Isolation, structural elucidation and biosynthetic pathway of bioactive prenyl quinone compounds from Panus lecomtei based on untargeted metabolomics combined with molecular networking.

Panus lecomtei is a relatively unfamiliar and undeveloped mushroom. This study generated ethyl acetate extracts of P. lecomtei intracellular (I), extracellular (E) and total fermentation broth (T). Both E and T extracts demonstrated antioxidant and antibacterial activities at 100 to 200 µg/mL. The composition differences of metabolites of these extracts were further studied based on comparative metabolomics by LS/MS and molecular network analysis. The results revealed that there were over 2000 significantly distinct metabolites among the three extracts, with abundant prenyl quinone compounds. Furthermore, the molecular network clarified the conversion relationship of P. lecomtei metabolites. Seven known prenyl quinone derivatives (1-7) were isolated from the E extract. Among them, compound 3 displayed excellent antioxidant activity and modest antibacterial activity. Compound 5 was discovered in fungi for the first time. Finally, a potential biosynthetic route for prenyl quinone in P. lecomtei was suggested.

PTBP1 crotonylation promotes colorectal cancer progression through alternative splicing-mediated upregulation of the PKM2 gene.

BACKGROUND: Aerobic glycolysis is a tumor cell phenotype and a hallmark in cancer research. The alternative splicing of the pyruvate kinase M (PKM) gene regulates the expressions of PKM1/2 isoforms and the aerobic glycolysis of tumors. Polypyrimidine tract binding protein (PTBP1) is critical in this process; however, its impact and underlying mechanisms in colorectal cancer (CRC) remain unclear. This study aimed to investigate the role of PTBP1 crotonylation in CRC progression. METHODS: The crotonylation levels of PTBP1 in human CRC tissues and cell lines were analyzed using crotonylation proteomics and immunoprecipitation. The main crotonylation sites were identified by immunoprecipitation and immunofluorescent staining. The glycolytic capacities of CRC cells were evaluated by measuring the glucose uptake, lactate production, extracellular acidification rate, and glycolytic proton efflux rate. The role and mechanism of PTBP1 crotonylation in PKM alternative splicing were determined by Western blot, quantitative real-time PCR (RT-qPCR), RNA immunoprecipitation, and immunoprecipitation. The effects of PTBP1 crotonylation on the behaviors of CRC cells and CRC progression were assessed using CCK-8, colony formation, cell invasion, wound healing assays, xenograft model construction, and immunohistochemistry. RESULTS: The crotonylation level of PTBP1 was elevated in human CRC tissues compared to peritumor tissues. In CRC tissues and cells, PTBP1 was mainly crotonylated at K266 (PTBP1 K266-Cr), and lysine acetyltransferase 2B (KAT2B) acted as the crotonyltranferase. PTBP1 K266-Cr promoted glycolysis and lactic acid production, increasing the PKM2/PKM1 ratio in CRC tissues and cells. Mechanistically, PTBP1 K266-Cr enhanced the interaction of PTBP1 with heterogeneous nuclear ribonucleoprotein A1 and A2 (hnRNPA1/2), thus affecting the PKM alternative splicing. PTBP1 K266-Cr facilitated CRC cell proliferation, migration, and metastasis in vitro and in vivo. Pathologically, a high level of PTBP1 K266-Cr was associated with poor prognosis in CRC patients. CONCLUSIONS: Crotonylation of PTBP1 coordinates tumor cell glycolysis and promotes CRC progression by regulating PKM alternative splicing and increasing PKM2 expression.

Kidney function after liver transplantation: the contrasting roles of inflammation and tubular repair.

Kidney injury is a significant complication in end-stage liver disease (ESLD), leading to increased morbidity and mortality. While liver transplant alone (LTA) can promote kidney recovery (KR), non-recovery associates with adverse outcomes, but the underlying pathophysiology is still unclear. We studied 10 LTA recipients with or without kidney failure (KF) and measured serum levels of OPN and TIMP-1 (previously identified predictors of KR), 92 proinflammatory proteins (Olink), and urinary cell populations. Our findings revealed elevated OPN and TIMP-1 levels in KF patients, strongly correlated with tubular epithelial cells in urine. Proteomic analysis showed distinct profiles in KF, non-KF, and healthy donors, indicating an ongoing proinflammatory signature in KF. Cytokines correlated with OPN and TIMP-1 levels. We propose that high pre-LTA OPN and TIMP-1 levels are crucial for tubular regeneration and normalize with kidney recovery. Insufficient pre-LTA OPN levels may lead to persistent kidney failure. Our present data also newly indicate that kidney failure post-LTA is an active condition, in which tubular cells are persistently shed in the urine. The strict association between systemic inflammation and tubular cell loss suggests a pathogenic link that could offer therapeutic opportunities to promote kidney recovery.

Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFß and Hedgehog signal pathway.

PURPOSE: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug. METHOD: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance. RESULTS: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFß and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC. CONCLUSIONS: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFß, Hedgehog axis.

Metformin Use and Risk of Delirium in Older Adults With Type 2 Diabetes.

OBJECTIVE: Delirium is a precursor and risk factor for dementia, emphasizing the urgency of effective prevention and management strategies in older adults with type 2 diabetes (T2D). Identifying long-term, safe, and effective medications to prevent diabetes-related delirium is crucial because of its significant impact on this population. This study aimed to evaluate the protective effects of metformin against delirium in older adults with T2D, using a competing risk analysis of death to provide a more accurate assessment. RESEARCH DESIGN AND METHODS: Metformin users were compared with a cohort of nonusers. Multivariable Cox regression and Fine and Gray methods were used to assess the risk of delirium and mortality. RESULTS: Our study included 66,568 metformin users and 66,568 nonusers, matched by propensity score. The use of metformin was associated with a significantly lower risk of delirium, with adjusted hazard ratios ranging from 0.77 to 0.81. A dose-response relationship was observed, indicating that higher cumulative and daily doses of metformin were associated with greater reductions in delirium risk. CONCLUSIONS: Metformin use is associated with a reduced risk of delirium in older adults with T2D, with higher doses offering greater protection.

Renal protection of HWL-088 and ZLY032, two dual GPR40/PPARδ agonists, in adenine-induced renal fibrosis model.

This research examined the potential of novel GPR40/PPARδ dual agonists, HWL-088 and ZLY-032, to protect the kidneys in a mouse model of adenine-induced renal fibrosis. Mice were given a diet containing 0.25% adenine to develop renal fibrosis and then received different dosages of HWL-088 or ZLY-032. After being euthanized, tissue and serum samples were collected for morphological, histological, and molecular examination. Compared to the control group, mice fed adenine showed an increase in kidney-to-body weight ratio, serum creatinine, and urea levels. Hematoxylin and eosin staining revealed alleviated glomerulosclerosis, tubular dilation, and inflammatory cell infiltration in mice treated with HWL-088 or ZLY-032. Furthermore, Masson staining and immunohistochemistry demonstrated that these dual agonists protected against renal interstitial fibrosis and inflammation, corroborated by decreased expression levels of fibrosis-related proteins (TGF-ß, Collα1, TIMP-1) and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6). Accordingly, it can be inferred that GPR40/PPARδ dual agonists HWL-088 and ZLY-032 could yield significant renoprotective effects by inhibiting inflammation and fibrosis. Overall, these results may contribute to the development of novel therapeutic strategies for renal fibrosis.

Trajectory analysis of Bacillus subtilis in micro-droplets.

In order to study Bacillus subtilis biofilm formation in microdroplets, we use microfluidics technology to make the droplets and confocal microscopy to capture bacterial movement and biofilm formation in the droplets. We develop a multi-target tracking methodology, using a YOLOv5 detector to identify cells and a DeepSORT algorithm to track cell movements. We find that Bacillus subtilis bacteria with autonomous migration and biofilm-forming ability prefer to cluster and swarm near the microdroplet surface, rather than in the droplet interior. Bacterial mobility depends on phenotype and spatial location within the droplet. The motile cells move about 3.5 times faster than the matrix-producing cells. When the cells are near the wall of the droplet, the direction of the motion of motile cells is along that wall. When the cells are inside the droplet, the direction of the motion of motile cells is disordered, i.e., there is no clear directional or goal-oriented movement. This contrast increases the cell contact probability and facilitates the formation of a Bacillus subtilis biofilm in the droplet. Furthermore, we develop a mathematical model to describe the motion behavior of Bacillus subtilis in microdroplets, which is useful for exploring the influence of motility on biofilm formation.

Investigations of associations between TNF-α promoter polymorphisms and genetic susceptibility to type 2 diabetes mellitus: A cross-sectional study in Chinese Han population.

Type 2 diabetes (T2DM) is characterised by insulin resistance and a relative shortage of insulin secretion. Tumour necrosis factor-α (TNF-α) plays an important role in insulin resistance by impairing insulin signal transduction. The variants of the TNF-α promoter region are considered to influence its transcription and are associated with the TNF-α level. Therefore, it is worth detecting the association of the variants in the TNF-α gene with the development of T2DM. The aim of this study was to investigate the association of five variants (rs1799964, rs1800630, rs1799724, rs1800629 and rs361525) in the TNF-α gene promoter region with T2DM in a Chinese Han population. A total of 713 subjects with T2DM and 751 nondiabetic subjects were genotyped using the TaqMan method. The associations of the five variants with the development of T2DM were evaluated. The associations of the five variant genotypes with metabolic traits in nondiabetic subjects were analysed. Our data showed that the A allele of rs1800629 could increase the risk of developing T2DM (p = .002, OR = 1.563; 95% CI: 1.18-2.08). According to inheritance mode analysis, compared with the G/G genotype, the G/A+2A/A genotype of rs1800629 showed a risk effect on T2DM in the log-additive mode (p = .002, OR = 1.56; 95% CI: 1.17-2.07). The haplotypes analysis identified that the rs1799724-rs1800629CA was associated with high risk of the development of T2DM (p = .002, OR = 1.559, 95% CI: 1.173-2.072). Conversely, the rs1799724-rs1800629CG was a protective haplotype of T2DM (p = .001, OR = 0.732, 95% CI: 0.607-0.884). Moreover, compared with the rs1799964 (T/T+C/T) genotype, the rs1799964 C/C genotype was associated with higher glycosylated haemoglobin (HbA1c) levels in nondiabetic subjects (p = .017). Our results revealed that the rs1800629 in the TNF-α gene promoter region was associated with T2DM in a Chinese Han population.

Meta-analysis of RCTs on the safety of non-fixation of mesh in TAPP inguinal hernia repair: an updated meta-analysis.

OBJECTIVE: This meta-analysis aims to compare the clinical efficacy of mesh non-fixation and fixation in laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair, systematically evaluating the application value of the mesh non-fixation technique in clinical settings. METHODS: A computerized search of PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases was conducted to identify randomized controlled trials (RCTs) comparing mesh non-fixation and fixation in TAPP inguinal hernia repair. Meta-analysis was performed using RevMan 5.3 software, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence grading system was employed for outcome quality assessment. Publication bias analysis was performed using Begg's test. A trial sequential analysis (TSA) was performed using TSA 0.9.5.10 Beta software. RESULTS: A total of nine RCTs involving 1,879 inguinal hernia patients were included. Meta-analysis results demonstrated that, compared to the fixation group, the non-fixation group exhibited significantly lower seroma occurrence rate [RR = 0.43, 95% CI (0.20, 0.89), P = 0.02, heterogeneity P = 0.28, I²=22%], Visual Analog Scale (VAS) pain score at 6 months postoperatively [MD=-0.21, 95% CI (-0.29, -0.12), P < 0.00001, heterogeneity P = 0.34, I²=0%], and cost [MD=-3.23 thousand yuan, 95% CI (-4.26, -2.19), P < 0.00001, heterogeneity P = 0.0003, I²=92%]. There were no statistically significant differences in overall complication rate [RR = 0.88, 95% CI (0.62, 1.23), P = 0.45, heterogeneity P = 0.11, I²=44%], overall infection event rate [RR = 0.96, 95% CI (0.36, 2.56), P = 0.93, heterogeneity P = 0.62, I²=0%] and recurrence rate [RR = 0.75, 95% CI (0.28, 1.99), P = 0.56, heterogeneity P = 0.44, I²=0%] between the two groups. The results of the TSA indicated that the observed lower seroma occurrence rate in the non-fixation group compared to the fixation group requires further validation through the inclusion of additional RCTs. CONCLUSION: Mesh non-fixation in TAPP inguinal hernia repair is deemed safe and does not elevate the risk of hernia recurrence. However, given certain limitations in this study, future comprehensive and reliable validation will require further multicenter, high-quality, large-sample double-blind RCTs.

Nanoenabled Self-Assembled Metal-Organic Algaecides Generated Photosynthetic Inhibition and Oxidative Stress for Sustainable Food Security.

Achieving food sustainability is one of the biggest challenges in the new millennium. Plant factory cultivation systems provide an alternative for food sustainability, while they often suffer from algal blooms. The overuse of conventional algaecides has caused significant environmental pollution and concerns about food security. Here, we design a nanoenabled metal-organic algaecide that is self-assembled from natural polyphenols and two functional metal ions for providing shading effects and delivering active ingredients synergistically to suppress algal blooms. Black wattle tannin (BWT) and Fe3+ ions are utilized to develop self-assembled FeBWT nanoalgaecides with significant shading effects for decreasing light transmission (up to 97 %) and effectively inhibiting algal photosynthesis. Further, the FeBWT is functionalized with Cu2+ ions (bimetallic Cu/FeBWT) to target the algal cells and release Cu2+ ions via phenolic-mediated cell surface interactions, thus enhancing the inhibition efficiency. Importantly, the biosafety of Cu/FeBWT is demonstrated through toxicity tests on zebrafish and NIH3T3 cells. In our real-world field test, the Cu/FeBWT demonstrates high algal inhibition performance (>95 %, over 30 days), and enhances the accumulation of food nutrients in model plant lettuces. Collectively, the supramolecular metal-organic nanoalgaecide provides a promise for nanoagrochemical application and promotes food sustainability and security.

[In Vitro Amplification of NK Cells from Feeder Layer Cells Expressing IL-21].

OBJECTIVE: To investigate the effect of feeder layer cells expressing interleukin (IL)-21 on the amplification of NK cells In Vitro . METHODS: The K562 cell line with IL-21 expression on its membrane was constructed by electroporation, and co-cultured with NK cells after inactivation. The proliferation of NK cells was observed. The killing function of the amplified NK cells In Vitro was evaluated by the lactate dehydrogenase (LDH) and interferon-γ (IFN-γ) release assay. A colorectal cancer xenograft model in NOD/SCID mice was established, and a blank control group, a NK cell group and an amplified NK cell group were set up to detect the tumor killing effect of amplified NK cells in vivo. RESULTS: K562 cells expressing IL-21 on the membrane were successfully constructed by electroporation. After co-culturing with K562 cells expressing IL-21 on the membrane for 17 days, the NK cells increased to 700 times, which showed an enhanced amplification ability compared with control group (P < 0.001). In the tumor cell killing experiment In Vitro , there was no significant difference in the killing activity on tumor cells between NK cells and amplified NK cells, and there was also no significant difference in mice in vivo. CONCLUSION: K562 cells expressing IL-21 on the membrane can significantly increase the amplification ability of NK cells In Vitro , but do not affect the killing function of NK cells In Vitro and in vivo. It can be used for the subsequent large-scale production of NK cells In Vitro .

Enhancing terminal erythroid differentiation in human embryonic stem cells through TRIB3 overexpression.

Tribbles pseudokinase 3 (TRIB3) expression significantly increases during terminal erythropoiesis in vivo. However, we found that TRIB3 expression remained relatively low during human embryonic stem cell (hESC) erythropoiesis, particularly in the late stage, where it is typically active. TRIB3 was expressed in megakaryocyte-erythrocyte progenitor cells and its low expression was necessary for megakaryocyte differentiation. Thus, we proposed that the high expression during late stage of erythropoiesis could be the clue for promotion of maturation of hESC-derived erythroid cells. To our knowledge, the role of TRIB3 in the late stage of erythropoiesis remains ambiguous. To address this, we generated inducible TRIB3 overexpression hESCs, named TRIB3tet-on OE H9, based on a Tet-On system. Then, we analyzed hemoglobin expression, condensed chromosomes, organelle clearance, and enucleation with or without doxycycline treatment. TRIB3tet-on OE H9 cells generated erythrocytes with a high proportion of orthochromatic erythroblast in flow cytometry, enhanced hemoglobin and related protein expression in Western blot, decreased nuclear area size, promoted enucleation rate, decreased lysosome and mitochondria number, more colocalization of LC3 with LAMP1 (lysosome marker) and TOM20 (mitochondria marker) and up-regulated mitophagy-related protein expression after treatment with 2 µg/mL doxycycline. Our results showed that TRIB3 overexpression during terminal erythropoiesis may promote the maturation of erythroid cells. Therefore, our study delineates the role of TRIB3 in terminal erythropoiesis, and reveals TRIB3 as a key regulator of UPS and downstream mitophagy by ensuring appropriate mitochondrial clearance during the compaction of chromatin.

Complementary information mutual learning for multimodality medical image segmentation.

Radiologists must utilize medical images of multiple modalities for tumor segmentation and diagnosis due to the limitations of medical imaging technology and the diversity of tumor signals. This has led to the development of multimodal learning in medical image segmentation. However, the redundancy among modalities creates challenges for existing subtraction-based joint learning methods, such as misjudging the importance of modalities, ignoring specific modal information, and increasing cognitive load. These thorny issues ultimately decrease segmentation accuracy and increase the risk of overfitting. This paper presents the complementary information mutual learning (CIML) framework, which can mathematically model and address the negative impact of inter-modal redundant information. CIML adopts the idea of addition and removes inter-modal redundant information through inductive bias-driven task decomposition and message passing-based redundancy filtering. CIML first decomposes the multimodal segmentation task into multiple subtasks based on expert prior knowledge, minimizing the information dependence between modalities. Furthermore, CIML introduces a scheme in which each modality can extract information from other modalities additively through message passing. To achieve non-redundancy of extracted information, the redundant filtering is transformed into complementary information learning inspired by the variational information bottleneck. The complementary information learning procedure can be efficiently solved by variational inference and cross-modal spatial attention. Numerical results from the verification task and standard benchmarks indicate that CIML efficiently removes redundant information between modalities, outperforming SOTA methods regarding validation accuracy and segmentation effect. To emphasize, message-passing-based redundancy filtering allows neural network visualization techniques to visualize the knowledge relationship among different modalities, which reflects interpretability.

Red Blood Cell Transfusion for Incidence of Retinopathy of Prematurity: Prospective Multicenter Cohort Study.

Background: Retinopathy of prematurity (ROP) is a leading cause of visual impairment and blindness in preterm infants. Objective: This study sought to investigate the association between red blood cell (RBC) transfusion and ROP in very preterm infants (VPIs) to inform clinical strategies for ROP prevention and treatment. Methods: We designed a prospective multicenter cohort study that included VPIs and follow-up data from January 2017 to December 2022 at 3 neonatal clinical medicine centers. They were categorized into a transfusion group (infants who received an RBC transfusion within 4 wk) and a nontransfusion group. The relationship between RBC transfusion and ROP incidence was assessed using binary logistic regression, with subgroup analyses based on gestational age, birth weight, sex, and sepsis status. Inverse probability of treatment weighting and propensity score matching were applied to account for all potential confounding factors that could affect ROP development, followed by sensitivity analysis. Results: The study included 832 VPIs, including 327 in the nontransfusion group and 505 in the transfusion group. The transfusion group had a lower average birth weight and gestational age and a greater incidence of ROP, ≥stage 2 ROP, and severe ROP. Logistic regression analysis revealed that the transfusion group had a significantly greater risk of ROP (adjusted odds ratio [aOR] 1.70, 95% CI 1.14-2.53, P=.009) and ≥stage 2 ROP (aOR 1.68, 95% CI 1.02-2.78, P=.04) but not severe ROP (aOR 1.75, 95% CI 0.61-5.02, P=.30). The trend analysis also revealed an increased risk of ROP with an increasing number of transfusions and a larger volume of blood transfused (P for trend<.001). Subgroup analyses confirmed a consistent trend, with the transfusion group at a higher risk for ROP across all subgroups. Inverse probability of treatment weighting and propensity score matching analyses supported the initial findings. Conclusions: For VPIs, RBC transfusion significantly increases the risk of ROP, and the risk increases with an increasing number of transfusions and volume of blood transfused.

Safety and efficacy of a novel dexmedetomidine nasal spray for pre-anesthetic sedation in children: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Off-label intranasal administration of injectable dexmedetomidine has been widely applied in the pediatric sedation setting. However, the development of an improved drug delivery system that is easy to use is needed. We developed a novel dexmedetomidine nasal spray that can be administered directly without dilution or configuration for pediatric pre-anesthetic sedation. This nasal spray has a fixed dose and is stable during storage. To the best of our knowledge, this is the first licensed nasal spray preparation of dexmedetomidine worldwide. OBJECTIVE: To evaluate the pre-anesthetic sedation efficacy and safety of the novel dexmedetomidine nasal spray in children. METHODS: The study was conducted at 11 sites in China between 24 November 2021 and 20 May 2022 and was registered in ClinicalTrials.gov (NCT05111431, first registration date: 20/10/2021). Subjects (n = 159) between 2 and 6 years old who were to undergo elective surgery were randomized to the dexmedetomidine group (n = 107) or the placebo group (n = 52) in a 2:1 ratio. The dosage was 30 µg or 50 µg based on the stratified body weight. The primary outcome measure was the proportion of subjects who achieved the desired child-parent separation and Ramsay scale ≥ 3 within 45 min of administration. Safety was monitored via the assessments of adverse events, blood pressure, heart rate, respiratory rate and blood oxygen saturation. RESULTS: The proportion of subjects achieving desired parental separation and Ramsay scale ≥ 3 within 45 min was significantly higher in the dexmedetomidine group (94.4%) vs the placebo group (32.0%) (P < 0.0001). As compared with placebo, dexmedetomidine treatment led to more subjects achieving Ramsay scale ≥ 3 or UMSS ≥ 2, and shorter time to reach desired parental separation, Ramsay scale ≥ 3 and UMSS ≥ 2 (all P < 0.0001). Adverse events were reported in 90.7% and 84.0% of subjects in the dexmedetomidine and placebo groups, respectively, and all the events were mild or moderate in severity. CONCLUSIONS: This novel dexmedetomidine nasal spray presented effective pre-anesthetic sedation in children with a tolerable safety profile.

The decorin and myostatin response to acute whole body vibration: impact of adiposity, sex, and race.

BACKGROUND: Traditional forms of exercise affect immune, metabolic, and myokine responses and contribute to a multitude of health benefits. Whole body vibration (WBV) has recently emerged as an exercise mimetic that may be more tolerable for those individuals that cannot perform traditional exercise. However, the myokines response to acute WBV in humans has yet to be fully elucidated. OBJECTIVE: To characterize the decorin and myostatin response to acute whole body vibration (WBV) and determine the impact of adiposity, sex, and race. SUBJECTS: One hundred twenty-nine adults (32.8 ± 0.4 years, 66.7% female, 53.5% non-Hispanic Black) were recruited as part of an ongoing, longitudinal twin cohort parent study. Participants were classified into three groups: those with obesity (OB: ≥30 kg/m2), those who are overweight (OW: ≥25 and <30 kg/m2), or those with normal weight (NW: <25 kg/m2) based on BMI. METHODS: Blood was collected at baseline (PRE), immediately post (POST), and 1 h (1H), 3 h (3H), and 24 h (24H) post WBV. The acute WBV protocol consisted of 10 cycles of 1 min of vibration exercise followed by 30 s of standing rest. RESULTS: The response was similar between NW and OW, so these groups were combined for analysis (NW/OW: BMI < 30 kg/m2). Overall, circulating concentrations of decorin were higher (p < 0.001) POST (8.80 ± 0.19 pg/mL) and significantly lower (p's ≤ 0.005) at 1H (8.66 ± 0.19 pg/mL) and 3H (8.68 ± 0.19 pg/mL), compared to PRE (8.71 ± 0.19 pg/mL). Decorin POST was greater (p = 0.016) in the OB group (8.82 ± 0.18 pg/mL) compared to the NW/OW group (8.77 ± 0.20 pg/mL). Overall, myostatin was higher (p = 0.002) POST (54.93 ± 1.04 pg/mL) and lower (p < 0.001) at 24H (49.13 ± 1.04 pg/mL) compared to PRE (53.49 ± 1.04 pg/mL). The myostatin response was lower (p's ≤ 0.001) in female and non-Hispanic White individuals compared to male and non-Hispanic Black individuals, respectively. CONCLUSIONS: A single bout of WBV can facilitate the release of decorin and myostatin into circulation, a similar response to traditional exercise. Additionally, adiposity, sex and race should be considered when evaluating the myokines response to WBV.

CTBP1 links metabolic syndrome to polycystic ovary syndrome through interruption of aromatase and SREBP1.

Some patients with polycystic ovarian syndrome (PCOS) suffered from metabolic syndrome (MetS) including dyslipidemia, hyperinsulinism, but the underlying mechanism is unclear. Although C-terminal Binding Protein 1 (CTBP1) is a transcriptional co-repressor frequently involved in hormone secretion disorders and MetS-associated diseases, the role of CTBP1 in PCOS is rarely reported. In the present study, we found that CTBP1 expression was significantly elevated in primary granulosa cells (pGCs) derived from the PCOS with MetS patients and was positively associated with serum triglyceride, but negatively correlated with serum estradiol (E2) or high-density lipoprotein. Mechanistic study suggested that CTBP1 physically bound to the promoter II of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) to inhibit the aromatase gene transcription and expression, resulting in the reduced E2 synthesis. Moreover, CTBP1 interacted with the phosphorylated SREBP1a at S396 in nuclei, leading to the FBXW7-dependent protein degradation, resulting in the reduced lipid droplets formation in pGCs. Therefore, we conclude that CTBP1 in GCs dysregulates the synthesis of steroid hormones and lipids through suppression of aromatase expression and promotion of SREBP1a protein degradation in PCOS patients, which may offer some fresh insights into the potential pathological mechanism for this tough disease.

A national-wide survey on clinical implementation of PGx testing into precision therapeutics for Chinese children: a long way before standard clinical practice.

BACKGROUND: Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China. METHODS: A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made. RESULTS: Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost. CONCLUSION: Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.

Association Between Obesity and Risk of Total and Obesity-Related Cancer in People With Incident Cardiovascular Disease.

BACKGROUND: Cardiovascular disease (CVD) and cancer frequently co-occur due to shared risk factors such as obesity, which is linked to CVD and 14 cancer types. This study explores whether CVD pathophysiologies, combined with obesity, increase cancer risk, impacting clinical management. METHODS AND RESULTS: Data from the ARIC (Atherosclerosis Risk in Communities) study, spanning 28 years, were analyzed. The cohort included 5127 participants with incident CVD (myocardial infarction, stroke, heart failure, coronary heart disease), of whom 1511 developed a first primary cancer. Follow-up began at CVD diagnosis after Visit 1. Obesity was assessed using body mass index, waist circumference, and waist-to-hip ratio. Incidence rate differences between obesity groups were adjusted for age, sex, and center, whereas the obesity-cancer association was estimated using Fine-Gray regression adjusted for shared risk factors including smoking. Cancer incidence in obese individuals with CVD (body mass index: rate differences=226.6/100 000 person-years) was higher than in those with normal weight. Although obesity was not linked to overall cancer after adjusting for shared risk factors, it was nominally associated with obesity-related cancers. Specifically, women with CVD and obesity had increased obesity-related cancer risk (body mass index: hazard ratio, 1.67 [95% CI, 1.17-2.31]). No significant associations were found in men, even after excluding prostate cancer. CONCLUSIONS: This study suggests that obesity is linked to higher obesity-related cancer risk in women with incident CVD, independent of shared risk factors. Further research is needed to eliminate residual confounding, understand sex differences, and explore how CVD pathophysiologies and obesity together influence cancer risk.

Daily Physical Activity Does Not Contribute to Differences in Muscle Oxidative Capacity Between Overweight and Obesity.

BACKGROUND: The interaction between physical activity, skeletal muscle health, and adiposity has been explored in normal weight and overweight/obesity grouped together; however, the overall risks associated with being overweight are less than those observed with obesity and can be confounded by disparities in both sex and race. Thus, the present study sought to investigate the intricate interplay of daily physical activity and skeletal muscle oxidative capacity (SMOC) in overweight and obesity, while exploring how sex and race impact this dynamic relationship. METHODS: One hundred and forty participants were grouped by body mass index (BMI) as overweight (n = 73; BMI >25-<30 kg/m2) or obese (n = 67; BMI ≥30 kg/m2). SMOC was assessed using near-infrared spectroscopy and daily physical activity was assessed for 7 days using accelerometry. RESULTS: Overweight individuals exhibited a higher (p = 0.004) SMOC and engaged in more (p = 0.007) vigorous physical activity compared to obese individuals. In addition, SMOC was lower (p = 0.005) in obese non-Hispanic Black (NHB) men compared to overweight NHB men. No relationships between physical activity and SMOC were observed. CONCLUSION: Physical activity is not associated with differences in SMOC in overweight and obesity. Obese individuals engage in less vigorous physical activity and exhibit lower SMOC compared to overweight individuals and these differences are emphasised in NHB men.