Unilateral biportal endoscopy vs. open decompression for lumbar epidural lipomatosis-cohort study using a prospective registry.

Objective: This study aimed to compare the outcomes of unilateral biportal endoscopy, unilateral laminectomy bilateral decompression (UBE-ULBD), and open lumbar decompression (OLD) in patients with lumbar epidural lipomatosis (LEL). Methods: This prospective observational study was conducted from March 2019 to May 2022 and encompassed 33 patients with LEL who underwent lumbar decompression. The study included 15 cases of UBE-ULBD decompression and 18 cases of open decompression, which were followed up for 1 year. The baseline characteristics, initial clinical manifestations, and surgical details [including estimated blood loss (EBL) and preoperative complications] of all patients were recorded. Radiographic evaluation included the cross-sectional area (CSA) of the thecal sac and paraspinal muscles on MRI. Clinical results were analyzed using the Short Form-36 Score (SF-36), the Numeric Pain Rating Scale (NRS) for lumbar and leg pain, creatine kinase, the Roland and Morris Disability Questionnaire (RMDQ), and the Oswestry Disability Index (ODI). Results: The dural sac CSA increased considerably at the 1-year postoperative follow-up in both groups (p < 0.001). The operative duration in the OLD group (48.2 ± 7.2 min) was shorter than that in the UBE-ULBD group (67.7 ± 6.3 min, p < 0.001). The OLD group (97.2 ± 19.8 mL) was associated with more EBL than the UBE-ULBD group (40.6 ± 13.6 mL, p < 0.001). The duration of hospitalization in the OLD group (5.4 ± 1.3 days) was significantly longer compared with the UBE-ULBD group (3.5 ± 1.2 days, p < 0.01). The SF-36, NRS, RMDQ, and ODI scores improved in both groups postoperatively (p < 0.001). Serum creatine kinase values in the UBE-ULBD group (101.7 ± 15.5) were significantly lower than those in the OLD group (330.8 ± 28.1 U/L) 1 day after surgery (p < 0.001). The degree of paraspinal muscle atrophy in the UBE-ULBD group (4.81 ± 1.94) was significantly lower than that in the OLD group (12.15 ± 6.99) at 1 year (p < 0.001). Conclusion: UBE-ULBD and OLD demonstrated comparable clinical outcomes in treating LEL. However, UBE-ULBD surgery was associated with shorter hospital stays, lower rates of incision infection, lighter paravertebral muscle injury, and lower EBL than OLD surgery. Consequently, UBE-ULBD can be recommended in patients with LEL if conservative treatment fails.

Nomogram Based on High-Resolution Vessel Wall MRI Features to Differentiate Moyamoya Disease From Atherosclerosis-Associated Moyamoya Vasculopathy.

BACKGROUND: The angiographic features of moyamoya disease (MMD) and atherosclerosis-associated moyamoya vasculopathy (AS-MMV) are similar, but the etiology and clinical treatment strategies are different. Differentiating MMD from AS-MMV helps to choose the appropriate treatment. PURPOSE: To investigate the feasibility of a nomogram based on high-resolution vessel wall (HR-VWI) MRI features to differentiate MMD from AS-MMV. STUDY TYPE: Retrospective. SUBJECTS: One hundred and two patients with MMD (N = 52) or AS-MMV (N = 50) in the training cohort (9-72 years; 54 females) and 70 patients with MMD (N = 42) or AS-MMV (N = 28) in the validation cohort (7-69 years; 33 females). FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional time-of-flight MR angiography (3D-TOF-MRA), spin echo high-resolution 3D T1-weighted imaging (3D-T1WI), 3D T2-weighted imaging (3D-T2WI), and contrast-enhanced 3D-T1WI. ASSESSMENT: Image assessment was performed by three neuroradiologists (with 10, 15, and 18 years of experience). Demographic characteristic and image features were evaluated and compared. Independent factors of MMD were screened to construct a nomogram model in the training cohort. The validation cohort was used to validated its generality. STATISTICAL TESTS: Interclass correlation coefficient (ICC), kappa, t-test, χ2 test, receiver operating characteristic (ROC) curve, area under the curve (AUC), calibration curve and concordance index (C-index). A P-value <0.05 was considered statistically significant. RESULTS: Significant differences were observed between MMD and AS-MMV in terms of age, vessel outer diameter, vessel wall thickening pattern, maximum thickness, dot sign, and anterior cerebral artery (ACA) involved. Age, outer diameter, dot sign, and ACA involved were independent factors. The C-index was 0.886 in the training cohort and 0.859 in the validation cohort. The ROC demonstrated high diagnostic efficacy with an AUC of 0.884 in the training cohort and 0.857 in the validation cohort. DATA CONCLUSION: A nomogram model based on age, vessel outer diameter, dot sign and ACA involved may effectively distinguish MMD from AS-MMV with good reliability and accuracy. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

ST-Phys: Unsupervised Spatio-Temporal Contrastive Remote Physiological Measurement.

Remote photoplethysmography (rPPG) is a non-contact method that employs facial videos for measuring physiological parameters. Existing rPPG methods have achieved remarkable performance. However, the success mainly profits from supervised learning over massive labeled data. On the other hand, existing unsupervised rPPG methods fail to fully utilize spatio-temporal features and encounter challenges in low-light or noise environments. To address these problems, we propose an unsupervised contrast learning approach, ST-Phys. We incorporate a low-light enhancement module, a temporal dilated module, and a spatial enhanced module to better deal with long-term dependencies under the random low-light conditions. In addition, we design a circular margin loss, wherein rPPG signals originating from identical videos are attracted, while those from distinct videos are repelled. Our method is assessed on six openly accessible datasets, including RGB and NIR videos. Extensive experiments reveal the superior performance of our proposed ST-Phys over state-of-the-art unsupervised rPPG methods. Moreover, it offers advantages in parameter reduction and noise robustness.

Earthworm-Inspired Ultra-Durable Sliding Triboelectric Nanogenerator with Bionic Self-Replenishing Lubricating Property for Wind Energy Harvesting and Self-Powered Intelligent Sports Monitoring.

Triboelectric nanogenerators (TENGs), a promising strategy for harvesting distributed low-quality power sources, face inevitable bottlenecks regarding long-term abrasion and poor durability. Herein, both issues are addressed by selecting an earthworm-inspired self-replenishing bionic film (ERB) as the tribo-material of sliding-freestanding TENGs (SF-TENGs), it consists of an interconnected 3D porous network structure capable of storing and releasing lubricant under cyclic mechanical stimuli. Thanks to the superiority of self-replenishing property, there is no need for periodic replenishment and accurate content control of lubricant over the interfacial-lubricating SF-TENGs based on dense tribo-layers. Additionally, an SF-TENG based on ERB film (ERB-TENG) demonstrates remarkable output stability with only a slight attenuation of 1% after continuous operation for 100 000 cycles. Moreover, the ERB-TENG displays a distinguished anti-wear property, exhibiting no distinct abrasion with an ultra-low coefficient of friction (0.077) and maintaining output stability over a prolonged period of 35 days. Furthermore, integration with an energy management circuit enables the ERB-TENG to achieve a 39-fold boost in charging speed. This work proposes a creative approach to enhance the durability and extend the lifespan of TENG devices, which is also successfully applied to wind energy harvesting and intelligent sports monitoring.

NEK2 promotes TP53 ubiquitination to enhance the proliferation and migration of TP53 wild-type glioblastoma cells.

The most common primary malignant tumor in the adult brain is glioblastoma multiforme (GBM); however, its underlying pathogenic mechanism remains elusive. The never in mitosis (NIMA)-related kinase 2 (NEK2) has been closely associated with the prognosis of various malignancies. Nevertheless, the complete elucidation of NEK2's potential clinical value, particularly in glioma prognosis and development, remains lacking. U87MG and A172 glioblastoma cells were infected with sh-NEK2 lentivirus or oe-NEK2 plasmid to investigate the effect of NEK2 on cell proliferation, migration, and invasion. Cell viability was measured using CCK-8 and colony formation assays, while Transwell assay was utilized to assess cell migration and invasion. Protein expression levels were determined through western blot analysis. Additionally, CGGA and TCGA databases were used for bioinformatics analysis in order to examine the NEK2 expression. Through comprehensive bioinformatics analysis, we identified elevated mRNA expression levels of NEK2 in gliomas compared to normal tissues, which correlated with poor prognosis among glioma patients. Moreover, functional experiments revealed that silencing NEK2 suppressed glioma cell proliferation while overexpression of NEK2 promoted migration and invasion capabilities. Finally, our study uncovered that NEK2 regulates the malignant progression of TP53 wild-type glioblastoma by facilitating TP53 ubiquitination.

Interpretable deep learning insights: Unveiling the role of 1 Gy volume on lymphopenia after radiotherapy in breast cancer.

BACKGROUND: Lymphopenia is known for its significance on poor survivals in breast cancer (BC) patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in BC. MATERIAL AND METHODS: BC patients treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. RESULTS: Totally 918 consecutive patients with invasive BC enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. CONCLUSION: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in BC patients. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study warranted for RT plan optimization.

Imprinted lncRNA KCNQ1OT1 regulates CDKN1C expression through promoter binding and chromatin folding in pigs.

Long noncoding RNAs (lncRNAs) are implicated in a number of regulatory functions in eukaryotic genomes. In humans, KCNQ1OT1 is a 91 kb imprinted lncRNA that inhibits multiple surrounding genes in cis. Among them, CDKN1C is closely related to KCNQ1OT1 and is involved in multiple epigenetic disorders. Here, we found that pigs also had a relatively conserved paternal allele expressing KCNQ1OT1 and had a shorter 5' end (∼27 kb) compared to human KCNQ1OT1. Knockdown of KCNQ1OT1 using antisense oligonucleotides (ASO) showed that upregulation of CDKN1C expression in pigs. However, porcine KCNQ1OT1 did not affect the DNA methylation status of the CpG islands in the promoters of KCNQ1OT1 and CDKN1C. Inhibition of DNA methyltransferase using Decitabine treatment resulted in a significant increase in both KCNQ1OT1 and CDKN1C expression, suggesting that the regulation between KCNQ1OT1 and CDKN1C may not be dependent on RNA interference. Further use of chromosome conformation capture and reverse transcription-associated trap detection in the region where CDKN1C was located revealed that KCNQ1OT1 bound to the CDKN1C promoter and affected chromosome folding. Phenotypically, inhibition of KCNQ1OT1 at the cumulus-oocyte complex promoted cumulus cell transformation, and to upregulated the expression of ALPL at the early stage of osteogenic differentiation of porcine bone marrow mesenchymal stem cells. Our results confirm that the expression of KCNQ1OT1 imprinting in pigs as well as porcine KCNQ1OT1 regulates the expression of CDKN1C through direct promoter binding and chromatin folding alteration. And this regulatory mechanism played an important role in cell differentiation.

Barley Protein LFBEP-C1 from Lactiplantibacillus plantarum dy-1 Fermented Barley Extracts by Inhibiting Lipid Accumulation in a Caenorhabditis elegans Model.

Objective: This study aimed to investigate the lipid-lowering activity of LFBEP-C1 in high glucose-fed Caenorhabditis elegans (C. elegans). Methods: In this study, the fermented barley protein LFBEP-C1 was prepared and tested for its potential anti-obesity effects on C. elegans. The worms were fed Escherichia coli OP50 ( E. coli OP50), glucose, and different concentrations of LFBEP-C1. Body size, lifespan, movement, triglyceride content, and gene expression were analyzed. The results were analyzed using ANOVA and Tukey's multiple comparison test. Results: Compared with the model group, the head-swing frequency of C. elegans in the group of LFBEP-C1 at 20 µg/mL increased by 33.88%, and the body-bending frequency increased by 27.09%. This indicated that LFBEP-C1 improved the locomotive ability of C. elegans. The average lifespan of C. elegans reached 13.55 days, and the body length and width of the C. elegans decreased after LFBEP-C1 intake. Additionally, LFBEP-C1 reduced the content of lipid accumulation and triglyceride levels. The expression levels of sbp-1, daf-2, and mdt-15 significantly decreased, while those of daf-16, tph-1, mod-1, and ser-4 significantly increased after LFBEP-C1 intake. Changes in these genes explain the signaling pathways that regulate lipid metabolism. Conclusion: LFBEP-C1 significantly reduced lipid deposition in C. elegans fed a high-glucose diet and alleviated the adverse effects of a high-glucose diet on the development, lifespan, and exercise behavior of C. elegans. In addition, LFBEP-C1 regulated lipid metabolism mainly by mediating the expression of genes in the sterol regulatory element-binding protein, insulin, and 5-hydroxytryptamine signaling pathways.

NLRP4E regulates actin cap formation through SRC and CDC42 during oocyte meiosis.

BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.

Physiological and molecular bases of the nickel toxicity responses in tomato.

Nickel (Ni), a component of urease, is a micronutrient essential for plant growth and development, but excess Ni is toxic to plants. Tomato (Solanum lycopersicum L.) is one of the important vegetables worldwide. Excessive use of fertilizers and pesticides led to Ni contamination in agricultural soils, thus reducing yield and quality of tomatoes. However, the molecular regulatory mechanisms of Ni toxicity responses in tomato plants have largely not been elucidated. Here, we investigated the molecular mechanisms underlying the Ni toxicity response in tomato plants by physio-biochemical, transcriptomic and molecular regulatory network analyses. Ni toxicity repressed photosynthesis, induced the formation of brush-like lateral roots and interfered with micronutrient accumulation in tomato seedlings. Ni toxicity also induced reactive oxygen species accumulation and oxidative stress responses in plants. Furthermore, Ni toxicity reduced the phytohormone concentrations, including auxin, cytokinin and gibberellic acid, thereby retarding plant growth. Transcriptome analysis revealed that Ni toxicity altered the expression of genes involved in carbon/nitrogen metabolism pathways. Taken together, these results provide a theoretical basis for identifying key genes that could reduce excess Ni accumulation in tomato plants and are helpful for ensuring food safety and sustainable agricultural development.

Single-Stranded Nucleic Acid Transmembrane Molecular Carriers Based on Positively Charged Helical Foldamers.

Transmembrane delivery of biologically active nucleic acids is an important process in cells and has inspired one to develop advanced drug delivery techniques. In this contribution, molecular-level single-stranded nucleic acid transmembrane carriers are reported based on 3.2 nm long Huc's foldamers (AOrnQ3Q3)8 and (mQ3Q2)8 with linearly and helically aligned positive charges, respectively. These two foldamers not only show very strong DNA affinity via electrostatic interactions but also discriminatively bind single-stranded DNA (ss-DNA) and double-stranded DNA (ds-DNA), corroborating the importance of precise charge arrangement in the electrostatic interactions. More importantly, these two foldamers are capable of efficiently transporting ss-DNA across the lipid membranes, and the ss-DNA transport activity of (AOrnQ3Q3)8 with linearly aligned charges is higher than that of (mQ3Q2)8 with helically aligned charges. Thus a type of novel single-stranded nucleic acid transmembrane molecular carriers based on positively charged helical foldamers are introduced. Further, effective and enhanced expression in EGFP-mRNA transfection experiments strongly demonstrates the potential of positively charged foldamers for RNA transmembrane transport and therapy.

Sensitive and rapid identification of pathogens by droplet digital PCR in a cohort of septic patients: a prospective diagnostic study.

BACKGROUND: There is a critical need for a rapid and sensitive pathogen detection method for septic patients. This study aimed to investigate the diagnostic efficacy of Digital droplet polymerase chain reaction (ddPCR) in identifying pathogens among suspected septic patients. METHODS: We conducted a prospective pilot diagnostic study to clinically validate the multiplex ddPCR panel in diagnosing suspected septic patients. A total of 100 sepsis episodes of 89 patients were included in the study. RESULTS: In comparison to blood culture, the ddPCR panel exhibited an overall sensitivity of 75.0% and a specificity of 69.7%, ddPCR yielded an additional detection rate of 17.0% for sepsis cases overall, with a turnaround time of 2.5 h. The sensitivity of ddPCR in the empirical antibiotic treatment and the non-empirical antibiotic treatment group were 78.6% versus 80.0% (p > 0.05). Antimicrobial resistance genes were identified in a total of 13 samples. Whenever ddPCR detected the genes beta-lactamase-Klebsiella pneumoniae carbapenemase (blaKPC) or beta-lactamase-New Delhi metallo (blaNDM), these findings corresponded to the cultivation of carbapenem-resistant gram-negative bacteria. Dynamic ddPCR monitoring revealed a consistent alignment between the quantitative ddPCR results and the trends observed in C-reactive protein and procalcitonin levels. CONCLUSIONS: Compared to blood culture, ddPCR exhibited higher sensitivity for pathogen diagnosis in suspected septic patients, and it provided pathogen and drug resistance information in a shorter time. The quantitative results of ddPCR generally aligned with the trends seen in C-reactive protein and procalcitonin levels, indicating that ddPCR can serve as a dynamic monitoring tool for pathogen load in septic patients.

Integrated serum pharmacochemistry with network pharmacology and pharmacological validation to elucidate the mechanism of yiqitongmai decoction (YQTMD) against myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: Yiqitongmai decoction (YQTMD), a classic TCM, has been widely used in clinical treatment for MI. However, it is still difficult to clarify the potential active compounds and pharmacological mechanisms of it in treating MI. AIM OF THE STUDY: To explore the active ingredients, pharmacological effects, potential targets and mechanisms of YQTMD against MI. MATERIALS AND METHODS: Serum pharmacochemistry by UPLC-MS/MS was applied to analyze the phytochemical components in serum from YQTMD. These components were then used to predict the potential targets using network pharmacology approach and molecular dynamics simulations, and then the protective effect of them on H9c2 cells following hypoxic conditions was assessed. Afterwards, the pharmacological effects of YQTMD on MI in mice were tested by determining electrocardiogram (ECG), echocardiography, cardiac biomarkers, oxidative stress, inflammation and pathophysiological changes. The protein levels involving STAT3 signal were detected using Western blot and immunofluorescence assays. Furthermore, STAT3 inhibitor Sttatic was employed to further elucidate the underlying mechanisms. RESULTS: Totally, 26 compounds derived from YQTMD were identified in mice serum, and 201 genes associated with the compounds were collected. The compounds including safflomin A, ferulic acid, gypenoside XVII, ginsenoside Rg1 and glycyrrhizic acid were identified as the critical compounds of YQTMD to regulate STAT3 pathway. In vitro, compounds combination significantly enhanced the viability of H9c2 cells and reduced ROS level compared to model cells. The in vivo results showed that YQTMD effectively reduced myocardial injury, as evidenced by the decreased serum cardiac injury markers, reduction in the size of myocardial infarct, restoration of abnormal alterations in ECG and decrease in cardiomyocyte apoptosis. Additionally, YQTMD attenuated MI-induced cardiac dysfunction, alleviated pathological changes, reduced MDA levels, and enhanced SOD and GSH levels compared with model mice. Significantly, the levels of IL-6, IL-1ß, and TNF-α were observed to decrease in the YQTMD group. The expression levels of key proteins (p-STAT3, HIF-1α, NOX2, TLR5 and Caspase3) in STAT3 pathway were also regulated by YQTMD. However, the cardioprotective effects of YQTMD on MI were attenuated by STAT3 inhibitor Sttatic. CONCLUSIONS: This study investigated the active ingredients and potential mechanisms of YQTMD for MI treatment based on serum pharmacochemistry and network pharmacology approaches, revealing that YQTMD exerts its therapeutic effects on MI by alleviating oxidative stress, inflammation and apoptosis through adjusting STAT3 signaling pathway.

Multiomics Analysis Reveals Leucine Deprivation Promotes Bile Acid Synthesis by Upregulating Hepatic CYP7A1 and Intestinal Turicibacter sanguinis in Mice.

BACKGROUND: Leucine, a branched-chain amino acid, participates in the regulation of lipid metabolism and the composition of the intestinal microbiota. However, the related mechanism remains unclear. OBJECTIVES: Here, we aimed to reveal the potential mechanisms by which hepatic CYP7A1 (a rate-limiting enzyme for bile acid [BA] synthesis) and gut microbiota coregulate BA synthesis under leucine deprivation. METHODS: To this end, 8-wk-old C57BL/6J mice were fed with either unpurified diets or leucine-free diets for 1 wk. Then, we investigated whether secondary BAs were synthesized by Turicibacter sanguinis in 7-wk-old C57BL/6J germ-free mice gavaged with T. sanguinis for 2 wk by determining BA concentrations in the plasma, liver, and cecum contents using liquid chromatography-tandem mass spectrometry. RESULTS: The results showed that leucine deprivation resulted in a significant increase in total BA concentration in the plasma and an increase in the liver, but no difference in total BA was observed in the cecum contents before and after leucine deprivation. Furthermore, leucine deprivation significantly altered BA profiles such as taurocholic acid and ω-muricholic acid in the plasma, liver, and cecum contents. CYP7A1 expression was significantly upregulated in the liver under leucine deprivation. Leucine deprivation also regulated the composition of the gut microbiota; specifically, it significantly upregulated the relative abundance of T. sanguinis, thus enhancing the conversion of primary BAs into secondary BAs by intestinal T. sanguinis in mice. CONCLUSIONS: Overall, leucine deprivation regulated BA profiles in enterohepatic circulation by upregulating hepatic CYP7A1 expression and increasing intestinal T. sanguinis abundance. Our findings reveal the contribution of gut microbiota to BA metabolism under dietary leucine deprivation.

Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer.

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

The short-term effects of individual and mixed ambient air pollutants on suicide mortality: A case-crossover study.

It is critical to explore intervenable environmental factors in suicide mortality. Based on 30,688 suicide cases obtained from the Mortality Surveillance System of the Jiangsu Provincial Centre for Disease Control and Prevention, we utilized a case-crossover design, and found that the OR of suicide deaths increased by a maximum of 0.71 % (95 % CI: 0.09 %, 1.32 %), 0.68 % (95 % CI: 0.12 %, 1.25 %), 0.77 % (95 % CI: 0.19 %, 1.37 %), 2.95 % (95 % CI: 1.62 %, 4.29 %), 4.18 % (95 % CI: 1.55 %, 6.88 %), and 0.93 % (95 % CI: 0.10 %, 1.77 %), respectively, for per 10 µg/m3 increase in the particulate matter (PM) with diameters ≤ 2.5 µm (PM2.5), PM with diameters ≤ 10 µm (PM10), ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), and per 0.1 mg/m3 increase in carbon monoxide (CO) concentrations with the conditional logistic regression analysis. People living in county-level cities were more susceptible. Particularly, a significant positive association was found between air pollutant mixture exposure and suicide deaths (OR=1.04,95 % CI: 1.01, 1.06). The excess fraction of suicide deaths due to air pollution reached a maximum of 8.07 %. In conclusion, we found associations between individual and mixed ambient air pollutants and suicide deaths, informing the development of integrated air pollution management and targeted measures for suicide prevention and intervention. ENVIRONMENTAL IMPLICATION: As a major contributor to the global burden of disease, air pollution was confirmed by accumulating studies to have adverse impact on mental health, and potentially lead to suicide deaths. However, systematic studies on the association between air pollution and suicide mortality are lacking. We explored the associations of multiple air pollutants and pollution mixtures with suicide deaths and assessed excess suicide mortality due to air pollution, emphasizing the importance of air pollution control on suicide prevention. Our study provides evidence to support mechanistic studies on the association between air pollution and suicide, and informs comprehensive air pollution management.

Hippocampal excitation-inhibition balance underlies the 5-HT2C receptor in modulating depressive behaviours.

The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) in depression is a topic of debate, and the underlying mechanisms remain largely unclear. We now elucidate hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviors, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons by using behavioral analyses, microdialysis coupled with mass spectrum, and electrophysiological recording. Moreover, 5-HT2CR modulated neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction through influencing intracellular Ca2+ release, as determined by fiber photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON by specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP, abolished 5-HT2CR inhibition-induced depressive-like behaviors, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and a consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviors in the presence of 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviors and highlight the hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioral consequences of 5-HT2CR inhibition.

Effects of adding bile acids to dietary storage japonica brown rice on growth performance, meat quality, and intestinal microbiota of growing-finishing Min pigs.

Introduction: This study investigated the effects of storage japonica brown rice (SJBR) and bile acids (BA) on the growth performance, meat quality, and intestinal microbiota of growing-finishing Min pigs. Methods: A total of 24 healthy Min pigs with a similar body weight of 42.25 ± 2.13 kg were randomly divided into three groups with eight replicates of one pig each. The groups were as follows: CON (50% corn), SJBR (25% corn +25% SJBR), and SJBR + BA (25% corn +25% SJBR +0.025% hyodeoxycholic acid). The experimental period lasted from day 90 (the end of the nursery phase) to day 210 (the end of the finishing phase). Results: The results showed the following: (1) Compared with the CON group, there was no significant difference in the average daily gain (ADG) and average daily feed intake (ADFI) of the SJBR and SJBR + BA groups, and the feed conversion ratio (FCR) was significantly decreased (p < 0.05). (2) Compared with the CON group, the total protein (TP) content in the serum was significantly increased, and the blood urea nitrogen (BUN) content was significantly decreased (p < 0.05) in the SJBR and SJBR + BA groups; moreover, HDL-C was significantly higher by 35% (p < 0.05) in the SJBR + BA group. (3) There were no significant differences in carcass weight, carcass length, pH, drip loss, cooking loss, and shear force among the groups; the eye muscle area was significantly increased in the SJBR group compared with the CON group (p < 0.05); back fat thickness was significantly decreased in the SJBR + BA group compared with the SJBR group (p < 0.05); and the addition of SJBR significantly increased the mRNA expression of MyHC I in the longissimus dorsi (LD) muscle of growing-finishing Min pigs (p < 0.05). (4) The cecal bacteria were detected using 16S rDNA, and the proportion of Lactobacillus was increased gradually at the genus level, but there was no significant difference among the different groups. Conclusion: In conclusion, 25% SJBR can improve the growth performance and increase the abundance of intestinal beneficial bacteria, and based on this, adding bile acids can reduce the back fat thickness of growing-finishing Min pigs.