeleton remodeling and ATP production, mediated cell proliferation and metastasis, upregulated OAS1 expression, decreases p-AMPK expression and inhibited apoptosis in GC cells. Conversely, knockdown of EIF2AK2 resulted in the opposite effect. However, overexpression of OAS1 mediated the upregulation of mitochondrial membrane potential and promoted ATP production and NAD+/NADH ratio, but knockdown of OAS1 inhibited the above effects. In addition, knockdown of OAS1 had no effect on EIF2AK2 expression, but inhibited AMPK and upregulated p-AMPK expression. In conclusion, our study identified EIF2AK2 and OAS1 as previously undescribed regulators of energy metabolism in GC cells. We hypothesized that EIF2AK2-OAS1 axis may regulate energy metabolism and inhibit cellular malignant behavior in cancer cells by affecting ATP production to induce AMPK phosphorylation, suggesting EIF2AK2 as a potential therapeutic target for cancer cell progression.

Cerebrospinal Fluid Proteomics Identifies Potential Biomarkers for Early-Onset Alzheimer's Disease.

Background: Early-onset Alzheimer's disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer's disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. Objective: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. Methods: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. Results: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results. Conclusions: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins.