Formation and evolution of thermokarst landslides in the Qinghai-Tibet Plateau, China.

Thermokarst landslide (TL) activity in the Qinghai-Tibet Plateau (QTP) is intensifying due to climate warming-induced permafrost degradation. However, the mechanisms driving landslide formation and evolution remain poorly understood. This study investigates the spatial distribution, annual frequency, and monthly dynamics of TLs along the Qinghai-Tibet engineering corridor (QTEC), in conjunction with in-situ temperature and rainfall observations, to elucidate the interplay between warming, permafrost degradation, and landslide activity. Through the analysis of high-resolution satellite imagery and field surveys, we identified 1298 landslides along the QTEC between 2016 and 2022, with an additional 386 landslides recorded in a typical landslide-prone sub-area. In 2016, 621 new active-layer detachments (ALDs) were identified, 1.3 times the total historical record. This surge aligned with unprecedented mean annual and August temperatures. The ALDs emerged primarily between late August and early September, coinciding with maximum thaw depth. From 2016 to 2022, 97.8 % of these ALDs evolved into retrogressive thaw slumps (RTSs), identified as active landslides. Landslides typically occur in alpine meadows at moderate altitudes and on gentle northward slopes. The thick ice layer near the permafrost table serves as the material basis for ALD occurrence. Abnormally high temperature significantly increased the active layer thickness (ALT), resulting in melting of the ice layer and formation of a thawed interlayer, which was the direct causing factor for ALD. By altering the local material, micro-topography, and thermal conditions, ALD activity significantly increases RTS susceptibility. Understanding the mechanisms of ALD formation and evolution into RTS provides a theoretical foundation for infrastructure development and disaster mitigation in extreme environments.

Homology-independent targeted insertion-mediated derivation of M1-biased macrophages harbouring Megf10 and CD3ζ from human pluripotent stem cells.

BACKGROUND: Macrophages engineered with chimeric antigen receptors (CAR) are suitable for immunotherapy based on their immunomodulatory activity and ability to infiltrate solid tumours. However, the production and application of genetically edited, highly effective, and mass-produced CAR-modified macrophages (CAR-Ms) are challenging. METHODS: Here, we used homology-independent targeted insertion (HITI) for site-directed CAR integration into the safe-harbour region of human pluripotent stem cells (hPSCs). This approach, together with a simple differentiation protocol, produced stable and highly effective CAR-Ms without heterogeneity. FINDINGS: These engineered cells phagocytosed cancer cells, leading to significant inhibition of cancer-cell proliferation in vitro and in vivo. Furthermore, the engineered CARs, which incorporated a combination of CD3ζ and Megf10 (referred to as FRP5Mζ), markedly enhanced the antitumour effect of CAR-Ms by promoting M1, but not M2, polarisation. FRP5Mζ promoted M1 polarisation via nuclear factor kappa B (NF-κB), ERK, and STAT1 signalling, and concurrently inhibited STAT3 signalling even under M2 conditions. These features of CAR-Ms modulated the tumour microenvironment by activating inflammatory signalling, inducing M1 polarisation of bystander non-CAR macrophages, and enhancing the infiltration of T cells in cancer spheroids. INTERPRETATION: Our findings suggest that CAR-Ms have promise as immunotherapeutics. In conclusion, the guided insertion of CAR containing CD3ζ and Megf10 domains is an effective strategy for the immunotherapy of solid tumours. FUNDING: This work was supported by KRIBB Research Initiative Program Grant (KGM4562431, KGM5282423) and a Korean Fund for Regenerative Medicine (KFRM) grant funded by the Korean government (Ministry of Science and ICT,Ministry of Health and Welfare) (22A0304L1-01).

Two new guaiane-type sesquiterpene glycosides from Atractylodes Japonica Koidz. ex Kitam.

Two new guaiane-type sesquiterpene glycosides, atractylodes guaianoside I (1) and atractylodes guaianoside II (2), along with eleven known sesquiterpenes (3-13), were isolated from Atractylodes Japonica Koidz. ex Kitam. The structures of these two new compounds were elucidated by extensive spectroscopic analyses and mass spectrometric techniques. And their absolute configurations were confirmed by electronic circular dichroism (ECD) calculations. In addition, the isolated compounds were evaluated for their cytotoxic activities against three cancer cell lines HT-29, A-549, and MCF-7. Results showed that new compound 2 had inhibitory effects on three types of cancer cells, while new compound 1 only had inhibitory effects on HT-29 and MCF-7.

Healthy life expectancy with cardiovascular disease among Chinese rural population based on the prospective cohort study.

BACKGROUND: Limited research has explored the impact of cardiovascular disease (CVD) on healthy life expectancy (HLE) especially in resource-limited areas. This study aimed to investigate the association between CVD and HLE in Chinese rural population. METHODS: This study included 11,994 participants aged 45 years and older from the baseline and follow-up surveys of the Henan rural cohort study. Healthy status was measured via a Visual Analogue Scale. The multistate Markov model was applied to estimate the association between CVD and transitions in health, unhealthiness and death. Gender-specific total life expectancy, HLE and unhealthy life expectancy were calculated by the multistate life table method. RESULTS: During a mean follow-up time of 3.85 (3.84-3.86) years, there were 588 deaths recorded. For individuals with CVD, the risk of switching from health to unhealthiness status was increased by 71% [hazard ratio (HR) = 1.71, 95% CI: 1.42-2.07], the chance of recovery was reduced by 30% (HR = 0.70, 95% CI: 0.60-0.82). Men aged 45 years without CVD could gain an extra 7.08 (4.15-10.01) years of HLE and lose 4.00 (1.60-6.40) years of unhealthy life expectancy compared to their peers with CVD, respectively. The corresponding estimates among women were 8.62 (5.55-11.68) years and 5.82 (2.59-9.04) years, respectively. CONCLUSIONS: This study indicated that CVD was significantly associated with poorer health status and lower HLE among Chinese rural population. It is an important public health policy to adopt targeted measures to reduce the CVD burden and enhance the quality of life and HLE in resource-limited areas.

Engineering Escherichia coli for D-allulose biosynthesis from glycerol.

D-allulose, a naturally occurring monosaccharide, is present in small quantities in nature. It is considered a valuable low-calorie sweetener due to its low absorption in the digestive tract and zero energy for growth. Most of the recent efforts to produce D-allulose have focused on in vitro enzyme catalysis. However, microbial fermentation is emerging as a promising alternative that offers the advantage of combining enzyme manufacturing and product synthesis within a single bioreactor. Here, a novel approach was proposed for the efficient biosynthesis of D-allulose from glycerol using metabolically engineered Escherichia coli. FbaA, Fbp, AlsE, and A6PP were used to construct the D-allulose synthesis pathway. Subsequently, PfkA, PfkB, and Pgi were disrupted to block the entry of the intermediate fructose-6-phosphate (F6P) into the Embden-Meyerhof-Parnas (EMP) and pentose phosphate (PP) pathways. Additionally, GalE and FryA were inactivated to reduce D-allulose consumption by the cells. Finally, a fed-batch fermentation process was implemented to optimize the performance of the cell factory. As a result, the titer of D-allulose reached 7.02 g/L with a maximum yield of 0.287 g/g.

Antibiotic-induced gut microbiota disruption promotes vascular calcification by reducing short-chain fatty acid acetate.

BACKGROUND: Vascular calcification is a common vascular lesion associated with high morbidity and mortality from cardiovascular events. Antibiotics can disrupt the gut microbiota (GM) and have been shown to exacerbate or attenuate several human diseases. However, whether antibiotic-induced GM disruption affects vascular calcification remains unclear. METHODS: Antibiotic cocktail (ABX) treatment was utilized to test the potential effects of antibiotics on vascular calcification. The effects of antibiotics on GM and serum short-chain fatty acids (SCFAs) in vascular calcification mice were analyzed using 16 S rRNA gene sequencing and targeted metabolomics, respectively. Further, the effects of acetate, propionate and butyrate on vascular calcification were evaluated. Finally, the potential mechanism by which acetate inhibits osteogenic transformation of VSMCs was explored by proteomics. RESULTS: ABX and vancomycin exacerbated vascular calcification. 16 S rRNA gene sequencing and targeted metabolomics analyses showed that ABX and vancomycin treatments resulted in decreased abundance of Bacteroidetes in the fecal microbiota of the mice and decreased serum levels of SCFAs. In addition, supplementation with acetate was found to reduce calcium salt deposition in the aorta of mice and inhibit osteogenic transformation in VSMCs. Finally, using proteomics, we found that the inhibition of osteogenic transformation of VSMCs by acetate may be related to glutathione metabolism and ubiquitin-mediated proteolysis. After adding the glutathione inhibitor Buthionine sulfoximine (BSO) and the ubiquitination inhibitor MG132, we found that the inhibitory effect of acetate on VSMC osteogenic differentiation was weakened by the intervention of BSO, but MG132 had no effect. CONCLUSION: ABX exacerbates vascular calcification, possibly by depleting the abundance of Bacteroidetes and SCFAs in the intestine. Supplementation with acetate has the potential to alleviate vascular calcification, which may be an important target for future treatment of vascular calcification.

[Analysis of Antibiotic Resistance of Bioaerosols from Wastewater Treatment Process].

To explore the prevalence and source of antibiotic resistant genes （ARGs） and pathogenic antibiotic resistant bacteria （PARB） associated with bioaerosols in wastewater treatment plants （WWTPs）, metagenomic sequencing and assembly were applied to elucidate the antibiotic resistome of bioaerosols and wastewater in WWTPs. The results showed that more subtypes of ARGs and a higher abundance of PARB were found in bioaerosols from WWTPs and downwind than those from upwind. Multidrug and macB were respectively the most dominant type and subtype of ARGs in bioaerosols from WWTPs. In total, 37 types of PARB carried at least two or more ARG types and were characterized by multiple drug resistance. At the fine grid, aerated tank, and sludge dewatering room, wastewater was the main source of bioaerosol ARGs and PARB. A total of 32 PARB were easily aerosolized in at least one wastewater treatment unit, such as Pseudomonas aeruginosa and Escherichia coli. This study will provide theoretical support for the risk assessment and health protection of antibiotic resistant pollution associated with bioaerosols from WWTPs.

First isolation, identification, and pathogenicity evaluation of an EV-G6 strain in China.

Enterovirus G (EV-G) belongs to the Picornaviridae family and infects porcine populations worldwide. A total of 20 EV-G genotypes (EV-G1 to EV-G20) have been identified. In this study, we isolated and characterized an EV-G strain, named EV-G/YN29/2022, from the feces of diarrheic pigs. This was the first EV-G6 strain isolated in China. Comparison of the whole genome nucleotide and corresponding amino acid sequences showed that the isolate was more closely related to those of the EV-G6 genotype than other genotypes, with the complete genome sequence similarity ranging from 83.7% (Iba46442) to 84.4% (PEV-B-KOR), and corresponding amino acid homology ranged from 96% (Iba46442) to 96.8% (PEV-B-KOR). Similarly, the VP1 gene and corresponding amino acid sequences of EV-G/YN29/2022 were highly similar to those of the EV-G6 genotype (>82.9% and >94.3%, respectively). Thus, the isolated strain was classified as EV-G6 genotype. This was the first EV-G6 strain isolated in China. Pathogenicity analyses revealed that EV-G/YN29/2022 infection caused mild diarrhea, typical skin lesions, and weight reduction. The strain was mainly distributed to the intestinal tissue but was also found in the brain, mesenteric lymph nodes, spleen, and liver. Our results can be used as a reference to further elucidate the epidemiology, evolution, and pathogenicity of EV-G.

Intermittent Fasting Targets Osteocyte Neuropeptide Y to Relieve Osteoarthritis.

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.

Cytokine release syndrome triggered by programmed death 1 blockade (sintilimab) therapy in a psoriasis patient: A case report.

BACKGROUND: In recent years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy across diverse malignancies. Notably, in patients with advanced gastric cancer, the use of programmed death 1 (PD-1) blockade has significantly prolonged overall survival, marking a pivotal advancement comparable to the impact of Herceptin over the past two decades. While the therapeutic benefits of ICIs are evident, the increasing use of immunotherapy has led to an increase in immune-related adverse events. CASE SUMMARY: This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis. Following sintilimab therapy, the patient developed severe rashes accompanied by cytokine release syndrome (CRS). Fortunately, effective management was achieved through the administration of glucocorticoid, tocilizumab, and acitretin, which resulted in favorable outcomes. CONCLUSION: Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

New lignans from Phyllanthodendron dunnianum.

A new lignan phyllanins A (1) and a lignan phyllanins B (2) for which the absolute configuration was determined for the first time, along with four known lignans (3-6) were isolated from the branch and leaf extracts of Phyllanthodendron dunnianum. Their planar structures were mainly determined by a combination of 1D and 2D NMR, HRESIMS spectral analyses, and the absolute configurations of the compounds 1 and 2 were established by DFT GIAO 13C NMR and electronic circular dichroism (ECD) calculations. In addition, all these six lignans were firstly tested for the antibacterial activities against MRSA, Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Escherichia coli. Among these compounds, 2 and 5 showed potential antibacterial activities against MRSA and S. aureus with MIC values of 4 and 8 µg/mL, respectively.

Functional Characterization of the MeSSIII-1 Gene and Its Promoter from Cassava.

Soluble starch synthases (SSs) play important roles in the synthesis of cassava starch. However, the expression characteristics of the cassava SSs genes have not been elucidated. In this study, the MeSSIII-1 gene and its promoter, from SC8 cassava cultivars, were respectively isolated by PCR amplification. MeSSIII-1 protein was localized to the chloroplasts. qRT-PCR analysis revealed that the MeSSIII-1 gene was expressed in almost all tissues tested, and the expression in mature leaves was 18.9 times more than that in tuber roots. MeSSIII-1 expression was induced by methyljasmonate (MeJA), abscisic acid (ABA), and ethylene (ET) hormones in cassava. MeSSIII-1 expression patterns were further confirmed in proMeSSIII-1 transgenic cassava. The promoter deletion analysis showed that the -264 bp to -1 bp MeSSIII-1 promoter has basal activity. The range from -1228 bp to -987 bp and -488 bp to -264 bp significantly enhance promoter activity. The regions from -987 bp to -747 bp and -747 bp to -488 bp have repressive activity. These findings will provide an important reference for research on the potential function and transcriptional regulation mechanisms of the MeSSIII-1 gene and for further in-depth exploration of the regulatory network of its internal functional elements.

[Effects of Total Intravenous Anesthesia on Circadian Rhythms in Patients Undergoing Cardiac Transcatheter Closure].

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs.1.90±1.47;MD(95%CI):0.52(0.20-0.84),t=3.327,P=0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs.1.13±0.98;MD(95%CI):-0.43(-0.81--0.05),t=-2.319,P=0.028] and PER2 [0.82±0.63 vs.0.50±0.31;MD(95%CI):-0.33(-0.53--0.12),t=-3.202,P=0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3:03±0:59 vs.2:42±0:37;MD(95%CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency [(67±64)min vs.(37±21)min;MD(95%CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration [(436±83)min vs.(499±83)min;MD(95%CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency [(87.59±10.35)% vs.(92.98±4.27)%;MD(95%CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score [1.13±0.78 vs.0.80±0.71;MD(95%CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score [6.60±3.17 vs.4.03±2.58;MD(95%CI):-2.57(-3.87--1.27),t=-4.039,P<0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery. Conclusion Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Young osteocyte-derived extracellular vesicles facilitate osteogenesis by transferring tropomyosin-1.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.

Validation of mitochondrial biomarkers and immune dynamics in polycystic ovary syndrome.

PROBLEM: Polycystic ovary syndrome (PCOS), a prevalent endocrine-metabolic disorder, presents considerable therapeutic challenges due to its complex and elusive pathophysiology. METHOD OF STUDY: We employed three machine learning algorithms to identify potential biomarkers within a training dataset, comprising GSE138518, GSE155489, and GSE193123. The diagnostic accuracy of these biomarkers was rigorously evaluated using a validation dataset using area under the curve (AUC) metrics. Further validation in clinical samples was conducted using PCR and immunofluorescence techniques. Additionally, we investigate the complex interplay among immune cells in PCOS using CIBERSORT to uncover the relationships between the identified biomarkers and various immune cell types. RESULTS: Our analysis identified ACSS2, LPIN1, and NR4A1 as key mitochondria-related biomarkers associated with PCOS. A notable difference was observed in the immune microenvironment between PCOS patients and healthy controls. In particular, LPIN1 exhibited a positive correlation with resting mast cells, whereas NR4A1 demonstrated a negative correlation with monocytes in PCOS patients. CONCLUSION: ACSS2, LPIN1, and NR4A1 emerge as PCOS-related diagnostic biomarkers and potential intervention targets, opening new avenues for the diagnosis and management of PCOS.

Two new sesterterpenoids from Atractylodes japonica Koidz. ex Kitam.

Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3-12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15-88.85 µM except for 9-12.

Prediction model of measurement errors in current transformers based on deep learning.

The long-term monitoring stability of electronic current transformers is crucial for accurately obtaining the current signal of the power grid. However, it is difficult to accurately distinguish between the fluctuation of non-stationary random signals on the primary side of the power grid and the gradual error of the transformers themselves. A current transformer error prediction model, CNN-MHA-BiLSTM, based on the golden jackal optimization (GJO) algorithm, which is used to obtain the optimal parameter values, bidirectional long short-term memory (BiLSTM) network, convolutional neural networks (CNNs), and multi-head attention (MHA), is proposed to address the difficulty of measuring error evaluation. This model can be used to determine the operation of transformers and can be widely applied to assist in determining the stability of transformer operation and early faults. First, CNN is used to mine the vertical detail features of error data at a certain moment, improving the speed of error prediction. Furthermore, a cascaded network with BiLSTM as the core is constructed to extract the horizontal historical features of the error data. The GJO algorithm is used to adjust the parameters of the BiLSTM model; optimize the hidden layer nodes, training frequency, and learning rate; and integrate MHA mechanism to promote the model to pay attention to the characteristic changes of the data in order to improve the accuracy of error prediction. Finally, this method is applied to the operation data of transformer in substations, and four time periods of data are selected to verify the model effectiveness of the current transformer dataset. The analysis results of single step and multi-step examples indicate that the proposed model has significant advantages in terms of accuracy and stability in error prediction.

Effect of cytochrome P450 2C19 (CYP2C19) gene polymorphism and clopidogrel reactivity on long term prognosis of patients with coronary heart disease after PCI.

Objective: To investigate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity and its association with long-term clinical outcome in patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). Methods: In total, 675 patients were enrolled. Based on the platelet inhibition rate, patients were categorized into two groups: clopidogrel low responsiveness (CLR) and normal clopidogrel responsiveness (NCR). The CLR group was divided into ticagrelor and clopidogrel group based on the antiplatelet drugs used in the follow-up treatment. Patients were classified into three groups (normal metabolizer, intermediate metabolizer, and poor metabolizer) based on the CYP2C19 genotype. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clopidogrel reactivity. The cumulative rates of 12-month all-cause deaths, major adverse cardiovascular events (MACCEs), and bleeding events were calculated. Results: CLR was observed in 44.4% of the overall population. Significant differences were observed in the platelet inhibition rate of clopidogrel among the three metabolic genotypes (P < 0.05). At the 12-month follow-up, 13 patients (1.9%) died and 96 patients (14.2%) experienced MACCEs. Patients with CLR (9.6% vs. 11.7% vs. 22.1%, P < 0.05) or poor metabolizer (10.7% vs. 16.4% vs. 22.6%, P = 0.026) experienced a higher rate of MACCEs. A MACCEs risk score between zero and two was calculated. The highest incidence of MACCEs significantly increased with the 2-positive results, and the area under the curve (AUC) was 0.712 (95% CI: 0.650-0.774, P < 0.05). There was no significant difference between the group with a score of one and the occurrence of MACCEs (P > 0.05). Conclusions: Low response to clopidogrel in CHD patients is correlated with CYP2C19 gene polymorphism. CYP2C19 genotyping combined with platelet reactivity is an independent predictor of 12-months MACCEs in patients with clopidogrel treatment after PCI, which is better than either test alone.

Genetic prediction of modifiable lifestyle factors for erectile dysfunction.

Background: The causal relationship between certain lifestyle factors and erectile dysfunction (ED) is still uncertain. Aim: The study sought to investigate the causal effect of 9 life factors on ED through 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR). Methods: Genetic instruments to proxy 9 risk factors were identified by genome-wide association studies. The genome-wide association studies estimated the connection of these genetic variants with ED risk (n = 223 805). We conducted SVMR, inverse variance-weighting, Cochran's Q, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MVMR analyses to explore the total and direct relationship between life factors and ED. Outcomes: The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results: In SVMR analyses, suggestive associations with increased the risk of ED were noted for ever smoked (odds ratio [OR], 5.894; 95% confidence interval [CI], 0.469 to 3.079; P = .008), alcohol consumption (OR, 1.495; 95% CI, 0.044 to 0.760; P = .028) and body mass index (BMI) (OR, 1.177; 95% CI, 0.057 to 0.268; P = .003). Earlier age at first intercourse was significantly related to reduced ED risk (OR, 0.659; 95% CI, -0.592 to -0.244; P = 2.5 × 10-6). No strong evidence was found for the effect of coffee intake, time spent driving, physical activity, and leisure sedentary behaviors on the incidence of ED (All P > .05). The result of MVMR analysis for BMI (OR, 1.13; 95% CI, 1.01 to 1.25; P = .045) and earlier age at first intercourse (OR, 0.77; 95% CI, 0.56 to 0.99; P = .018) provided suggestive evidence for the direct impact on ED, while no causal factor was detected for alcoholic drinks per week and ever smoked. Clinical implications: This study provides evidence for the impact of certain modifiable lifestyle factors on the development of ED. Strengths and limitations: We performed both SVMR and MVMR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion: Ever smoked, alcoholic drinks per week, BMI, and age first had sexual intercourse were causally related to ED, while the potential connection between coffee intake, physical activity, recreational sedentary habits, and increased risk of ED needs to be further confirmed.

Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1-/-) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay. RESULTS: In vivo, Itln-1-/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation. CONCLUSION: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.