Design, Synthesis, and Biological Evaluation of Hydrophobic-Tagged Glutathione Peroxidase 4 (GPX4) Degraders.

Ferroptosis is an iron-dependent form of oxidative cell death induced by lipid peroxidation accumulation. Glutathione peroxidase 4 (GPX4) plays a key role in the regulation of ferroptosis and is considered to be a promising therapeutic target for cancer and other human diseases. Herein, we describe our design, synthesis, and biological evaluation of a series of HyT-based degraders of the GPX4. One of the most promising compounds, 7b (ZX782), effectively induces dose- and time-dependent degradation of GPX4 protein and potently suppresses the growth of human fibrosarcoma HT1080 cells, which are highly sensitive to ferroptosis and widely used for evaluating compound specificity in ferroptosis. Mechanism investigation indicated that 7b depletes GPX4 through both the ubiquitin-proteasome and the autophagy-lysosome. Furthermore, the degradation of GPX4 induced by 7b could significantly increase the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, ultimately leading to ferroptosis. Overall, compound 7b exhibits robust potency in depleting endogenous GPX4, thereby modulating ferroptosis in cancer cells.

Fibroblast-Derived Extracellular Vesicle-Packaged Long Noncoding RNA Upregulated in Diabetic Skin Enhances Keratinocyte MMP-9 Expression and Delays Diabetic Wound Healing.

Accurate communication between fibroblasts and keratinocytes is crucial for diabetic wound healing. Extracellular vesicles are being explored as essential mediators of intercellular communication in the skin. However, the mechanisms underlying wound healing mediated by fibroblast-derived extracellular vesicles (Fib-EVs) remain unclear. The present study evaluated the role of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) packed in Fib-EVs in the wound healing of streptozotocin-induced diabetes and the potential mechanisms of the effects. We demonstrated that high glucose induced the enrichment of lnc-URIDS in Fib-EVs, facilitated the transfer of lnc-URIDS to primary rat epidermal keratinocytes, and increased the expression of matrix metalloproteinase-9. Mechanistically, the binding of lnc-URIDS to YTH domain family protein-2 enhanced the degradation of YTH domain family protein-2 in the lysosomes, which increased the translational activity of the messenger RNA of matrix metalloproteinase-9 and ultimately induced the degradation of collagen for wound healing. The results provided an insight into the crosstalk and cooperation between fibroblasts and keratinocytes in collagen homeostasis in diabetic wounds and clarified the mechanism by which lnc-URIDS degrades collagen for diabetic wound healing.

Characterization of oxidative stress-induced cgahp, a gene coding for alkyl hydroperoxide reductase, from industrial importance Corynebacterium glutamicum.

Alkyl hydroperoxide reductase (Ahp), comprised of four different subunits AhpC, AhpD, AhpE, and AhpF, is a thiol-based antioxidative enzyme with the ability to protect bacteria against oxidative stress. Functionally, AhpC and AhpE considered as peroxidases directly detoxify peroxides, while AhpD and AhpF as oxidoreductases restore oxidized peroxidases to their reduced form. Corynebacterium glutamicum ncgl0877 encodes a putative Ahp with a unique Cys-Pro-Phe-Cys (C-P-G-C) active-site motif, similar with those of the thiol-disulfide oxidoreductases such as thioredoxin (Trx), mycoredoxin-1 (Mrx1) and AhpD. However, its physiological and biochemical functions remain unknown in C. glutamicum. Here, we report that NCgl0877, designated CgAhp, is involved in the protection against organic peroxide (OP) stress. The cgahp-deleted strain is notably more sensitive to OP stress. The cgahp expression is controlled by a MarR-type transcriptional repressor OasR (organic peroxide- and antibiotic-sensing regulator). The physiological role of CgAhp in resistance to OP stresses is corroborated by its induced expression under stresses. Although CgAhp has a weak peroxidase activity toward OP, it mainly supports the OP-scavenging activity of the thiol-dependent peroxidase preferentially linked to the dihydrolipoamide dehydrogenase (Lpd)/dihydrolipoamide succinyltransferase (SucB)/NADH system. The C-P-G-C motif of CgAhp is essential to maintain the reductase activity. In conclusion, our study identifies CgAhp, behaving like AhpD, as a key disulfide oxidoreductase involved in the oxidative stress tolerance and the functional electron donor for peroxidase.

CSI Feedback Model Based on Multi-Source Characterization in FDD Systems.

In wireless communication, to fully utilize the spectrum and energy efficiency of the system, it is necessary to obtain the channel state information (CSI) of the link. However, in Frequency Division Duplexing (FDD) systems, CSI feedback wastes part of the spectrum resources. In order to save spectrum resources, the CSI needs to be compressed. However, many current deep-learning algorithms have complex structures and a large number of model parameters. When the computational and storage resources are limited, the large number of model parameters will decrease the accuracy of CSI feedback, which cannot meet the application requirements. In this paper, we propose a neural network-based CSI feedback model, Mix_Multi_TransNet, which considers both the spatial characteristics and temporal sequence of the channel, aiming to provide higher feedback accuracy while reducing the number of model parameters. Through experiments, it is found that Mix_Multi_TransNet achieves higher accuracy than the traditional CSI feedback network in both indoor and outdoor scenes. In the indoor scene, the NMSE gains of Mix_Multi_TransNet are 4.06 dB, 4.92 dB, 4.82 dB, and 6.47 dB for compression ratio η = 1/8, 1/16, 1/32, 1/64, respectively. In the outdoor scene, the NMSE gains of Mix_Multi_TransNet are 3.63 dB, 6.24 dB, 4.71 dB, 4.60 dB, and 2.93 dB for compression ratio η = 1/4, 1/8, 1/16, 1/32, 1/64, respectively.

A variation in SORBS1 is associated with type 2 diabetes and high-density lipoprotein cholesterol in Chinese population.

AIM: Sorbin and SH3-domain-containing-1 (SORBS1) play important roles in insulin signalling and cytoskeleton regulation. Variants of the SORBS1 gene have been inconsistently reported to be associated with type 2 diabetes or diabetic kidney disease (DKD). METHODS: Two independent case-control studies based on two randomized sampling cohorts (cohort 1, n = 3345; cohort 2, n = 2282) were used to confirm the association between rs2281939 of SORBS1 and impaired glucose regulation (IGR). An additional hospital-based cohort (cohort 3, n = 2135) and cohort 1 were used to investigate the association between rs2281939 and DKD. The phenotype of rare variants of SORBS1 was explored in 453 patients with early onset type 2 diabetes (diagnosed before 40 years of age, EOD). RESULTS: The G allele was associated with type 2 diabetes (additive model: OR = 1.25, 95% CI [1.03-1.52], p = 0.022) in cohort 1, and IGR in cohort 2 (additive model: OR = 1.22, 95% CI [1.05-1.43], p = 0.01). We found that the G allele was also associated with HDL-c levels in women in both cohort 1 (p = 0.03) and 2 (p = 0.029) in the dominant model. The rare variant carriers also had lower HDL-c and LDL-c levels than non-carriers in patients with EOD. No association between rs2281939 or rare variants and DKD was observed. CONCLUSIONS: The variants in the SORBS1 gene were associated with IGR and HDL-c levels but not with DKD in the Chinese Han population.

Diagnostic accuracy of anthropometric indices for discriminating elevated blood pressure in pediatric population: a systematic review and a meta-analysis.

BACKGROUND: Childhood obesity is more likely to increase the chance of many adult health problems. Numerous studies have shown obese children to be more prone to elevated blood pressure (BP) and hypertension. It is important to identify an obesity anthropometric index with good discriminatory power for them in pediatric population. METHODS: MEDLINE/PubMed, Web of Science, and Cochrane databases were retrieved comprehensively for eligible studies on childhood obesity and hypertension/elevated BP through June 2021. The systematic review and meta-analysis of studies used receiver operating characteristics (ROC) curves for evaluating the discriminatory power of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) in distinguishing children with elevated BP and hypertension. RESULTS: 21 cross-sectional studies involving 177,943 children and 3-19 years of age were included in our study. Meta-analysis showed that the pooled area under the reporting receiver-operating characteristic curves (AUC) and 95% confidence intervals (CIs) for BMI, WC, and WHtR to detect hypertension of boys were 0.68 (0.64, 0.72), 0.69 (0.64, 0.74), 0.67 (0.63, 0.71), for elevated BP, the pooled AUCs and 95% CIs were 0.67 (0.61, 0.73), 0.65 (0.58, 0.73), 0.65 (0.61, 0.71). The pooled AUCs and 95% CIs for BMI, WC and WHtR of predicting hypertension were 0.70 (0.66, 0.75), 0.69 (0.64, 0.75), 0.67 (0.63, 0.72) in girls, the pooled AUCs and 95% CIs of predicting elevated BP were 0.63 (0.61, 0.65), 0.62 (0.60, 0.65), 0.62 (0.60, 0.64) respectively. There was no anthropometric index was statistically superior in identifying hypertension and elevated BP, however, the accuracy of BMI predicting hypertension was significantly higher than elevated BP in girls (P < 0.05). The subgroup analysis for the comparison of BMI, WC and WHtR was performed, no significant difference in predicting hypertension and elevated BP in pediatric population. CONCLUSIONS: This systematic review showed that no anthropometric index was superior in identifying hypertension and elevated BP in pediatric population. While compared with predicting elevated BP, all the indicators showed superiority in predicting hypertension in children, the difference was especially obvious in girls. A better anthropometric index should be explored to predict children's early blood pressure abnormalities.

A Method for Sorting High-Quality Fresh Sichuan Pepper Based on a Multi-Domain Multi-Scale Feature Fusion Algorithm.

Post-harvest selection of high-quality Sichuan pepper is a critical step in the production process. To achieve this, a visual system needs to analyze Sichuan pepper with varying postures and maturity levels. To quickly and accurately sort high-quality fresh Sichuan pepper, this study proposes a multi-scale frequency domain feature fusion module (MSF3M) and a multi-scale dual-domain feature fusion module (MS-DFFM) to construct a multi-scale, multi-domain fusion algorithm for feature fusion of Sichuan pepper images. The MultiDomain YOLOv8 Model network is then built to segment and classify the target Sichuan pepper, distinguishing the maturity level of individual Sichuan peppercorns. A selection method based on the average local pixel value difference is proposed for sorting high-quality fresh Sichuan pepper. Experimental results show that the MultiDomain YOLOv8-seg achieves an mAP50 of 88.8% for the segmentation of fresh Sichuan pepper, with a model size of only 5.84 MB. The MultiDomain YOLOv8-cls excels in Sichuan pepper maturity classification, with an accuracy of 98.34%. Compared to the YOLOv8 baseline model, the MultiDomain YOLOv8 model offers higher accuracy and a more lightweight structure, making it highly effective in reducing misjudgments and enhancing post-harvest processing efficiency in agricultural applications, ultimately increasing producer profits.

The effects of repetitive transcranial magnetic and transcranial direct current stimulation on memory functions in older adults with mild cognitive impairment: a systematic review and meta-analysis.

Mild cognitive impairment (MCI) is a condition that impairs activities of daily living, and often transforms to dementia. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) show promise in improving cognitive functions in MCI patients. In this meta-analysis, we aimed to compare the effects of rTMS and tDCS on memory functions in MCI patients. We explored eight databases from their inception to March 16, 2024. We obtained 11 studies with 406 patients with MCI. We used the standardized mean difference (SMD) with a 95% confidence interval (CI) to synthesize the effect size. rTMS and tDCS significantly improved memory functions in MCI patients (SMD = 0.61; 95% CI: 0.41-0.82; p < 0.00001; I2 = 22%). In subgroup analysis of number of stimulation sessions, both rTMS and tDCS over 10 sessions (SMD = 0.84; 95% CI: 0.50-1.17, p < 0.00001, I2 = 0%) significantly improved the memory function in MCI patients. The subgroup analyses on different stimulation types (SMD = 0.78; 95% CI: 0.51-1.06; p < 0.00001; I2 = 0%) and treatment persistent effects (SMD = 0.93; 95% CI: 0.51-1.35, p < 0.0001, I2 = 0%) showed that rTMS was more effective than tDCS. rTMS with a stimulation frequency of 10 Hz (SMD = 0.86; 95% CI: 0.51-1.21; p < 0.00001; I2 = 0%) and over 10 sessions (SMD = 0.98; 95% CI: 0.58-1.38; p < 0.00001; I2 = 0%) at multiple sites (SMD = 0.97; 95% CI: 0.44-1.49; p = 0.0003; I2 = 0%) showed a great improvement in the memory performance of patients with MCI. rTMS was more likely to appear temporary side effects (risk ratio (RR) = 3.18, 95% CI: 1.29-7.83, p = 0.01). This meta-analysis suggests that rTMS and tDCS are safe and efficient tools to improve memory functions in patients with MCI, while rTMS had a larger effect than tDCS. rTMS with a stimulation frequency of 10 Hz targeted on multiple sites over 10 sessions showed the greatest effect. We could not conclude parameters of tDCS because of insufficient data. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024558991.

Enhancing kiwifruit flower pollination detection through frequency domain feature fusion: a novel approach to agricultural monitoring.

The pollination process of kiwifruit flowers plays a crucial role in kiwifruit yield. Achieving accurate and rapid identification of the four stages of kiwifruit flowers is essential for enhancing pollination efficiency. In this study, to improve the efficiency of kiwifruit pollination, we propose a novel full-stage kiwifruit flower pollination detection algorithm named KIWI-YOLO, based on the fusion of frequency-domain features. Our algorithm leverages frequency-domain and spatial-domain information to improve recognition of contour-detailed features and integrates decision-making with contextual information. Additionally, we incorporate the Bi-Level Routing Attention (BRA) mechanism with C3 to enhance the algorithm's focus on critical areas, resulting in accurate, lightweight, and fast detection. The algorithm achieves a m A P 0.5 of 91.6% with only 1.8M parameters, the AP of the Female class and the Male class reaches 95% and 93.5%, which is an improvement of 3.8%, 1.2%, and 6.2% compared with the original algorithm. Furthermore, the Recall and F1-score of the algorithm are enhanced by 5.5% and 3.1%, respectively. Moreover, our model demonstrates significant advantages in detection speed, taking only 0.016s to process an image. The experimental results show that the algorithmic model proposed in this study can better assist the pollination of kiwifruit in the process of precision agriculture production and help the development of the kiwifruit industry.

Artificial intelligence applied to development of predictive stability model for intracranial aneurysms.

BACKGROUND: We aimed to develop multiple machine learning models to predict the risk of early intracranial aneurysms (IAs) rupture, evaluate and compare the performance of predictive models. METHODS: Information related to patients diagnosed with IA by CT angiography and clinicians in Central hospital of Dalian University of Technology from January 2010 to June 2022 was collected, including clinical characteristics, blood indicators and IA morphological parameters. IA with rupture or maximum growth ≥ 0.5 mm within 1 month of first diagnosis was considered unstable. The relevant factors affecting IA stability were screened and predictive models were developed based on the above three levels, including random forest (RF), support vector machine (SVM), and artificial neural network (ANN). Sensitivity, specificity, accuracy and area under curve (AUC) value were used to evaluate the predictive models. RESULTS: A total of 989 IA patients were included in the study, including 561 stable patients and 428 unstable patients. For RF models, the training set showed that sensitivity, specificity, accuracy and the AUC values were 72.8-83.7%, 76.9-86.9%, 75.1-84.1% and 0.748 (0.719-0.778)-0.839 (0.814-0.864), respectively; after test set validation, the results were 71.9-78.8%, 75.0-84.0%, 73.6-81.1% and 0.734 (0.688-0.781)-0.809 (0.768-0.850), respectively. For SVM models, the training set were 66.0-80.2%, 76.5-85.5%, 71.7-82.3%, 0.712 (0.682-0.743)-0.913 (0.884-0.924), respectively; the test set were 44.2-78.3%, 63.4-84.4%, 57.9-80.9%, 0.699 (0.651-0.747)-0.806 (0.765-0.848), respectively. For ANN models, the training set were 66.8-83.0%, 75.3-82.3%, 71.6-82.1%, 0.783 (0.757-0.808)-0.897 (0.879-0.914); the test set were 63.1-76.3%, 65.5-84.0%, 64.4-80.6%, 0.680 (0.593-0.694)-0.860 (0.821-0.899). The results of variable importance showed that age, white blood cell count (WBC) and uric acid (UA) played an important role in predicting the stability of IA. CONCLUSIONS: The predictive stability models of IA based on three artificial intelligence methods shows good clinical application. Age, WBC and UA played an important role in predicting the IA stability, and were potentially important predictors.

Clinical characteristics, immunological alteration and distinction of MOG-IgG-associated disorders and GFAP-IgG-associated disorders.

The classification of autoimmune encephalitis (AE) is based on the presence of different types of antibodies. Currently, the clinical manifestations and treatment regimens of patients with all types of AE exhibit similarities. However, the presence of immunological distinctions among different types of AE remains uncertain. In this study, we prospectively collected clinical data, as well as blood and cerebrospinal fluid (CSF) samples from patients diagnosed with MOG antibody-associated disease (MOGAD) or GFAP astrocytopathy (GFAP-A), in order to assess changes in inflammatory biomarkers such as immunoglobulin oligoclonal bands, cytokines in serum and CSF, as well as peripheral blood lymphocyte subtypes within different subsets. To further distinguish the immune response in patients with MOGAD and GFAP-A from that of healthy individuals, we prospectively recruited 20 hospitalized patients diagnosed with AE. Among them, 15 (75%) tested positive for MOG antibodies, 4 (20%) tested positive for GFAP antibodies, and 1 (5%) tested positive for both MOG and GFAP antibodies. These patients were then followed up for a period of 18 months. Compared to healthy controls (HC), AE patients exhibited elevated levels of MIP-1beta, SDF-1alpha, IL-12p70, IL-5, IL-1RA, IL-8 and decreased levels of IL-23, IL-31, IFN-alpha, IL-7, TNF-beta and TNF-alpha in serum. The CSF of AE patients showed increased levels of IL-1RA, IL-6 and IL-2 while decreased levels of RANTES, IL-18,IL-7,TNF-beta,TNF-alpha,RANTES,Eotaxin,and IL-9. The level of MCP-1 in the CSF of GFAP-A patients was found to be lower compared to that of MOGAD patients, while RANTES levels were higher. And the levels of IL-17A, Eotaxin, GRO-alpha, IL-8, IL-1beta, MIP-1beta were higher in the CSF of patients with epilepsy. The presence of intrathecal immune responses is also observed in patients with spinal muscular atrophy (SMA). However, no biomarker was found to be associated with disease severity in patients with AE. Among the 17 patients, recovery was observed, while 2 patients experienced persistent symptoms after an 18-month follow-up period. Additionally, within one year of onset, 8 patients had a single recurrence. Therefore, the immunological profiles of MOGAD and GFAP-A patients differ from those of normal individuals, and the alterations in cytokine levels may also exhibit a causal association with the clinical presentations, such as seizure.

ZX703: A Small-Molecule Degrader of GPX4 Inducing Ferroptosis in Human Cancer Cells.

Ferroptosis is a novel form of oxidative cell death triggered by iron-dependent lipid peroxidation. The induction of ferroptosis presents an attractive therapeutic strategy for human diseases, such as prostate cancer and breast cancer. Herein, we describe our design, synthesis, and biological evaluation of endogenous glutathione peroxidase 4 (GPX4) degraders using the proteolysis targeting chimera (PROTAC) approach with the aim of inducing ferroptosis in cancer cells. Our efforts led to the discovery of compound 5i (ZX703), which significantly degraded GPX4 through the ubiquitin-proteasome and the autophagy-lysosome pathways in a dose- and time-dependent manner. Moreover, 5i was found to induce the accumulation of lipid reactive oxygen species (ROS) in HT1080 cells, thereby inducing ferroptosis. This study provides an attractive intervention strategy for ferroptosis-related diseases.

The Hub Genes Related to Osteoporosis Were Identified by Bioinformatics Analysis.

Osteoporosis (OP) is commonly encountered, which is a kind of systemic injury of bone mass and microstructure, leading to brittle fractures. With the aging of the population, this disease will pose a more serious impact on medical, social, and economic aspects, especially postmenopausal osteoporosis (PMOP). This study is aimed at figuring out potential therapeutic targets and new biomarkers in OP via bioinformatics tools. After differentially expressed gene (DEG) analysis, we successfully identified 97 upregulated and 172 downregulated DEGs. They are mainly concentrated in actin binding, regulation of cytokine production, muscle cell promotion, chemokine signaling pathway, and cytokine-cytokine receiver interaction. According to the diagram of protein-protein interaction (PPI), we obtained 10 hub genes: CCL5, CXCL10, EGFR, HMOX1, IL12B, CCL7, TBX21, XCL1, PGR, and ITGA1. Expression analysis showed that Egfr, Hmox1, and Pgr were significantly upregulated in estrogen-treated osteoporotic patients, while Ccl5, Cxcl10, Il12b, Ccl7, Tbx21, Xcl1, and Itga1 were significantly downregulated. In addition, the analysis results of Pearson's correlation revealed that CCL7 has a strong positive association with IL12b, TBX21, and CCL5 and so was CCL5 with IL12b. Conversely, EGFR has a strong negative association with XCL1 and CXCL10. In conclusion, this study screened 10 hub genes related to OP based on the GEO database, laying a biological foundation for further research on new biomarkers and potential therapeutic targets in OP.

Altered adolescents obesity metabolism is associated with hypertension: a UPLC-MS-based untargeted metabolomics study.

Objective: This study aimed to explore the relationship between the plasma metabolites of adolescent obesity and hypertension and whether metabolite alterations had a mediating effort between adolescent obesity and hypertension. Methods: We applied untargeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to detect the plasma metabolomic profiles of 105 adolescents. All participants were selected randomly based on a previous cross-sectional study. An orthogonal partial least squares- discriminant analysis (OPLS-DA), followed by univariate statistics and enrichment analysis, was used to identify differential metabolites. Using logistic regression for variable selection, an obesity-related metabolite score (OMS, OMS=∑k=1nßnmetabolite n) was constructed from the metabolites identified, and hypertension risk was estimated. Results: In our study, based on P< 0.05, variable importance in projection (VIP) > 1.0, and impact value > 0.1, we identified a total of 12 differential metabolites. Significantly altered metabolic pathways were the sphingolipid metabolism, purine metabolism, pyrimidine metabolism, phospholipid metabolism, steroid hormone biosynthesis, tryptophan, tyrosine, and phenylalanine biosynthesis. The logistic regression selection resulted in a four-metabolite score (thymidine, sphingomyelin (SM) d40:1, 4-hydroxyestradiol, and L-lysinamide), which was positively associated with hypertension risk (odds ratio: 7.79; 95% confidence interval: 2.13, 28.47; for the quintile 4 compared with quartile 1 of OMS) after multivariable adjustment. Conclusions: The OMS constructed from four differential metabolites was used to predict the risk of hypertension in adolescents. These findings could provide sensitive biomarkers for the early recognition of hypertension in adolescents with obesity.

Combining body mass index and waist height ratio to assess the relationship between obesity and serum uric acid levels in adolescents.

Background: The study aims to explore the relationship between obesity and serum uric acid in adolescents by combining body mass index and waist height ratio. Methods: 475 adolescents in our study were classified as normal weight without central obesity (NW), normal weight but central obesity (NWCO), overweight or obesity without central obesity (OB) and overweight or obesity with central obesity (OBCO). Odds ratios (OR) and 95% confidence intervals (CI) for hyperuricemia were calculated using a logistic regression model. The dose-response association between obesity indicators and serum uric acid were explored by restricted cubic spline model. Results: The highest serum uric acid level and the OR for hyperuricemia were found in the OBCO group, regardless of sex. After controlling for waist height ratio, the risk of hyperuricemia increased with increasing body mass index in boys and girls. The restricted cubic spline model showed that boys had higher ORs for hyperuricemia at the 25th and 75th percentiles of body mass index than for waist height ratio and girls had a higher OR for hyperuricemia than waist height ratio at the 25th percentile of body mass index. Conclusions: Hyperuricemia in adolescence was not only associated with the overweight or obesity in BMI, but with the combination of overweight or obesity in BMI and central obesity in WHtR. However, in boys and girls, the increased risk of hyperuricemia associated with elevated body mass index was significantly better than that of waist height ratio.

Rare Variant in Metallothionein 1E Increases the Risk of Type 2 Diabetes in a Chinese Population.

OBJECTIVE: To uncover novel targets for the treatment of type 2 diabetes (T2D) by investigating rare variants with large effects in monogenic forms of the disease. RESEARCH DESIGN AND METHODS: We performed whole-exome sequencing in a family with diabetes. We validated the identified gene using Sanger sequencing in additional families and diabetes- and community-based cohorts. Wild-type and variant gene transgenic mouse models were used to study the gene function. RESULTS: Our analysis revealed a rare variant of the metallothionein 1E (MT1E) gene, p.C36Y, in a three-generation family with diabetes. This risk allele was associated with T2D or prediabetes in a community-based cohort. MT1E p.C36 carriers had higher HbA1c levels and greater BMI than those carrying the wild-type allele. Mice with forced expression of MT1E p.C36Y demonstrated increased weight gain, elevated postchallenge serum glucose and liver enzyme levels, and hepatic steatosis, similar to the phenotypes observed in human carriers of MT1E p.C36Y. In contrast, mice with forced expression of MT1E p.C36C displayed reduced weight and lower serum glucose and serum triglyceride levels. Forced expression of wild-type and variant MT1E demonstrated differential expression of genes related to lipid metabolism. CONCLUSIONS: Our results suggest that MT1E could be a promising target for drug development, because forced expression of MT1E p.C36C stabilized glucose metabolism and reduced body weight, whereas MT1E p.C36Y expression had the opposite effect. These findings highlight the importance of considering the impact of rare variants in the development of new T2D treatments.

The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes.

Diabetes is one of the most common phenotypes of Wolfram syndrome owing to the presence of the variants of the WFS1 gene and is often misdiagnosed as other types of diabetes. We aimed to explore the prevalence of WFS1-related diabetes (WFS1-DM) and its clinical characteristics in a Chinese population with early-onset type 2 diabetes (EOD). We sequenced all exons of the WFS1 gene in 690 patients with EOD (age at diagnosis ≤ 40 years) for rare variants. Pathogenicity was defined according to the standards and guidelines of the American College of Medical Genetics and Genomics. We identified 33 rare variants predicted to be deleterious in 39 patients. The fasting [1.57(1.06-2.22) ng/ml] and postprandial C-peptide levels [2.8(1.75-4.46) ng/ml] of the patients with such WFS1 variations were lower than those of the patients without WFS1 variation [2.09(1.43-3.05) and 4.29(2.76-6.07) respectively, ng/ml]. Six (0.9%) patients carried pathogenic or likely pathogenic variants; they met the diagnostic criteria for WFS1-DM according to the latest guidelines, but typical phenotypes of Wolfram syndrome were seldom observed. They were diagnosed at an earlier age and usually presented with an absence of obesity, impaired beta cell function, and the need for insulin treatment. WFS1-DM is usually mistakenly diagnosed as type 2 diabetes, and genetic testing is helpful for individualized treatment.

Expression and clinical significance of FGFR1 and FGFR2 in laryngeal squamous cell carcinoma.

Background: Fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor receptor 2 (FGFR2) may be of significance in the development of laryngeal squamous cell carcinoma (SCC) tissues. Examination of the expression results of these factors may offer new insights into treatment of the disease, such as genetic and histological targeted target therapy. Methods: We selected tissue from 30 cases of laryngeal SCC, 23 cases of adjacent normal mucosa, and 26 cases of benign laryngeal mucosal tissues from patients who received surgery at the Otolaryngology Department of the Affiliated Hospital of Chengde Medical College between September 2020 and January 2022. The laryngeal cancers included nine cases of supraglottic, 20 glottic (vocal cord), and one case of subglottic cancer, while all benign laryngeal mucosal lesions were obtained from vocal cord polyps. The expression of FGFR1 and FGFR2 was detected in 30 laryngeal cancers, 23 adjacent normal mucosa, and 26 vocal cord polyps by immunohistochemical technology [immunohistochemistry (IHC)], and the correlation analysis of their expression in laryngeal cancer was performed. P<0.05 was represented statistically significant. Results: The expression of FGFR1 and FGFR2 was significantly different in laryngeal SCC and the normal tissue >0.5 cm from the tumor margin (P<0.05), and between laryngeal SCC and vocal polyps (P<0.05). There was no difference in FGFR1 and FGFR2 expression (P>0.05) between normal mucosal margins and vocal cord polyp tissue, and no correlation between FGFR1 and FGFR2 in laryngeal SCC and sex, age, smoking history, alcohol consumption history, tumor diameter, tumor lymph node metastasis, tumor differentiation degree, and Tumor-Node-Metastasis (TNM) stage (P>0.05), A moderate positive correlation between FGFR1 expression and FGFR2 expression in laryngeal SCC was seen (Rs=0.499, P<0.01). Conclusions: FGFR1 and FGFR2 may participate in the occurrence of SCC of the throat: (I) positive FGFR1 and FGFR2 expressions are not associated with gender, age, smoking history, alcohol consumption history, tumor diameter, lymph node metastasis, degree of differentiation, or TNM stage. (II) FGFR2 increases successively with higher FGFR1 expression and with a positive correlation in laryngeal SCC.

Social support can alleviate the fear of cancer recurrence in postoperative patients with lung carcinoma.

OBJECTIVE: To explore the status and influencing factors of the fear of cancer recurrence (FCR) in postoperative patients with lung carcinoma (LC). METHODS: The survey results of 219 LC patients who underwent surgical treatment in a tertiary grade A cancer hospital in Beijing from January 2020 to September 2021 were retrospectively analyzed by using the general information questionnaire, Social Support Rating Scale (SSRS), and the Fear of Progression Questionnaire-Short Form (FoP-Q-SF). RESULTS: The score of the FoP-Q-SF was (25.68±3.15 points) in postoperative LC patients, and education level and per capita monthly household income were identified as the independent risk factors affecting FCR. There was an inverse correlation between FCR and social support in postoperative LC patients (P<0.05). CONCLUSIONS: Postoperative LC patients experience a moderate-level of FCR, especially females and those with a low family income. Social support plays an essential role in alleviating FCR. Nursing suggestions should be given according to individual differences of patients, and social health service resources should be effectively utilized to reduce FCR.

Effect of Heat Stress on Egg Production, Steroid Hormone Synthesis, and Related Gene Expression in Chicken Preovulatory Follicular Granulosa Cells.

This study was conducted to elucidate the molecular mechanisms underlying heat stress (HS)-induced abnormal egg-laying in laying hens. Hy-Line brown laying hens were exposed to HS at 32 °C or maintained at 22 °C (control) for 14 days. In addition, granulosa cells (GCs) from preovulatory follicles were subjected to normal (37 °C) or high (41 °C or 43 °C) temperatures in vitro. Proliferation, apoptosis, and steroidogenesis were investigated, and the expression of estrogen and progesterone synthesis-related genes was detected. The results confirmed that laying hens reared under HS had impaired laying performance. HS inhibited proliferation, increased apoptosis, and altered the GC ultrastructure. HS also elevated progesterone secretion by increasing the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and 3b-hydroxysteroid dehydrogenase (3ß-HSD). In addition, HS inhibited estrogen synthesis in GCs by decreasing the expression of the follicle-stimulating hormone receptor (FSHR) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The upregulation of heat shock 70 kDa protein (HSP70) under HS was also observed. Collectively, laying hens exposed to high temperatures experienced damage to follicular GCs and steroidogenesis dysfunction, which reduced their laying performance. This study provides a molecular mechanism for the abnormal laying performance of hens subjected to HS.