Targeting TrkB-PSD-95 coupling to mitigate neurological disorders.

Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.

Background: Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia. Methods: Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort. Results: Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions. Conclusion: Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts. Clinical trial registration: ClinicalTrials.gov, identifier NCT02280434.b.

Mitochondrial-targeted cyclometalated Ir(III)-5,7-dibromo/dichloro-2-methyl-8-hydroxyquinoline complexes and their anticancer efficacy evaluation in Hep-G2 cells.

Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline (HL-2) as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate (IR) was 63.0% (p <0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.

GPCR-MAPK signaling pathways underpin fitness trade-offs in whitefly.

Trade-offs between evolutionary gain and loss are prevalent in nature, yet their genetic basis is not well resolved. The evolution of insect resistance to insecticide is often associated with strong fitness costs; however, how the fitness trade-offs operates remains poorly understood. Here, we show that the mitogen-activated protein kinase (MAPK) pathway and its upstream and downstream actors underlie the fitness trade-offs associated with insecticide resistance in the whitefly Bemisia tabaci. Specifically, we find a key cytochrome P450 gene CYP6CM1, that confers neonicotinoids resistance to in B. tabaci, is regulated by the MAPKs p38 and ERK through their activation of the transcription factor cAMP-response element binding protein. However, phosphorylation of p38 and ERK also leads to the activation of the transcription repressor Cap "n" collar isoform C (CncC) that negatively regulates exuperantia (Ex), vasa (Va), and benign gonial cell neoplasm (Bg), key genes involved in oogenesis, leading to abnormal ovary growth and a reduction in female fecundity. We further demonstrate that the transmembrane G protein-coupled receptor (GPCR) neuropeptide FF receptor 2 (NPFF2) triggers the p38 and ERK pathways via phosphorylation. Additionally, a positive feedback loop between p38 and NPFF2 leads to the continuous activation of the MAPK pathways, thereby constitutively promoting neonicotinoids resistance but with a significant reproductive cost. Collectively, these findings provide fundamental insights into the role of cis-trans regulatory networks incurred by GPCR-MAPK signaling pathways in evolutionary trade-offs and applied knowledge that can inform the development of strategies for the sustainable pest control.

Preparation and Electrochromic Properties of MnO2/PPy Composite Films with Coral-like Structures.

MnO2/polypyrrole (PPy) composite films were deposited on fluorine-doped tin oxide (FTO) conductive glasses by a two-step wet-chemical method, including electrochemical deposition and chemical bath deposition (CBD). The porous MnO2 films were first grown on FTO glasses by an electrodeposition method. Second, polypyrrole nanoparticles were polymerized by the oxidation-reduction reaction between MnO2 and pyrrole, using the presynthesized MnO2 as the skeleton. Then, MnO2/PPy composite films with coral-like structures were obtained. The electrochemical and electrochromic (EC) properties of the prepared films were investigated. The results show that, compared to the single MnO2 or PPy film, the MnO2/PPy composite film has a larger optical modulation (67.3% at a wavelength of 900 nm), faster response times (4 s for coloration and 3 s for bleaching), and a higher coloration efficiency (218.16 cm2·C-1). The high coloration efficiency attests to the exceptional performance of the composite film in converting electrical signals into vivid color changes. The electrochemical stability test results show that the composite film maintains a stable EC performance after 200 coloration/bleaching cycles. The coral-like structures of the composite film are responsible for the better EC properties.

Nanoscale Sequential Reactor Design Achieves Effective Removal of Disinfection Byproduct Precursors in Catalytic Ozonation.

Transforming dissolved organic matter (DOM) is a crucial approach to alleviating the formation of disinfection byproducts (DBPs) in water treatment. Although catalytic ozonation effectively transforms DOM, increases in DBP formation potential are often observed due to the accumulation of aldehydes, ketones, and nitro compound intermediates during DOM transformation. In this study, we propose a novel strategy for the sequential oxidation of DOM, effectively reducing the levels of accumulation of these intermediates. This is achieved through the development of a catalyst with a tailored surface and nanoconfined active sites for catalytic ozonation. The catalyst features a unique confinement structure, wherein Mn-N4 moieties are uniformly anchored on the catalyst surface and within nanopores (5-20 Å). This design enables the degradation of the large molecular weight fraction of DOM on the catalyst surface, while the transformed smaller molecular weight fraction enters the nanopores and undergoes rapid degradation due to the confinement effect. The generation of *Oad as the dominant reactive species is essential for effectively reducing these ozone refractory intermediates. This resulted in over 70% removal of carbonaceous and nitrogenous DBP precursors as well as brominated DBP precursors. This study highlights the importance of the nanoscale sequential reactor design and provides new insights into eliminating DBP precursors by the catalytic ozonation process.

Vortioxetine for depression in adults: A systematic review and dose-response meta-analysis of randomized controlled trials.

AIM: Major depressive disorder (MDD) is a prevalent psychiatric condition and vortioxetine offers promising antidepressant effects due to its unique pharmacological profile. However, the dose-response relationships of vortioxetine for MDD is not well established. We aimed to conduct dose-response meta-analyses to fill this gap. METHODS: We systematically searched multiple electronic databases for randomized controlled trials of vortioxetine for MDD, with the last search conducted on 08 February, 2024. The dose-response relationship was evaluated using a one-stage random-effects dose-response meta-analysis with restricted cubic spline model. The primary outcome was efficacy (mean change in depression scale score), with secondary outcomes including response, dropout for any reasons (acceptability), dropout for adverse events (tolerability), and any adverse events (safety). RESULTS: The dose-response meta-analysis comprised 16 studies, with 4,294 participants allocated to the vortioxetine group and 2,299 participants allocated to the placebo group. The estimated 50% effective dose was 4.37 mg/day, and the near-maximal effective dose (95% effective dose) was 17.93 mg/day. Visual inspection of the dose-efficacy curve suggests that a plateau possibly had not been reached yet at 20 mg/day. Acceptability, tolerability and safety decreased as the dose increased. Subgroup analysis indicated that no significant differences were observed in acceptability, tolerability and safety among the dosage groups. CONCLUSIONS: Vortioxetine may potentially provide additional therapeutic benefits when exceeding the current licensed dosage without significantly impacting safety. Conducting clinical trials exceeding the current approved dosage appears necessary to fully comprehend its efficacy and risk.

Cadmium exposure induces changes in gut microbial composition and metabolic function in long-tailed dwarf hamsters, Cricetulus longicaudatus.

Numerous studies have demonstrated that exposure to cadmium disrupts the diversity and composition of the gut microbiota, resulting in damage to organ tissue. However, there remains a lack of comprehensive understanding regarding the broader ecological reality associated with this phenomenon. In this study, we conducted a thorough evaluation of the effects of different concentrations of Cd (6, 12, 24, and 48 mg/L) over a period of 35 consecutive days on the organ viscera and the gut microbiota of long-tailed dwarf hamsters, Cricetulus longicaudatus (Rodentia: Cricetidae), using histopathological analysis, 16S rDNA, and metagenome sequencing. Our findings revealed that the results suggest that Cd exposure induced liver, spleen, and kidney damage, potentially leading to increased intestinal permeability and inflammation. These alterations were accompanied by significant perturbations in the gut microbiota composition, particularly affecting potentially pathogenic bacteria such as Prevotella and Treponema within the gut ecosystem. Consequently, host susceptibility to underlying diseases was heightened due to these changes. Notably though, Cd exposure did not significantly impact the overall structure of the gut microbiota itself. Additionally, Cd exposure induced significant changes in the metabolic functions, with the pathways related to disease and environmental information processing notably enhanced, possibly indicating stronger innate defense mechanisms against external injuries among wild mammals exposed to Cd. This study offers a novel approach to comprehensively evaluate the significant impact of Cd pollution on ecosystems by investigating both structural and functional alterations in the digestive system, as well as disruptions in intestinal flora among wild mammals.

Aptamer Functionalized Hypoxia-potentiating Agent and Hypoxia-inducible Factor Inhibitor Combined with Hypoxia-activated Prodrug for Enhanced Tumor Therapy.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. Hypoxia-activated prodrugs (HAPs) have shown promise as potential therapeutic agents for TNBC. While increasing hypoxia levels may promote the HAP activation, it raises concerns regarding HIF1α-dependent drug resistance. It is desirable to develop a targeted approach that enhances tumor hypoxia for HAP activation without promoting HIF1α-dependent drug resistance in TNBC treatment. Herein, we proposed a multi-responsive carrier-free self-assembled nanomedicine named AQ4N@CA4T1ASO. This nanomedicine first targeted tumors by the TNBC-targeting aptamers (T1), and then disassembled in the reductive and acidic conditions within tumors. The released Combretastatin 4 (CA4) could exacerbate hypoxia, thereby promoting the conversion of inactive Banoxantrone (AQ4N) to its active form, AQ4. Simultaneously, the released antisense oligonucleotide (ASO) could attenuate hypoxia-induced HIF1α mRNA expression, thereby sensitizing the tumor to chemotherapy. Overall, this smart nanomedicine represents a profound targeted therapy strategy, combining "hypoxia-potentiating, hypoxia-activated, chemo-sensitization" approaches for TNBC treatment. In vivo study demonstrated significant suppression of tumor growth, highlighting the promising potential of this nanomedicine for future clinical translation.

Efficacy of virtual reality exercise in knee osteoarthritis rehabilitation: a systematic review and meta-analysis.

Background: This systematic review and meta-analysis aims to investigate the effects of virtual reality (VR) exercise compared to traditional rehabilitation on pain, function, and muscle strength in patients with knee osteoarthritis (KOA). Additionally, the study explores the mechanisms by which VR exercise contributes to the rehabilitation of KOA patients. Methods: We systematically searched PubMed, the Cochrane Library, Embase, Web of Science, Scopus, and PEDro according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our search spanned from the library construction to 24 May 2024, focusing on randomized controlled trials Primary outcomes included pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and muscle strength. Meta-analysis was conducted using RevMan (version 5.4) and Stata (version 14.0). The bias risk of included studies was assessed using the Cochrane RoB 2.0 tool, while the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: This meta-analysis and systematic review included nine studies involving 456 KOA patients. The results indicated that VR exercise significantly improved pain scores (SMD, -1.53; 95% CI: -2.50 to -0.55; p = 0.002), WOMAC total score (MD, -14.79; 95% CI: -28.26 to -1.33; p = 0.03), WOMAC pain score (MD, -0.93; 95% CI: -1.52 to -0.34; p = 0.002), knee extensor strength (SMD, 0.51; 95% CI: 0.14 to 0.87; p = 0.006), and knee flexor strength (SMD, 0.65; 95% CI: 0.28 to 1.01; p = 0.0005), but not significantly for WOMAC stiffness (MD, -0.01; 95% CI: -1.21 to 1.19; p = 0.99) and physical function (MD, -0.35; 95% CI: -0.79 to -0.09; p = 0.12). Conclusion: VR exercise significantly alleviates pain, enhances muscle strength and WOMAC total score in KOA patients, but improvements in joint stiffness and physical function are not significant. However, the current number of studies is limited, necessitating further research to expand on the present findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024540061, identifier CRD42024540061.

Bionic Artificial Skin Based on Self-Healable Ionogel Composites with Tailored Mechanics and Robust Interfaces.

Bionic artificial skin which imitates the features and functions of human skin, has broad applications in wearable human-machine interfaces. However, equipping artificial materials with skin-like mechanical properties, self-healing ability, and high sensitivity remains challenging. Here, inspired by the structure of human skin, an artificial skin based on ionogel composites with tailored mechanical properties and robust interface is prepared. Combining finite element analysis and direct ink writing (DIW) 3D printing technology, an ionogel composite with a rigid skeleton and an ionogel matrix is precisely designed and fabricated, realizing the mechanical anisotropy and nonlinear mechanical response that accurately mimic human skin. Robust interface is created through co-curing of the skeleton and matrix resins, significantly enhancing the stability of the composite. The realization of self-healing ability and resistance to crack growth further ensure the remarkable durability of the artificial skin for sensing application. In summary, the bionic artificial skin mimics the characteristics of human skin, including mechanical anisotropy, nonlinear mechanical response, self-healing capability, durability and high sensitivity when applied as flexible sensors. These strategies provide strong support for the fabrication of tissue-like materials with adaptive mechanical behaviors.

Predicting risk of the subsequent early pregnancy loss in women with recurrent pregnancy loss based on preconception data.

BACKGROUND: For women who have experienced recurrent pregnancy loss (RPL), it is crucial not only to treat them but also to evaluate the risk of recurrence. The study aimed to develop a risk predictive model to predict the subsequent early pregnancy loss (EPL) in women with RPL based on preconception data. METHODS: A prospective, dynamic population cohort study was carried out at the Second Hospital of Lanzhou University. From September 2019 to December 2022, a total of 1050 non-pregnant women with RPL were participated. By December 2023, 605 women had subsequent pregnancy outcomes and were randomly divided into training and validation group by 3:1 ratio. In the training group, univariable screening was performed on RPL patients with subsequent EPL outcome. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression were utilized to select variables, respectively. Subsequent EPL prediction model was constructed using generalize linear model (GLM), gradient boosting machine (GBM), random forest (RF), and deep learning (DP). The variables selected by LASSO regression and multivariate logistic regression were then established and compared using the best prediction model. The AUC, calibration curve, and decision curve (DCA) were performed to assess the prediction performances of the best model. The best model was validated using the validation group. Finally, a nomogram was established based on the best predictive features. RESULTS: In the training group, the GBM model achieved the best performance with the highest AUC (0.805). The AUC between the variables screened by the LASSO regression (16-variables) and logistic regression (9-variables) models showed no significant difference (AUC: 0.805 vs. 0.777, P = 0.1498). Meanwhile, the 9-variable model displayed a well discrimination performance in the validation group, with an AUC value of 0.781 (95%CI 0.702, 0.843). The DCA showed the model performed well and was feasible for making beneficial clinical decisions. Calibration curves revealed the goodness of fit between the predicted values by the model and the actual values, the Hosmer-Lemeshow test was 7.427, and P = 0.505. CONCLUSIONS: Predicting subsequent EPL in RPL patients using the GBM model has important clinical implications. Future prospective studies are needed to verify the clinical applicability. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry with the registration number of ChiCTR2000039414 (27/10/2020).

LPS-induced senescence of macrophages aggravates calcification and senescence of vascular smooth muscle cells via IFITM3.

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.

Potential biomarkers for evaluating the BCG vaccination response based on humoral immunity.

Background: The current prophylactic tuberculosis vaccine Bacille Calmette-Guérin (BCG), was derived in the 1920s, but the humoral immune responses induced by BCG vaccination have not been fully elucidated to date. In this study, our aim was to reveal the profiles of antibody responses induced by BCG vaccination in adults and identify the potential biomarkers for evaluating the BCG vaccination response. Methods: Proteome microarrays were performed to reveal the serum profiles of antibody responses induced by BCG vaccination in adults. ELISA was used to validate the potential biomarkers in validation cohort (79 healthy controls and 58 BCG-vaccinated subjects). Then combined panel was established by logistic regression analysis based on OD values of potential biomarkers. Results: Multiple antigens elicited stronger serum IgG or IgM antibody responses in BCG vaccinated subjects than healthy subjects at 12 weeks post BCG vaccination; among the antigens, Rv0060, Rv2026c and Rv3379c were further verified using 137 serum samples and presented the moderate performance in assessment of the BCG vaccination response by receiver operating characteristic analysis. Furthermore, a combined panel exhibited an improved AUC of 0.923, and the sensitivity and specificity were 77.59 % and 91.14 %, respectively. In addition, the antibody response against Rv0060, Rv2026c and Rv3379c was related to the clinical background to a certain extent. Conclusions: The novel antigens identified in our study could offer better knowledge towards developing a more efficacious vaccine based on humoral immune responses, and they could be potential biomarkers in assessments of BCG vaccination responses.

A novel artificial intelligence model for measuring fetal intracranial markers during the first trimester based on two-dimensional ultrasound image.

OBJECTIVE: To establish reference ranges of fetal intracranial markers during the first trimester and develop the first novel artificial intelligence (AI) model to measure key markers automatically. METHODS: This retrospective study used two-dimensional (2D) ultrasound images from 4233 singleton normal fetuses scanned at 11+0-13+6 weeks of gestation at the Affiliated Suzhou Hospital of Nanjing Medical University from January 2018 to July 2022. We analyzed 10 key markers in three important planes of the fetal head. Based on these, reference ranges of 10 fetal intracranial markers were established and an AI model was developed for automated marker measurement. AI and manual measurements were compared to evaluate differences, correlations, consistency, and time consumption based on mean error, Pearson correlation analysis, intraclass correlation coefficients (ICCs), and average measurement time. RESULTS: The results of AI and manual methods had strong consistency and correlation (all ICC values >0.75, all r values >0.75, and all P values <0.001). The average absolute error of both only ranged from 0.124 to 0.178 mm. AI achieved a 100% detection rate for abnormal cases. Additionally, the average measurement time of AI was only 0.49 s, which was more than 65 times faster than the manual measurement method. CONCLUSION: The present study first established the normal standard reference ranges of fetal intracranial markers based on a large Chinese population data set. Furthermore, the proposed AI model demonstrated its capability to measure multiple fetal intracranial markers automatically, serving as a highly effective tool to streamline sonographer tasks and mitigate manual measurement errors, which can be generalized to first-trimester scanning.

MTF1 genetic variants are associated with lung cancer risk in the Chinese Han population.

BACKGROUND: Metal-regulatory transcription factor 1 (MTF1), a conserved metal-binding transcription factor in eukaryotes, regulates the proliferation of cancer cells by activating downstream target genes and then participates in the formation and progression of tumors, including lung cancer (LC). The expression level of MTF1 is down-regulated in LC, and high expression of MTF1 is associated with a good prognosis of LC. However, the association between MTF1 polymorphism and LC risk has not been explored. METHODS: The genotyping of MTF1 Single nucleotide polymorphisms (SNPs) including rs473279, rs28411034, rs28411352, and rs3748682 was identified by the Agena MassARRAY system among 670 healthy controls and 670 patients with LC. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistics regression to assess the association of these SNPs with LC risk. RESULTS: MTF1 rs28411034 (OR 1.22, 95% CI 1.03-1.45, p = 0.024) and rs3748682 (OR 1.24, 95% CI 1.04-1.47, p = 0.014) were associated with higher LC susceptibility overall. Moreover, the effect of rs28411034 and rs3748682 on LC susceptibility was observed in males, subjects with body mass index (BMI) ≥ 24 kg/m2, smokers, drinkers, and patients with lung squamous carcinoma (OR and 95% CI > 1, p < 0.05). Besides, rs28411352 (OR 0.73, 95% CI 0.55-0.97, p = 0.028,) showed protective effect for reduced LC risk in drinkers. CONCLUSIONS: We were first who reported that rs28411034 and rs3748682 tended to be relevant to increased LC susceptibility among the Chinese Han population. These results of this study could help to recognize the pathogenic mechanisms of the MTF1 gene in LC progress.

Comparison of visual outcomes and optical aberrations after SMILE with intraoperative Kappa angle adjustments between small and large Kappa angles.

This study compares postoperative visual outcomes and optical aberrations after Small Incision Lenticule Extraction (SMILE) in patients with both small (S-Kappa: Kappa angle < 0.2 mm) and large Kappa (L-Kappa: Kappa angle ≥ 0.2 mm) angles. The evaluated aberrations include total higher-order aberrations (HOAs), horizontal coma (HC), vertical coma (VC), and spherical aberrations (SA), with procedures incorporating intraoperative Kappa angle adjustments. We retrospectively analyzed patient records undergoing SMILE utilizing linear mixed models (LMM). We assessed adjusted mean uncorrected distance visual acuity (UDVA), Strehl ratio (SR), total HOAs, VC, and SA at pupils of 3 mm and 6 mm for both S-Kappa and L-Kappa. The disparities between S-Kappa and L-Kappa were evaluated by LMM's adjusted mean differences. The differences in optical metrics were also assessed in eyes grouped by myopia levels: low, moderate, and high. A sensitivity analysis was conducted on a threshold of Kappa angle at 0.3 mm. Eight-five patients (169 eyes) were analyzed, and no significant pre-operative difference was found in UDVA (p = .222) or spherical equivalent (p = .433). Post-operative differences were found in SR at 3 mm pupil size (-0.06, p = .022), total HOA 3 mm (0.15, p = .022), HC 3 mm (0.04, p = .042), VC 3 mm and 6 mm (-0.08, p = .041; 0.04, p = .041). The stratified analysis for high myopia revealed significant differences in UDVA (-0.04, p = .037), HC 3 mm (0.07, p = .03), VC 6 mm (-0.21, p = .001), and SA 3 mm and 6 mm (0.07, p = .037; -0.09, p = .037). Sensitivity analysis showed no significant difference using a 0.3 mm Kappa threshold. While some optical aberrations exhibited statistical differences between S-Kappa and L-Kappa, their clinical significance is limited. Thus, a large Kappa angle might not substantially influence post-operative optical aberrations when intraoperative Kappa angle adjustments are implemented.

A Peritrophin-44 gene in Litopenaeus vannamei is involved in disease resistance.

Peritrophic membrane (PM) is a pellicle structure present in the midgut of some invertebrates, such as insects and crustaceans. It could isolate harmful components and pathogens in food from intestinal epithelial cells; and it also plays a role in improving digestion and absorption efficiency. So PM is important for survival of its owner. In current study, 44 PM proteins were identified in Litopenaeus vannamei by PM proteome analysis. Among these PM proteins, the Peritrophin-44 homologous protein (LvPT44) was further studied. Chitin-binding assay indicated that LvPT44 could bind to colloidal chitin, and immunoeletron microscopy analysis shown that it was located to PM of L. vannamei. Furthermore, LvPT44 promoter was found to be activated by L. vannamei STAT and c-Jun. Besides, LvPT44 was induced by ER-stress as well as white spot syndrome virus infection. Knocked-down expression of LvPT44 by RNA inference increased the cumulative mortality of shrimp that caused by ER-stress or white spot syndrome virus. These results suggested that LvPT44 has an important role in disease resistance.

Ciliary neurotrophic factor promotes the development of homocysteine-induced vascular endothelial injury through inflammation mediated by the JAK2/STAT3 signaling pathway.

Elevated homocysteine (Hcy) levels have been recognized as significant risk factor for cardiovascular and cerebrovascular diseases, closely related to endothelial injury. While expression of Ciliary Neurotrophic Factor (CNTF) significantly increases during Hcy-induced vascular endothelial cell injury, the precise molecular pathways through which CNTF operates remain to be clarified. To induce vascular endothelial cell injury, human umbilical vein endothelial cells (HUVECs) were treated with Hcy. Cell viability and apoptosis in HUVECs were assessed using the CCK-8 assay and flow cytometry. Western blot analysis determined the expression levels of the JAK2-STAT3 pathway, inflammation-related factors (IL-1ß, NLRP3, ICAM-1, VCAM-1), and apoptosis-related factors (cleaved Caspase-3 and Bax). Immunofluorescence staining and western blotting were employed to examine CD31 and α-SMA expression. Knockdown of CNTF was achieved using lentiviral interference, and its effects on inflammation and cell injury were evaluated. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter analysis were conducted to investigate the interaction between the MAFK and CNTF promoters. Our results indicated that Hcy induced high expression of CNTF and activated the JAK2-STAT3 signaling pathway, thereby upregulating factors associated with inflammation and cell apoptosis. Inhibiting CNTF alleviated Hcy-induced inflammation and cell injury. MAFK was identified as a transcription factor promoting CNTF transcription, and its overexpression exacerbated inflammation and cell injury in Hcy-treated HUVECs through the CNTF-JAK2-STAT3 axis, which could be reversed by knocking down CNTF. Activation of MAFK leads to CNTF upregulation, which activates the JAK2-STAT3 signaling pathway, regulating inflammation and inducing injury in Hcy-exposed vascular endothelial cells. Targeting CNTF or its upstream regulator MAFK may represent potential therapeutic strategies for mitigating endothelial dysfunction associated with hyperhomocysteinemia and cardiovascular diseases.

Mitochondria-targeted polyprodrug nanoparticles induce mitochondrial stress for immunogenic chemo-photodynamic therapy of ovarian cancer.

Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.