Coronary artery calcification and cardiovascular outcome as assessed by intravascular OCT and artificial intelligence.

Coronary artery calcification (CAC) is a marker of atherosclerosis and is thought to be associated with worse clinical outcomes. However, evidence from large-scale high-resolution imaging data is lacking. We proposed a novel deep learning method that can automatically identify and quantify CAC in massive intravascular OCT data trained using efficiently generated sparse labels. 1,106,291 OCT images from 1,048 patients were collected and utilized to train and evaluate the method. The Dice similarity coefficient for CAC segmentation and the accuracy for CAC classification are 0.693 and 0.932, respectively, close to human-level performance. Applying the method to 1259 ST-segment elevated myocardial infarction patients imaged with OCT, we found that patients with a greater extent and more severe calcification in the culprit vessels were significantly more likely to have major adverse cardiovascular and cerebrovascular events (MACCE) (p < 0.05), while the CAC in non-culprit vessels did not differ significantly between MACCE and non-MACCE groups.

Polystyrene microplastics alleviate the developmental toxicity of silver nanoparticles in embryo-larval zebrafish (Danio rerio) at the transcriptomic level.

Since silver nanoparticles (AgNPs) and polystyrene microplastics (PS-MP) share common environmental niches, their interactions can modulate their hazard impacts. Herein, we assessed the developmental toxicity of 1 mg/L PS-MP, 0.5 mg/L AgNPs and the mixtures of AgNPs and PS-MP on embryo-larval zebrafish. We found that AgNPs co-exposure with PS-MP remarkably decreased mortality rates, malformation rates, heart rates and yolk sac area, while it increased hatching rates and eye size compared to the AgNPs group. These phenomena revealed that the cell cycle, oxidative stress, apoptosis, lipid metabolism, ferroptosis and p53 signalling pathway were obviously affected by single AgNPs exposure at 96 hpf (hours post fertilization). Interestingly, all these effects were effectively ameliorated by co-exposure with PS-MP. The combination of transcriptomic and metabolomic analyses showed that the imbalance of DEGs (differentially expressed genes) and DEMs (differentially expressed metabolites) (PI, phosphatidylinositol and TAG-FA, triacylglycerol-fatty acid) disturbed both the cell cycle and lipid metabolism following single AgNPs exposure and co-exposure with PS-MP. These findings suggest that PS-MP attenuates the developmental toxicity of AgNPs on embryo-larval zebrafish. Overall, this study provides important insight into understanding the transcriptional responses and mechanisms of AgNPs alone or in combination with PS-MPs on embryo-larval zebrafish, providing a reference for ecological risk assessment of combined exposure to PS-MP and metal nanoparticles.

Discovery of potent LRRK2 inhibitors by ensemble virtual screening strategy and bioactivity evaluation.

Leucine-rich repeat kinase 2 (LRRK2) has been reported to be associated with familial and idiopathic Parkinson's disease (PD) risk and is a promising target for drug discovery against PD. To identify novel and effective LRRK2 inhibitors, an ensemble virtual screening strategy by combining fingerprint similarity, complex-based pharmacophore and structure-based molecular docking was proposed and applied. Using this strategy, we finally selected 25 compounds from ∼1.7 million compounds for in vitro and in vivo tests. Firstly, the kinase inhibitory activity tests of compounds based on ADP-Glo assay identified three most potent compounds LY2023-19, LY2023-24 and LY2023-25 with IC50 of 556.4 nM, 218.1 nM and 22.4 nM for LRRK2 G2019S mutant, respectively. The further cellular experiments also indicated that three hit compounds significantly inhibited Ser935 phosphorylation of both wide-type and G2019S LRRK2 with IC50 ranging from 27 nM to 1674 nM in HEK293T cells. The MD simulations of three compounds and G2019S LRRK2 showed the hydrogen bond formed by Glu1948 and Ala1950 is crucial for the binding of LRRK2. Afterwards, 6-OHDA-induced PD zebrafish model was constructed to evaluate the neuroprotective effects of hit compounds. The locomotion of the 6-OHDA treated zebrafish larvae was improved after treatment with LY2023-24. The obtained results can provide valuable guidance for the development of PD drugs by targeting LRRK2.

Cerebral arterial blood flow, attention, and executive and cognitive functions in depressed patients after acute hypertensive cerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage mainly occurs in middle-aged and elderly patients with hypertension, and surgery is currently the main treatment for hypertensive cerebral hemorrhage, but the bleeding caused by surgery will cause damage to the patient's nerve cells, resulting in cognitive and motor dysfunction, resulting in a decline in the patient's quality of life. AIM: To investigate associations between cerebral arterial blood flow and executive and cognitive functions in depressed patients after acute hypertensive cerebral hemorrhage. METHODS: Eighty-nine patients with depression after acute hypertensive cerebral hemorrhage who were admitted to our hospital between January 2019 and July 2021 were selected as the observation group, while 100 patients without depression who had acute hypertensive cerebral hemorrhage were selected as the control group. The attention span of the patients was assessed using the Paddle Pin Test while executive function was assessed using the Wisconsin Card Sorting Test (WCST) and cognitive function was assessed using the Montreal Cognitive Assessment Scale (MoCA). The Hamilton Depression Rating Scale (HAMD-24) was used to evaluate the severity of depression of involved patients. Cerebral arterial blood flow was measured in both groups. RESULTS: The MoCA score, net scores I, II, III, IV, and the total net score of the scratch test in the observation group were significantly lower than those in the control group (P < 0.05). Concurrently, the total number of responses, number of incorrect responses, number of persistent errors, and number of completed responses of the first classification in the WCST test were significantly higher in the observation group than those in the control group (P < 0.05). Blood flow in the basilar artery, left middle cerebral artery, right middle cerebral artery, left anterior cerebral artery, and right anterior cerebral artery was significantly lower in the observation group than in the control group (P < 0.05). The basilar artery, left middle cerebral artery, right middle cerebral artery, left anterior cerebral artery, and right anterior cerebral artery were positively correlated with the net and total net scores of each part of the Paddle Pin test and the MoCA score (P < 0.05), and negatively correlated with each part of the WCST test (P < 0.05). In the observation group, the post-treatment improvement was more prominent in the Paddle Pin test, WCST test, HAMD-24 score, and MoCA score compared with those in the pre-treatment period (P < 0.05). Blood flow in the basilar artery, left middle cerebral artery, right middle cerebral artery, left anterior cerebral artery, and right anterior cerebral artery significantly improved in the observation group after treatment (P < 0.05). CONCLUSION: Impaired attention, and executive and cognitive functions are correlated with cerebral artery blood flow in patients with depression after acute hypertensive cerebral hemorrhage and warrant further study.

Synthesis and Biological Activity of 2-Chloro-8-methoxy-5-methyl-5H-indolo [2,3-b] Quinoline for the Treatment of Colorectal Cancer by Modulating PI3K/AKT/mTOR Pathways.

Developing novel drugs from natural products has proven to be a very effective strategy. Neocryptolepine was isolated from Cryptolepis sanguinolenta, a traditional endemic African herb, which exerts a wide range of biological activities such as antimalaria, antibacterial, and antitumor. 2-Chloro-8-methoxy-5-methyl-5H-indolo [2,3-b] quinoline (compound 49) was synthesized, and its cytotoxicity was assessed on pancreatic cancer PANC-1 cells, colorectal cancer HCT116 cells, liver cancer SMMC-7721 cells, and gastric cancer AGS cells in vitro. The results of the in vitro assay showed that compound 49 exerted remarkable cytotoxicity on colorectal cancer HCT116 and Caco-2 cells. The cytotoxicity of compound 49 to colorectal cancer HCT116 cells was 17 times higher than that of neocryptolepine and to human normal intestinal epithelial HIEC cells was significantly reduced. Compound 49 exhibited significant cytotoxicity against the colorectal cancer HCT116 and Caco-2 cells, with IC50 of 0.35 and 0.54 µM, respectively. The mechanism of cytotoxicity of compound 49 to colorectal cancer HCT116 and Caco-2 cells was further investigated. The results showed that compound 49 could inhibit colony formation and cell migration. Moreover, compound 49 could arrest the cell cycle at the G2/M phase, promote the production of reactive oxygen species, reduce mitochondrial membrane potential, and induce apoptosis. The results of Western blot indicated that compound 49 showed cytotoxicity on HCT116 and Caco-2 cells by modulating the PI3K/AKT/mTOR signaling pathway. In conclusion, these results suggested that compound 49 may be a potentially promising lead compound for the treatment of colorectal cancer.

Hippocampal mitophagy contributes to spatial memory via maintaining neurogenesis during the development of mice.

BACKGROUND: Impaired mitochondrial dynamics have been identified as a significant contributing factor to reduced neurogenesis under pathological conditions. However, the relationship among mitochondrial dynamics, neurogenesis, and spatial memory during normal development remains unclear. This study aims to elucidate the role of mitophagy in spatial memory mediated by neurogenesis during development. METHODS: Adolescent and adult male mice were used to assess spatial memory performance. Immunofluorescence staining was employed to evaluate levels of neurogenesis, and mitochondrial dynamics were assessed through western blotting and transmission electron microscopy. Pharmacological interventions further validated the causal relationship among mitophagy, neurogenesis, and behavioral performance during development. RESULTS: The study revealed differences in spatial memory between adolescent and adult mice. Diminished neurogenesis, accompanied by reduced mitophagy, was observed in the hippocampus of adult mice compared to adolescent subjects. Pharmacological induction of mitophagy in adult mice with UMI-77 resulted in enhanced neurogenesis and prolonged spatial memory retention. Conversely, inhibition of mitophagy with Mdivi-1 in adolescent mice led to reduced hippocampal neurogenesis and impaired spatial memory. CONCLUSION: The observed decline in spatial memory in adult mice is associated with decreased mitophagy, which affects neurogenesis in the dentate gyrus. This underscores the therapeutic potential of enhancing mitophagy to counteract age- or disease-related cognitive decline.

Global trends in Cryptococcus and its interactions with the host immune system: a bibliometric analysis.

Objectives: This manuscript undertakes a systematic examination of the research landscape concerning global Cryptococcus species and their dynamism with the host immune system spanning the past decade. It furnishes a detailed survey of leading knowledge institutions and critical focal points in this area, utilizing bibliometric analysis. Methods: VOSviewer and CiteSpace software platforms were employed to systematically analyze and graphically depict the relevant literature indexed in the WoSCC database over the preceding ten years. Results: In the interval between October 1, 2013, and October 1, 2023, a corpus of 795 publications was amassed. The primary research institutions involved in this study include Duke University, the University of Minnesota, and the University of Sydney. The leading trio of nations, in terms of publication volume, comprises the United States, China, and Brazil. Among the most prolific authors are Casadevall, Arturo; Wormley, Floyd L., Jr.; and Olszewski, Michal A., with the most highly cited author being Perfect, Jr. The most esteemed journal is Mbio, while Infection and Immunity commands the highest citation frequency, and the Journal of Clinical Microbiology boasts the most significant impact factor. Present research foci encompass the intricate interactions between Cryptococcus pathogenesis and host immunity, alongside immune mechanisms, complications, and immunotherapies. Conclusion: This represents the first exhaustive scholarly review and bibliometric scrutiny of the evolving landscapes in Cryptococcus research and its interactions with the host immune system. The analyses delineated herein provide insights into prevailing research foci and trajectories, thus furnishing critical directions for subsequent inquiries in this domain.

Changes in Serum Interleukin-8 Levels Predict Response to Immune Checkpoint Inhibitors Immunotherapy in Unresectable Hepatocellular Carcinoma Patients.

Background: Effective biomarkers are needed to predict the efficacy of immune checkpoint inhibitors (ICIs) therapy in hepatocellular carcinoma (HCC). We evaluated the early changes in serum interleukin-8 (IL-8) levels as a biomarker of response to ICIs in patients with unresectable HCC. Methods: Eighty patients who received ICIs therapy alone or in combination with other treatments for unresectable HCC were included. Serum was collected at baseline and 2-4 weeks after the first dose. Serum IL-8 levels were measured using by ELISA. Results: In the progressive disease (PD) group, serum IL-8 levels increased significantly before the second dose of ICIs therapy compared with baseline levels (P < 0.001). Early changes in serum IL-8 levels were significantly associated with the response to ICIs therapy (P < 0.001). A cutoff value of 8.1% increase over the baseline most effectively predicted the response to ICIs. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy in patients with unresectable HCC. Patients with increases in serum IL-8 levels > 8.1% had significantly shorter overall survival (OS) and progression-free survival (PFS) than those with increases in serum IL-8 levels ≤ 8.1% (P < 0.001). Increases in serum IL-8 levels > 8.1% were independent prognosticators of worse OS (P = 0.003) and PFS (P < 0.001). Conclusion: Early changes in serum IL-8 levels, measured only 2-4 weeks after starting therapy, could predict the response to ICIs therapy, as well as OS and PFS of patients with unresectable HCC. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy and predicted worse OS and PFS.

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/ß inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

GHSR Deletion in ß-Cells of Male Mice: Ineffective in Obesity, but Effective in Protecting against Streptozotocin-Induced ß-Cell Injury in Aging.

Insulin secretion from pancreatic ß cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that ß-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced ß-cell injury in aging. ß-cell-specific-Ghsr-deficient (Ghsr-ßKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected ß-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-ßKO mice were subjected to STZ. We found that middle-aged and old Ghsr-ßKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that ß-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced ß-cell injury in aging.