USP28 Serves as a Key Suppressor of Mitochondrial Morphofunctional Defects and Cardiac Dysfunction in the Diabetic Heart.

BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.

Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome.

AIM: Doxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. METHODS AND RESULTS: Mice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition. CONCLUSION: HSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.

Identification of the genetic characteristics of copy number variations in experimental specific pathogen-free ducks using whole-genome resequencing.

BACKGROUND: Specific pathogen-free ducks are a valuable laboratory resource for waterfowl disease research and poultry vaccine development. High throughput sequencing allows the systematic identification of structural variants in genomes. Copy number variation (CNV) can explain the variation of important duck genetic traits. Herein, the genome-wide CNVs of the three experimental duck species in China (Jinding ducks (JD), Shaoxing ducks (SX), and Fujian Shanma ducks (SM)) were characterized using resequencing to determine their genetic characteristics and selection signatures. RESULTS: We obtained 4,810 CNV regions (CNVRs) by merging 73,012 CNVs, covering 4.2% of the duck genome. Functional analysis revealed that the shared CNVR-harbored genes were significantly enriched for 31 gene ontology terms and 16 Kyoto Encyclopedia of Genes and Genomes pathways (e.g., olfactory transduction and immune system). Based on the genome-wide fixation index for each CNVR, growth (SPAG17 and PTH1R), disease resistance (CATHL3 and DMBT1), and thermoregulation (TRPC4 and SLIT3) candidate genes were identified in strongly selected signatures specific to JD, SM, and SX, respectively. CONCLUSIONS: In conclusion, we investigated the genome-wide distribution of experimental duck CNVs, providing a reference to establish the genetic basis of different phenotypic traits, thus contributing to the management of experimental animal genetic resources.

SGLT2i reduces risk of developing HCC in patients with co-existing type 2 diabetes and hepatitis B infection: A territory-wide cohort study in Hong Kong.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) and chronic hepatitis B infection (CHB) are risk factors of HCC. Sodium glucose co-transporter 2 inhibitors (SGLT2i) inhibit HCC oncogenesis in preclinical studies. However, clinical studies are lacking. This study aimed to evaluate the impact of SGLT2i use on incident HCC using a territory-wide cohort of exclusively patients with co-existing T2D and CHB. APPROACH AND RESULTS: Patients with co-existing T2D and CHB between 2015 and 2020 were identified from the representative electronic database of the Hong Kong Hospital Authority. Patients with and without SGLT2i use were 1:1 matched by propensity score for their demographics, biochemistry results, liver-related characteristics, and background medications. Cox proportional hazards regression model was used to assess the association between SGLT2i use and incident HCC. A total of 2,000 patients with co-existing T2D and CHB (1,000 in each SGLT2i and non-SGLT2i group; 79.7% on anti-HBV therapy at baseline) were included after propensity-score matching. Over a follow-up of 3,704 person-years, the incidence rates of HCC were 1.39 and 2.52 cases per 100 person-year in SGLT2i and non-SGLT2i groups, respectively. SGLT2i use was associated with a significantly lower risk of incident HCC (HR 0.54, 95%CI: 0.33-0.88, p =0.013). The association remained similar regardless of sex, age, glycemic control, diabetes duration, presence of cirrhosis and hepatic steatosis, timing of anti-HBV therapy, and background antidiabetic agents including dipeptidyl peptidase-4 inhibitors, insulin, or glitazones (all p interaction>0.05). CONCLUSIONS: Among patients with co-existing T2D and CHB, SGLT2i use was associated with a lower risk of incident HCC.

Association between different insulin resistance surrogates and all-cause mortality in patients with coronary heart disease and hypertension: NHANES longitudinal cohort study.

BACKGROUND: Studies on the relationship between insulin resistance (IR) surrogates and long-term all-cause mortality in patients with coronary heart disease (CHD) and hypertension are lacking. This study aimed to explore the relationship between different IR surrogates and all-cause mortality and identify valuable predictors of survival status in this population. METHODS: The data came from the National Health and Nutrition Examination Survey (NHANES 2001-2018) and National Death Index (NDI). Multivariate Cox regression and restricted cubic splines (RCS) were performed to evaluate the relationship between homeostatic model assessment of IR (HOMA-IR), triglyceride glucose index (TyG index), triglyceride glucose-body mass index (TyG-BMI index) and all-cause mortality. The recursive algorithm was conducted to calculate inflection points when segmenting effects were found. Then, segmented Kaplan-Meier analysis, LogRank tests, and multivariable Cox regression were carried out. Receiver operating characteristic (ROC) and calibration curves were drawn to evaluate the differentiation and accuracy of IR surrogates in predicting the all-cause mortality. Stratified analysis and interaction tests were conducted according to age, gender, diabetes, cancer, hypoglycemic and lipid-lowering drug use. RESULTS: 1126 participants were included in the study. During the median follow-up of 76 months, 455 participants died. RCS showed that HOMA-IR had a segmented effect on all-cause mortality. 3.59 was a statistically significant inflection point. When the HOMA-IR was less than 3.59, it was negatively associated with all-cause mortality [HR = 0.87,95%CI (0.78, 0.97)]. Conversely, when the HOMA-IR was greater than 3.59, it was positively associated with all-cause mortality [HR = 1.03,95%CI (1.00, 1.05)]. ROC and calibration curves indicated that HOMA-IR was a reliable predictor of survival status (area under curve = 0,812). No interactions between HOMA-IR and stratified variables were found. CONCLUSION: The relationship between HOMA-IR and all-cause mortality was U-shaped in patients with CHD and hypertension. HOMA-IR was a reliable predictor of all-cause mortality in this population.

[18F]FDG PET integrated with structural MRI for accurate brain age prediction.

PURPOSE: Brain aging is a complex and heterogeneous process characterized by both structural and functional decline. This study aimed to establish a novel deep learning (DL) method for predicting brain age by utilizing structural and metabolic imaging data. METHODS: The dataset comprised participants from both the Universal Medical Imaging Diagnostic Center (UMIDC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The former recruited 395 normal control (NC) subjects, while the latter included 438 NC subjects, 51 mild cognitive impairment (MCI) subjects, and 56 Alzheimer's disease (AD) subjects. We developed a novel dual-pathway, 3D simple fully convolutional network (Dual-SFCNeXt) to estimate brain age using [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) and structural magnetic resonance imaging (sMRI) images of NC subjects as input. Several prevailing DL models were trained and tested using either MRI or PET data for comparison. Model accuracies were evaluated using mean absolute error (MAE) and Pearson's correlation coefficient (r). Brain age gap (BAG), deviations of brain age from chronologic age, was correlated with cognitive assessments in MCI and AD subjects. RESULTS: Both PET- and MRI-based models achieved high prediction accuracy. The leading model was the SFCNeXt (the single-pathway version) for PET (MAE = 2.92, r = 0.96) and MRI (MAE = 3.23, r = 0.95) on all samples. By integrating both PET and MRI images, the Dual-SFCNeXt demonstrated significantly improved accuracy (MAE = 2.37, r = 0.97) compared to all single-modality models. Significantly higher BAG was observed in both the AD (P < 0.0001) and MCI (P < 0.0001) groups compared to the NC group. BAG correlated significantly with Mini-Mental State Examination (MMSE) scores (r=-0.390 for AD, r=-0.436 for MCI) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores (r = 0.333 for AD, r = 0.372 for MCI). CONCLUSION: The integration of [18F]FDG PET with structural MRI enhances the accuracy of brain age prediction, potentially introducing a new avenue for related multimodal brain age prediction studies.

Discovery of novel 4-trifluoromethyl-2-anilinoquinoline derivatives as potential anti-cancer agents targeting SGK1.

Given the critical necessity for the development of more potent anti-cancer drugs, a series of novel compounds incorporating trifluoromethyl groups within the privileged 2-anilinoquinoline scaffold was designed, synthesized, and subjected to biological evaluation through a pharmacophore hybridization strategy. Upon evaluating the in vitro anti-cancer characteristics of the target compounds, it became clear that compound 8b, which contains a (4-(piperazin-1-yl)phenyl)amino substitution at the 2-position of the quinoline skeleton, displayed superior efficacy against four cancer cell lines by inducing apoptosis and cell cycle arrest. Following research conducted in a PC3 xenograft mouse model, it was found that compound 8b exhibited significant anti-cancer efficacy while demonstrating minimal toxicity. Additionally, the analysis of a 217-kinase panel pinpointed SGK1 as a potential target for this compound class with anti-cancer capabilities. This finding was further verified through molecular docking analysis and cellular thermal shift assays. To conclude, our results emphasize that compound 8b can be used as a lead compound for the development of anti-cancer drugs that target SGK1.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.

Transcatheter Aortic Valve Replacement and Coronary Protection Guided by Deep Learning and 3-Dimensional Printing.

OBJECTIVE: In this case report, the auxiliary role of deep learning and 3-dimensional printing technology in the perioperative period was discussed to guide transcatheter aortic valve replacement and coronary stent implantation simultaneously. CASE PRESENTATION: A 68-year-old man had shortness of breath and chest tightness, accompanied by paroxysmal nocturnal dyspnea, 2 weeks before presenting at our hospital. Echocardiography results obtained in the outpatient department showed severe aortic stenosis combined with regurgitation and pleural effusion. The patient was first treated with closed thoracic drainage. After 800 mL of pleural effusion was collected, the patient's symptoms were relieved and he was admitted to the hospital. Preoperative transthoracic echocardiography showed severe bicuspid aortic valve stenosis combined with calcification and aortic regurgitation (mean pressure gradient, 42 mmHg). Preoperative computed tomography results showed a type I bicuspid aortic valve with severe eccentric calcification. The leaflet could be seen from the left coronary artery plane, which indicated an extremely high possibility of coronary obstruction. After preoperative imaging assessment, deep learning and 3-dimensional printing technology were used for evaluation and simulation. Guided transcatheter aortic valve replacement and a coronary stent implant were completed successfully. Postoperative digital subtraction angiography showed that the bioprosthesis and the chimney coronary stent were in ideal positions. Transesophageal echocardiography showed normal morphology without paravalvular regurgitation. CONCLUSION: The perioperative guidance of deep learning and 3-dimensional printing are of great help for surgical strategy formulation in patients with severe bicuspid aortic valve stenosis with calcification and high-risk coronary obstruction.

Effects of a mixture of glycerol monolaurate and cinnamaldehyde supplementation on laying performance, egg quality, and antioxidant status in laying hens.

BACKGROUND: This study aimed to determine the effects of a mixture of glycerol monolaurate and cinnamaldehyde (GCM) supplementation on the laying performance, egg quality, antioxidant capacity, and serum parameters of laying hens. A total of 1120 14-week-old Jingfen-1 strain laying hens with similar performance were randomly allocated to four dietary treatments: control, and GCM groups supplemented with 250, 500, or 1000 mg kg-1 for 12 weeks. RESULTS: Compared with the control group, GCM-supplemented groups significantly reduced (P < 0.05) the rate of unqualified eggs of laying hens aged 17-24 weeks. Supplementation of GCM significantly increased (P < 0.05) yolk color and serum glutathione peroxidase (GSH-Px) activity but decreased (P < 0.05) the hydrogen peroxide (H2 O2 ) content in the serum of laying hens at the age of 20 weeks. Furthermore, groups supplemented with GCM showed a significant increase (P < 0.05) in Haugh unit, yolk color, activities of total superoxide dismutase and GSH-Px, and the glucose content in serum, and a decrease (P < 0.05) in the content of urea nitrogen and H2 O2 and malondialdehyde in serum of laying hens at the age of 24 weeks. 500 mg kg-1 GCM supplementation significantly increased (P < 0.05) the number of large white follicles and 1000 mg kg-1 GCM supplementation decreased the number of large yellow follicles in 28-week-old laying hens. CONCLUSION: These results indicated that GCM supplementation has positive effects on reducing egg loss and improving egg quality in the early laying period of laying hens. © 2023 Society of Chemical Industry.

Multi-target mechanism of misoprostol in pregnancy termination based on network pharmacology and molecular docking.

Misoprostol is a prostaglandin analogue that contracts the uterus, prompting the expulsion of the embryo. No systematic evaluation of the mechanisms of misoprostol has previously been performed. In this study, known targets of misoprostol were obtained from the DrugBank database; potential targets of misoprostol were predicted using data from the SwissTargetPrediction and PharmMapper databases; and the main targets of pregnancy termination were obtained from the GeneCards database. The protein-protein interaction (PPI) network of the shared genes between misoprostol and pregnancy termination was constructed using data from the STRING database, and the "misoprostol-pregnancy termination-pathway" network was constructed and potential targets was verified through molecular docking. We analyzed 37 shared target genes and obtained a network diagram of 134 potential targets, which the core therapeutic targets were HSP90AA1, EGFR, and MAPK1. GO functional and KEGG pathway enrichment analyses showed that misoprostol can modulate the VEGF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway in pregnancy termination and mainly interferes with protein phosphorylation, cell localization, and protein hydrolysis regulation processes. This research illustrates the mechanism underlying the pharmacological effect of misoprostol, namely pregnancy termination. However, further experimental verification is warranted for optimal use of misoprostol during clinical practice.

Le misoprostol est un analogue des prostaglandines qui contracte l'utérus, provoquant l'expulsion de l'embryon. Aucune évaluation systématique des mécanismes du misoprostol n'a été réalisée auparavant. Dans cette étude, les cibles connues du misoprostol ont été obtenues à partir de la base de données DrugBank ; Les cibles potentielles du misoprostol ont été prédites à l'aide des données des bases de données SwissTargetPrediction et PharmMapper ; et les principales cibles de l'interruption de grossesse ont été obtenues à partir de la base de données GeneCards. Le réseau d'interaction protéine-protéine (IPP) des gènes partagés entre le misoprostol et l'interruption de grossesse a été construit à l'aide des données de la base de données STRING, et le réseau « voie d'interruption de grossesse-misoprostol ¼ a été construit et les cibles potentielles ont été vérifiées par amarrage moléculaire. Nous avons analysé 37 gènes cibles partagés et obtenu un diagramme de réseau de 134 cibles potentielles, dont les principales cibles thérapeutiques étaient HSP90AA1, EGFR et MAPK1. Les analyses d'enrichissement des voies fonctionnelles GO et KEGG ont montré que le misoprostol peut moduler la voie de signalisation VEGF, la voie de signalisation du calcium et la voie de signalisation NF-κB lors de l'interruption de grossesse et interfère principalement avec les processus de phosphorylation des protéines, de localisation cellulaire et de régulation de l'hydrolyse des protéines. Cette recherche illustre le mécanisme sous-jacent à l'effet pharmacologique du misoprostol, à savoir l'interruption de grossesse. Cependant, une vérification expérimentale plus approfondie est justifiée pour une utilisation optimale du misoprostol au cours de la pratique clinique.

Transcatheter Mitral Valve-in-Valve Implantation Applying a Long Pre-Curved Sheath for Patients with Degenerated Bioprosthetic Mitral Valve.

Backgrounds: Percutaneous transseptal transcatheter mitral valve-in-valve implantation (TMViV) has become an alternative minimally invasive treatment choice for patients with degenerated mitral bioprosthesis and high surgical risk. However, transseptal approach is more technically challenging than transapical approach in TMViV procedures. Objective: The objective of this study was to introduce the experience of applying long pre-curved sheaths in transseptal TMViV procedures and to evaluate the effect of long pre-curved sheath techniques in TMViV procedures. Methods: Between January 2020 and December 2021, 27 patients with degenerated bioprosthetic mitral valve underwent TMViV procedures using a balloon-expandable valve via the transseptal approach. The regular 14/16F expandable sheath were used for low-profile delivery in first 10 cases, and 22F long pre-curved sheath were used in the next 17 cases during procedures. We retrospectively reviewed the catheter techniques, perioperative characteristics, and prognosis. The median follow-up time was 12 (1-21) months. To further scrutinize our data, we divided the group into the early 10 patients using 14/16F expandable sheath and the subsequent 17 patients with long pre-curved sheath in order to assess the impact of different sheaths and procedural details on outcomes. Results: Procedural success was obtained in all patients with no in-hospital mortality. Seventeen patients received 26 mm prostheses; the remaining ten patients received 29 mm prostheses. Post balloon dilatation was performed in one case. Total procedure time was (96.1 ± 28.2) min, the fluoroscopic time was (27.4 ± 6.5) min, and total contrast volume was (50.7 ± 10.1) mL. One patient received blood transfusion because of hemorrhage at the femoral puncture site. One patient received a permanent pacemaker implantation due to high-degree atrioventricular block at postoperative day 3. There were no other major post-procedure complications and the median length of hospital stay was 4 days. Twenty-five (92.6%) patients improved by ≥ 1 New York Heart Association (NYHA) functional class at 30 days. In subsequent sub analysis, there were shorter procedural time [(85.2 ± 24.3) vs. (115.2 ± 25.6) min, p = 0.0048] and shorter fluoroscopic time [(24.3 ± 5.2) vs. (31.3 ± 5.1) min, p = 0.0073] in cases with the long pre-curved sheath than ones with regular expandable sheath. The iatrogenic atrial septal defect (ASD) closure was performed because of the transeptal large right to left shunt in 2 cases with regular expandable sheath, but no patient needed intraoperative ASD closure in cases with the long pre-curved sheath. Conclusions: Transseptal TMViV using long pre-curved sheath could simplify transseptal approach with reliable outcomes for patients of degenerated mitral bioprosthesis.

OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential.

Reduction of mitochondrial membrane potential (Δψm ) is a hallmark of mitochondrial dysfunction. It activates adaptive responses in organisms from yeast to human to rewire metabolism, remove depolarized mitochondria, and degrade unimported precursor proteins. It remains unclear how cells maintain Δψm , which is critical for maintaining iron-sulfur cluster (ISC) synthesis, an indispensable function of mitochondria. Here, we show that yeast oxidative phosphorylation mutants deficient in complex III, IV, V, and mtDNA, respectively, exhibit activated stress responses and progressive reduction of Δψm . Extensive omics analyses of these mutants show that these mutants progressively activate adaptive responses, including transcriptional downregulation of ATP synthase inhibitor Inh1 and OXPHOS subunits, Puf3-mediated upregulation of import receptor Mia40 and global mitochondrial biogenesis, Snf1/AMPK-mediated upregulation of glycolysis and repression of ribosome biogenesis, and transcriptional upregulation of cytoplasmic chaperones. These adaptations disinhibit mitochondrial ATP hydrolysis, remodel mitochondrial proteome, and optimize ATP supply to mitochondria to convergently maintain Δψm , ISC biosynthesis, and cell proliferation.

Transcatheter Closure of a Paravalvular Leak After Transcatheter Aortic Valve Replacement With 3-Dimensional Printing Guidance: A Case Report.

PURPOSE: Our goal was to report the transcatheter closure of a paravalvular leak after transcatheter aortic valve replacement (TAVR) using 3-dimensional (3D) printing. CASE REPORT: A 66-year-old man who had undergone transapical and TAVR 2 years ago due to aortic regurgitation, presented with palpitations and shortness of breath owing to exacerbation of paravalvular regurgitation. Echocardiography suggested that the stented aortic valve was fixed securely in place and the valve leaflets moved normally after TAVR, but there was severe paravalvular regurgitation (3 bundles, volume 11.0 mL). Due to the high surgical risk, we closed the transcatheter paravalvular leak using preprocedural guidance with 3D printing and intraprocedural guidance with digital subtraction angiography. Postoperative echocardiography showed that the paravalvular leak was significantly reduced. 3D construction showed that the occluders and the stent valve were well placed. CONCLUSION: Transcatheter closure of a paravalvular leak of the aortic valve may be feasible with appropriate pre- and intraoperative 3D printing guidance. CLINICAL IMPACT: 3D printing technology may help surgeons to make accurate preoperative strategy before occlusion procedures.

Dietary nano-selenium alleviates heat stress-induced intestinal damage through affecting intestinal antioxidant capacity and microbiota in rainbow trout (Oncorhynchus mykiss).

Heat stress-induced intestinal damage is a key event in fish pathology. Nano-selenium (nano-Se) shows remarkably high biological activity and low toxicity, making it an ideal and ecological Se formulation; however, to date, the protective effects of nano-Se against heat stress-induced intestinal injury and pertinent molecular mechanisms remain unknown. Herein, rainbow trout (Oncorhynchus mykiss) were fed either a basal diet or basal diet + 5 mg/kg nano-Se. Samples were collected before (18 °C for 9 days; CG18 and Se18 groups) and after (24 °C for 8 h; CG24 and Se24 groups) heat stress treatment. On heat stress exposure, intestinal villus height, muscularis thickness, and goblet cell number decreased, and expression of tight junction proteins (ZO-1, occludin, and claudin-8d) was downregulated; dietary supplementation with nano-Se alleviated these effects. Furthermore, in the presence of nano-Se, catalase activity was elevated, and expression of diverse heat shock proteins (Hsp70b, Hsp90α, and Hsp30), selenoproteins (Gpx1a, Gpx1b1, and Trx), and anti-inflammatory cytokine (TGF-ß) was upregulated. In contrast, nano-Se supplementation significantly alleviated the increase of the expression of pro-inflammatory cytokines (IL-1ß and TNF-α) and the malondialdehyde content. We also observed that heat stress markedly increased the relative abundance of Actinobacteria, Firmicutes, Methylobacterium, Akkermansia, and Deinococcus and decreased that of Proteobacteria; nano-Se supplementation restored these changes, making their distribution similar to that in the control group. Overall, our findings suggest that nano-Se plays a protective role against heat stress-induced intestinal damage in rainbow trout by promoting the recovery of antioxidant enzyme activity, enhancing protein repair, alleviating inflammatory responses, and restoring intestinal microbiota composition.

Targeting FOS attenuates malignant phenotypes of breast cancer: Evidence from in silico and in vitro studies.

Data retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases can reveal important information behind molecular biomarkers and their associated oncogenesis. Therefore, this study was based on in silico predictions and in vitro experiments to explore regulatory network associated with breast carcinogenesis. The breast cancer (BC)-related data sets were retrieved from GEO database, followed by differential analysis and protein-protein interaction (PPI) analysis. Then, Fos proto-oncogene, AP-1 transcription factor subunit (FOS)-associated gene network was constructed, and the key gene-related genes in BC were screened by LinkedOmics. Finally, FOS expression was determined in BC tissues and cells, and gain-of-function assays were performed to define the role of FOS in BC cells. It was noted that seven differentially expressed genes (EGR1, RASSF9, FOSB, CDC20, KLF4, PTGS2, and FOS) were obtained from BC microarray data sets. FOS was the gene with the most nodes in PPI analysis. Poor FOS mRNA expression was identified in BC patients. Furthermore, FOS was mainly located in the extracellular matrix and was involved in cell processes. FOS was downregulated in BC tissues and cells, and FOS overexpression restrained the malignant phenotypes of BC cells. Collectively, ectopic expression of FOS curtails the development of BC.

Discharge of postoperative patients with an opioid prescription is associated with increased persistent opioid use, healthcare expenditures and mortality: a retrospective cohort study.

BACKGROUND: The risk factors for persistent opioid use after surgical discharge and the association between opioid prescription at discharge and postoperative emergency department visits, readmission, and mortality are unclear. METHODS: This population-based retrospective cohort study involved opioid-naive patients who underwent surgical procedures from January 1, 2000 to November 30, 2020. The data source was Hong Kong Hospital Authority Clinical Management System electronic health record. The primary outcome was the incidence of new persistent opioid use. Other study outcomes included 30-day emergency department visits, 30-day readmission, and 30-day all-cause mortality. Multivariable logistic regression models were used to estimate the association between opioid prescription at discharge and persistent opioid use, emergency department visits, readmission, and all-cause mortality. RESULTS: Over a median follow-up of 1 month with 36 104 person-years, 438 128 patients (opioid prescription: 32 932, no opioid prescription: 405 196) who underwent surgical procedures were analysed, of whom 15 112 (3.45%) had persistent opioid use after discharge. Prescribing opioids on discharge was associated with increased risks of developing persistent opioid use (odds ratio [OR]: 2.30, 95% confidence interval [CI]: 2.19-2.40, P<0.001), 30-day emergency department visits (OR: 1.28, 95% CI: 1.23-1.33, P<0.001), 30-day readmission (OR: 1.17, 95% CI: 1.13-1.20, P<0.001), and 30-day all-cause mortality (OR: 1.68, 95% CI: 1.53-1.86, P<0.001). CONCLUSIONS: In this large cohort of patients undergoing surgery, an opioid prescription on discharge was associated with a higher chance of persistent opioid use and increased risks of postoperative emergency department visits, readmission, and mortality. Minimising opioid prescriptions on discharge could improve perioperative patient outcomes.

Characterization of Colletotrichum Causing Anthracnose on Rubber Trees in Yunnan: Two New Records and Two New Species from China.

Among the most damaging diseases of rubber trees is anthracnose caused by the genus Colletotrichum, which leads to significant economic losses. Nonetheless, the specific Colletotrichum spp. that infect rubber trees in Yunnan Province, an important natural rubber base in China, have not been extensively investigated. Here, we isolated 118 Colletotrichum strains from rubber tree leaves exhibiting anthracnose symptoms in multiple plantations in Yunnan. Based on comparisons of their phenotypic characteristics and internal transcribed spacer ribosomal DNA sequences, 80 representative strains were chosen for additional phylogenetic analysis based on eight loci (act, ApMat, cal, CHS-1, GAPDH, GS, his3, and tub2), and nine species were identified. Colletotrichum fructicola, C. siamense, and C. wanningense were found to be the dominant pathogens causing rubber tree anthracnose in Yunnan. C. karstii was common, whereas C. bannaense, C. brevisporum, C. jinpingense, C. mengdingense, and C. plurivorum were rare. Among these nine species, C. brevisporum and C. plurivorum are reported for the first time in China, and two species are new to the world: C. mengdingense sp. nov. in the C. acutatum species complex and C. jinpingense sp. nov. in the C. gloeosporioides species complex. Their pathogenicity was confirmed with Koch's postulates by inoculating each species in vivo on rubber tree leaves. This study clarifies the geographic distribution of Colletotrichum spp. associated with anthracnose on rubber trees in representative locations of Yunnan, which is crucial for the implementation of quarantine measures.

The role of E2A in ATPR-induced cell differentiation and cycle arrest in acute myeloid leukaemia cells.

Acute myeloid leukaemia (AML) is a biologically heterogeneous disease with an overall poor prognosis; thus, novel therapeutic approaches are needed. Our previous studies showed that 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a new derivative of all-trans retinoic acid (ATRA), could induce AML cell differentiation and cycle arrest. The current study aimed to determine the potential pharmacological mechanisms of ATPR therapies against AML. Our findings showed that E2A was overexpressed in AML specimens and cell lines, and mediate AML development by inactivating the P53 pathway. The findings indicated that E2A expression and activity decreased with ATPR treatment. Furthermore, we determined that E2A inhibition could enhance the effect of ATPR-induced AML cell differentiation and cycle arrest, whereas E2A overexpression could reverse this effect, suggesting that the E2A gene plays a crucial role in AML. We identified P53 and c-Myc were downstream pathways and targets for silencing E2A cells using RNA sequencing, which are involved in the progression of AML. Taken together, these results confirmed that ATPR inhibited the expression of E2A/c-Myc, which led to the activation of the P53 pathway, and induced cell differentiation and cycle arrest in AML.

Boosting Oxygen Reduction Activity of Manganese Oxide Through Strain Effect Caused By Ion Insertion.

Transition-metal oxides with a strain effect have attracted immense interest as cathode materials for fuel cells. However, owing to the introduction of heterostructures, substrates, or a large number of defects during the synthesis of strain-bearing catalysts, not only is the structure-activity relationship complicated but also their performance is mediocre. In this study, a mode of strain introduction is reported. Transition-metal ions with different electronegativities are intercalated into the cryptomelane-type manganese oxide octahedral molecular sieves (OMS-2) structure with K ions as the template, resulting in the octahedral structural distortion of MnO6 and producing strains of different degrees. Experimental studies reveal that Ni-OMS-2 with a high compressive strain (4.12%) exhibits superior oxygen reduction performance with a half-wave potential (0.825 V vs RHE) greater than those of other reported manganese-based oxides. This result is related to the increase in the covalence of MnO6 octahedral configuration and shifting down of the eg band center caused by the higher compression strain. This research avoids the introduction of new chemical bonds in the main structure, weakens the effect of eg electron filling number, and emphasizes the pure strain effect. This concept can be extended to other transition-metal-oxide catalysts.