BPT-PLR: A Balanced Partitioning and Training Framework with Pseudo-Label Relaxed Contrastive Loss for Noisy Label Learning.

While collecting training data, even with the manual verification of experts from crowdsourcing platforms, eliminating incorrect annotations (noisy labels) completely is difficult and expensive. In dealing with datasets that contain noisy labels, over-parameterized deep neural networks (DNNs) tend to overfit, leading to poor generalization and classification performance. As a result, noisy label learning (NLL) has received significant attention in recent years. Existing research shows that although DNNs eventually fit all training data, they first prioritize fitting clean samples, then gradually overfit to noisy samples. Mainstream methods utilize this characteristic to divide training data but face two issues: class imbalance in the segmented data subsets and the optimization conflict between unsupervised contrastive representation learning and supervised learning. To address these issues, we propose a Balanced Partitioning and Training framework with Pseudo-Label Relaxed contrastive loss called BPT-PLR, which includes two crucial processes: a balanced partitioning process with a two-dimensional Gaussian mixture model (BP-GMM) and a semi-supervised oversampling training process with a pseudo-label relaxed contrastive loss (SSO-PLR). The former utilizes both semantic feature information and model prediction results to identify noisy labels, introducing a balancing strategy to maintain class balance in the divided subsets as much as possible. The latter adopts the latest pseudo-label relaxed contrastive loss to replace unsupervised contrastive loss, reducing optimization conflicts between semi-supervised and unsupervised contrastive losses to improve performance. We validate the effectiveness of BPT-PLR on four benchmark datasets in the NLL field: CIFAR-10/100, Animal-10N, and Clothing1M. Extensive experiments comparing with state-of-the-art methods demonstrate that BPT-PLR can achieve optimal or near-optimal performance.

Role of MicroRNA in linking diabetic retinal neurodegeneration and vascular degeneration.

Diabetic retinopathy is the major cause of blindness in diabetic patients, with limited treatment options that do not always restore optimal vision. Retinal nerve degeneration and vascular degeneration are two primary pathological processes of diabetic retinopathy. The retinal nervous system and vascular cells have a close coupling relationship. The connection between neurodegeneration and vascular degeneration is not yet fully understood. Recent studies have found that microRNA plays a role in regulating diabetic retinal neurovascular degeneration and can help delay the progression of the disease. This article will review how microRNA acts as a bridge connecting diabetic retinal neurodegeneration and vascular degeneration, focusing on the mechanisms of apoptosis, oxidative stress, inflammation, and endothelial factors. The aim is to identify valuable targets for new research and clinical treatment of diabetic retinopathy.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation.

Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer's disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3ß activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the "SD microbiota" replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3ß activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3ß activation in primary hippocampal neurons, suggesting that GSK-3ß, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3ß as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.

[Retrospective study on the diagnosis, treatment, and follow-up of 85 cases of hypophosphatemic rickets in children]. / 85ä¾‹ä½Žè¡€ç£·æ€§ä½å»ç— æ‚£å„¿è¯Šæ–­ã€æ²»ç–—ä¸Žéšè®¿çš„å›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To study the diagnosis, treatment, and complications of hypophosphatemic rickets (HR) in children, explore effectiveness evaluation indicators for the disease, and understand the pattern in height growth among these patients. METHODS: A retrospective analysis of the initial clinical data and five-year follow-up data of 85 children with HR treated at Children's Hospital of Nanjing Medical University from January 2008 to December 2022. RESULTS: Among the 85 children with HR, there were 46 males (54%) and 39 females (46%). The age at initial diagnosis ranged from 6 months to 13 years and 9 months, with a median age of 2.75 years. The average height standard deviation score was -2.0±1.1. At initial diagnosis, children exhibited reduced blood phosphate levels and elevated alkaline phosphatase (ALP), with 99% (84/85) presenting with lower limb deformities. The positive rate for PHEX gene mutations was 93% (55/59). One year post-treatment, there was a significant reduction in ALP levels and the gap between the lower limbs (P<0.05). The fastest height growth occurred in the first year after treatment, at 8.23 cm/year, with a peak height velocity (PHV) phase lasting about two years during puberty. The height increased by 9-20 cm in male children during the PHV stage and 10-15 cm in female children. Major complications included nephrocalcinosis and hyperparathyroidism. The incidence rate of nephrocalcinosis in the first year after treatment was 55% (22/40), which increased with the duration of the disease (P<0.001); an increased urinary phosphate/creatinine ratio was positively associated with a higher risk of nephrocalcinosis (OR=1.740, P<0.001). The incidence of hyperparathyroidism in the first year after treatment was 64% (27/42). CONCLUSIONS: For children presenting with lower limb deformities, short stature, and slow growth, early testing for blood levels of phosphate, calcium, and ALP, along with imaging examinations of the lower limbs, can aid in the early diagnosis of HR. Genetic testing may be utilized for definitive confirmation when necessary. ALP combined with improvements in skeletal deformities and annual height growth can serve as indicators of therapeutic effectiveness for HR. Compared to normal children, children with HR demonstrate a lower height increase during the PHV phase, necessitating close follow-up and timely adjustment of treatment plans Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 677-682.

Novel Diagnostic Biomarkers Related to Necroptosis and Immune Infiltration in Coronary Heart Disease.

Purpose: Necroptosis, a monitored form of inflammatory cell death, contributes to coronary heart disease (CHD) progression. This study examined the potential of using necroptosis genes as diagnostic markers for CHD and sought to elucidate the underlying roles. Methods: Through bioinformatic analysis of GSE20680 and GSE20681, we first identified the differentially expressed genes (DEGs) related to necroptosis in CHD. Hub genes were identified using least absolute shrinkage and selection operator (LASSO) regression and random forest analysis after studying immune infiltration and transcription factor-miRNA interaction networks according to the DEGs. Quantitative polymerase chain reaction and immunohistochemistry were used to further investigate hub gene expression in vivo, for which a diagnostic model was constructed and the predictive efficacy was validated. Finally, the CHD group was categorized into high- and low-score groups in accordance with the single-sample gene set enrichment analysis (ssGSEA) score of the necroptosis genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, GSEA, and further immune infiltration analyses were performed on the two groups to explore the possible roles of hub genes. Results: Based on the results of the LASSO regression and random forest analyses, four genes were used to construct a diagnostic model to establish a nomogram. Additionally, an extensive analysis of all seventeen necroptosis genes revealed notable distinctions in expression between high-risk and low-risk groups. Evaluation of immune infiltration revealed that neutrophils, monocytes, B cells, and activated dendritic cells were highly distributed in the peripheral blood of patients with CHD. Specifically, the high CHD score group exhibited greater neutrophil and monocyte infiltration. Conversely, the high-score group showed lower infiltration of M0 and M2 macrophages, CD8+ T, plasma, and resting mast cells. Conclusion: TLR3, MLKL, HMGB1, and NDRG2 may be prospective biomarkers for CHD diagnosis. These findings offer plausible explanations for the role of necroptosis in CHD progression through immune infiltration and inflammatory response.

19F MRI/CEUS Dual Imaging-Guided Sonodynamic Therapy Enhances Immune Checkpoint Blockade in Triple-Negative Breast Cancer.

Treatment of highly aggressive triple-negative breast cancer (TNBC) in the clinic is challenging. Here, a liposome nanodrug (LP@PFH@HMME) integrating imaging agents and therapeutic agents for bimodal imaging-guided sonodynamic therapy (SDT) is developed, which boosted immunogenicity to enable potent immunotherapy via immune checkpoint blockade (ICB) in TNBC. In the acidic tumor microenvironment (TME), LP@PFH@HMME undergoes "nano-to-micro" transformation due to a pH-responsive lipid fusion, which makes droplets much more sensitive to ultrasound (US) in contrast-enhanced ultrasound (CEUS) and SDT studies. The nanodrug demonstrates robust bimodal imaging ability through fluorine-19 magnetic resonance imaging (19F MRI) and CEUS bimodal imaging, and it exhibits excellent solubility in aqueous solution with relatively high 19F content and desirable long transverse relaxation time (T2 = 1.072 s), making it suitable for high-performance 19F MRI, in addition to effective accumulation of nanodrugs after tail vein injection. Thus, 19F MRI/CEUS dual imaging is achievable to show adequate time points for US irradiation of tumor sites to induce highly effective SDT, which produces abundant reactive oxygen species (ROS) triggering immunogenic cell death (ICD) to assist ICB-based immunotherapy. The combination treatment design of sonodynamic therapy with immunotherapy effectively inhibited TNBC growth and recurrence, highlighting the promise of multifunctional nanodrugs in treating TNBC.

Histone deacetylases and inhibitors in diabetes mellitus and its complications.

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, with its prevalence linked to both genetic predisposition and environmental factors. Epigenetic modifications, particularly through histone deacetylases (HDACs), have been recognized for their significant influence on DM pathogenesis. This review focuses on the classification of HDACs, their role in DM and its complications, and the potential therapeutic applications of HDAC inhibitors. HDACs, which modulate gene expression without altering DNA sequences, are categorized into four classes with distinct functions and tissue specificity. HDAC inhibitors (HDACi) have shown efficacy in various diseases, including DM, by targeting these enzymes. The review highlights how HDACs regulate ß-cell function, insulin sensitivity, and hepatic gluconeogenesis in DM, as well as their impact on diabetic cardiomyopathy, nephropathy, and retinopathy. Finally, we suggest that targeted histone modification is expected to become a key method for the treatment of diabetes and its complications. The study of HDACi offers insights into new treatment strategies for DM and its associated complications.

Photoresponsive Nanoarchitectonics Based on Copper-Porphyrins for Near-Infrared-Enhanced Bacterial Treatment.

Antibiotic resistance is one of the biggest challenges that causes incurable diseases and endangers public health. Metal-porphyrin-modified nanoarchitectonics can enhance the bacterial affinity and destruction of cell walls. Herein, a new photoresponsive nanoarchitectonics (BPGa@COF-Cu) was synthesized by doping Ga(III) on the surface of black phosphorus (BP) and subsequently loaded into a Cu(II)-based covalent-organic framework (COF-Cu). The COF-Cu was induced by the coupling reaction of terephthalic chloride with amino-substituted porphyrin derivatives (THPP), followed by the coordination of the Cu(II) ion. The material BPGa@COF-Cu is a nanoball, and the mean radius is ca. 250 nm. The photochemical properties of BPGa@COF-Cu show that it efficiently catalyzes H2O2 into ·OH. BPGa@COF-Cu can also produce both singlet oxygen and heat upon 808 nm irradiation. Further, BPGa@COF-Cu was employed to inhibit bacteria, and the results showed that it can destroy the membrane of bacteria. The MIC (minimal inhibition concentration) of BPGa@COF-Cu against E. coli was 1 µg/mL. All the data suggest that BPGa@COF-Cu is a multiple nanoarchitectonics for bacterial treatment.

Complete androgen insensitivity syndrome coexisting with müllerian duct remnants: a case report and literature review.

This study represents the first documentation of the coexistence of complete androgen insensitivity syndrome (CAIS) with Müllerian duct remnants (MDRs) in mainland China. Additionally, we provide a comprehensive review of the existing literature concerning CAIS with MDRs resulting from androgen receptor (AR) gene mutations. This study broadens the clinical spectrum of CAIS and offer novel insights for further exploration into Müllerian duct regression. A 14-year-old patient, initially raised as female, presented to the clinic with complaints of "primary amenorrhea." Physical examination revealed the following: armpit hair (Tanner stage 2), breast development (Tanner stage 4 with bilateral breast nodule diameter of 7 cm), sparse pubic hair (Tanner stage 3), clitoris measuring 0.8 cm × 0.4 cm, separate urethral and vaginal openings, and absence of palpable masses in the bilateral groin or labia majora. The external genital virilization score was 0 points. Serum follicle-stimulating hormone level was 13.43 IU/L, serum luteinizing hormone level was 31.24 IU/L, and serum testosterone level was 14.95 nmol/L. Pelvic magnetic resonance imaging (MRI) did not reveal a uterus or bilateral fallopian tubes, but nodules on both sides of the pelvic wall indicated cryptorchidism. The karyotype was 46,XY. Genetic testing identified a maternal-derived hemizygous variation c.2359C > T (p.Arg787*) in the AR gene. During abdominal exploration, dysplastic testicles and a dysplastic uterus were discovered. Histopathological analysis revealed the presence of fallopian tube-like structures adjacent to the testicles. The CAIS patient documented in this study exhibited concurrent MDRs, thus expanding the spectrum of clinical manifestations of AIS. A review of prior literature suggests that the incidence of CAIS combined with histologically MDRs is not uncommon. Consequently, the identification of MDRs in AIS cases may represent an integral aspect of clinical diagnosis for this condition.

Long-term outcomes and predictive factors of achieving low disease activity status in childhood systemic lupus erythematosus: a Chinese bicentric retrospective registered study.

Background: This study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS. Methods: A total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied. Results: The male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8-13.1 years), the disease duration was 1.0 month (IQR, 0.5-2.0 months), and follow-up was 36.5 months (IQR, 25.7-50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)-these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P < 0.001). Conclusion: Endothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.

Effects of Crocus sativus on glycemic control and cardiometabolic parameters among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials.

Metabolic syndrome (MetS) is a cluster of clinical syndromes that is closely associated with an elevated risk of developing atherosclerotic cardiovascular disease. In a series of animal experiments and clinical trials, crocus sativus and its component crocin have demonstrated promising hypoglycemic effects. However, there is currently insufficient evidence regarding their impact on cardiometabolic parameters. Our study aimed to assess the impact of Crocus sativus and crocin on glycemic control in individuals with metabolic syndrome and associated disorders, as well as their potential effects on improving cardiometabolic parameters. We searched Cochrane Library, PubMed, Embase, and Web of Science databases to ascertain the pertinent randomized controlled trials (RCTs) until December 30, 2023. Q-test and I2 statistics were utilized to evaluate heterogeneity among the included studies. Data were merged using a random-effects model and presented as (WMD) with a 95% confidence interval (CI). The current comprehensive review and meta-analysis, encompassing 13 RCTs involving a total of 840 patients diagnosed with metabolic syndrome and associated disorders, demonstrates that Crocus sativus was superior to placebo on Hemoglobin A1c(HbA1c) (WMD: -0.31;95% CI [-0.44,-0.19]. P = 0.002) and systolic blood pressure(SBP) (WMD:-7.49;95% CI [-11.67,-3.30]. P = 0.99) respectively. Moreover, Crocus sativus improved fasting blood glucose (FBG) (WMD:-7.25;95% CI [-11.82, -2.57]. P = 0.002) when used crocin and on other chronic diseases. Crocus sativus reduced the total cholesterol (TC) among the metabolic syndromepatients (WMD:-13.64;95%CI [-26.26, -1.03]. P = 0.03). We demonstrated that Crocus sativus exerts beneficial effects on glycemic control and cardiometabolic parameters in individuals with metabolic syndrome and related disorders.

Protective effect of phospholipids in lipoproteins against diabetic kidney disease: A Mendelian randomization analysis.

BACKGROUND: The etiology of diabetic kidney disease is complex, and the role of lipoproteins and their lipid components in the development of the disease cannot be ignored. However, phospholipids are an essential component, and no Mendelian randomization studies have yet been conducted to examine potential causal associations between phospholipids and diabetic kidney disease. METHODS: Relevant exposure and outcome datasets were obtained through the GWAS public database. The exposure datasets included various phospholipids, including those in LDL, IDL, VLDL, and HDL. IVW methods were the primary analytical approach. The accuracy of the results was validated by conducting heterogeneity, MR pleiotropy, and F-statistic tests. MR-PRESSO analysis was utilized to identify and exclude outliers. RESULTS: Phospholipids in intermediate-density lipoprotein (OR: 0.8439; 95% CI: 0.7268-0.9798), phospholipids in large low- density lipoprotein (OR: 0.7913; 95% CI: 0.6703-0.9341), phospholipids in low- density lipoprotein (after removing outliers, OR: 0.788; 95% CI: 0.6698-0.9271), phospholipids in medium low- density lipoprotein (OR: 0.7682; 95% CI: 0.634-0.931), and phospholipids in small low-density lipoprotein (after removing outliers, OR: 0.8044; 95% CI: 0.6952-0.9309) were found to be protective factors. CONCLUSIONS: This study found that a higher proportion of phospholipids in intermediate-density lipoprotein and the various subfractions of low-density lipoprotein, including large LDL, medium LDL, and small LDL, is associated with a lower risk of developing diabetic kidney disease.

Causal relationship between ulcerative colitis and male infertility: A two-sample Mendelian randomization study.

AIMS: To explore the causal relationship between ulcerative colitis (UC) and male infertility using Mendelian randomization method with single nucleotide polymorphism (SNP) as the instrumental variables. METHODS: Genetic loci closely associated with UC were extracted as instrumental variables and male infertility was the outcome variable in pooled data from the gene-wide association study (GWAS),which was derived from European ethnic groups. The UC data(ebi-a-GCST003045) contained a total sample size of 27432 individuals and 110944 SNPs, and the male infertility data(finn-b-N14_MALEINFERT) contained a total sample size of 73479 individuals and 16377329 SNPs. The SNPs highly correlated with UC were screened from ebi-a-GCST003045(P<5×10-8 as the screening condition, the linkage disequilibrium coefficient was 0.001,and the width of the linkage disequilibrium area was 10000 kb).SNPs related to male infertility from finn-b-N14_MALEINFERT (the minimum r2>0.8,replacing the missing SNPs with SNPs with high linkage, and deleting SNPs without substitution sites) were extracted. MR analysis was performed using MR-Egger regression, the weighted median and the inverse-variance weighted (IVW) respectively, and the causal relationship between UC and male infertility was evaluated by OR and 95% CI, and the Egger-intercept method was used to test for horizontal multiplicity, and the sensitivity analysis was performed using "leave-one-out method". Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study. RESULTS: A total of 86 SNPs were included as IVs, with OR and 95% CI of 1.095(0.820~1.462)、1.059(0.899~1.248)、1.125(1.002~1.264) for MR-Egger, the weighted median and IVW results respectively, and P value of less than 0.05 for IVW, indicating that a causal relationship between UC and male infertility was causally related. The results of MR analysis combined with BWMR analysis also showed positive genetic causal relationship between UC and male infertility.MR-Egger regression showed an intercept of -2.21×10-3 with a standard error of 0.006 and P = 0.751, there was no horizontal pleiotropy for the IVs of exposure factors. Heterogeneity tests showed no heterogeneity and the results of the "leave-one-out" sensitivity analysis were stable. CONCLUSION: There is a causal association between UC and male infertility, which increases the risk of developing male infertility.

Association between neck circumference and bone mineral loss: A cross-sectional study in Sichuan province in China.

BACKGROUND: The associations of fat distribution with bone health are debatable. We aimed to investigate the associations between neck circumference (NC) and bone mineral loss among the adult Chinese population in Sichuan province. METHODS: We examined overall NC size and NC stratums (≤35 cm, 3538 cm) with bone mineral density (BMD) at the femoral neck, lumbar spine, total hip skeletal sites in 135 men and 479 women respectively, and assessed whether adiposity, lipids, and calcium and phosphorus levels, might have a biased role in the relationship of NC and bone mineral loss with linear regression, logistic regression, and restricted cubic spline models. RESULTS: The overall NC size is not independently associated with BMD at all sites. However, stratification for NC revealed that the positive correlation between NC and BMD at all sites were significant in the NC stratum 1 (≤35 cm) in women (all p < 0.05) and NC stratum 2 (3538 cm) compared with NC stratum 1 using logistic regression. However, in women, no statistically significant association was observed between NC stratum 1 and BMD values after adjustment for the same confounders. CONCLUSIONS: Our findings suggest a NC stratum-specific association between NC size and bone mineral loss in men in Sichuan province in China, but not in women.

Thymic carcinoid with multiple bone metastases: A case report.

BACKGROUND: Thymic carcinoid (TC) is a rare entity among anterior mediastinal malignancies. TCs are neuroendocrine carcinomas that constitute approximately 2%-5% of all thymic epithelial tumors. CASE SUMMARY: The study reported a rare TC with multiple bone metastases. A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg. Magnetic resonance imaging scans revealed damage to the lumbar spine, sacrocaudal vertebrae and iliac crest, suggesting bone metastasis; computed tomography (CT) scan of the thorax showed a calcified anterior mediastinal mass; positron emission tomography-CT demonstrated multiple abnormal bone signals; and laboratory work-up showed no endocrine abnormalities. Fine-needle aspiration biopsy revealed predominantly single small, round to oval cells with scant cytoplasm and some loose clusters, suggesting endocrine manifestations. The pathological diagnosis was atypical carcinoid, which tend to originate from the thymus and was classified as intermediate-highly invasive. The patient underwent anlotinib-targeted therapy. Anlotinib (12 mg) was administered daily for 2 wk, after which the patient was allowed to rest for 21 d. Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29% after therapy. Treatment has a long stable disease benefit of more than 2.5 years. CONCLUSION: These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.

The progress of clinical research on the detection of 1,5-anhydroglucitol in diabetes and its complications.

1,5-Anhydroglucitol (1,5-AG) is sensitive to short-term glucose fluctuations and postprandial hyperglycemia, which has great potential in the clinical application of diabetes as a nontraditional blood glucose monitoring indicator. A large number of studies have found that 1,5-AG can be used to screen for diabetes, manage diabetes, and predict the perils of diabetes complications (diabetic nephropathy, diabetic cardiovascular disease, diabetic retinopathy, diabetic pregnancy complications, diabetic peripheral neuropathy, etc.). Additionally, 1,5-AG and ß cells are also associated with each other. As a noninvasive blood glucose monitoring indicator, salivary 1,5-AG has much more benefit for clinical application; however, it cannot be ignored that its detection methods are not perfect. Thus, a considerable stack of research is still needed to establish an accurate and simple enzyme assay for the detection of salivary 1,5-AG. More clinical studies will also be required in the future to confirm the normal reference range of 1,5-AG and its role in diabetes complications to further enhance the blood glucose monitoring system for diabetes.

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine.

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene ß-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

Effect of electroacupuncture stimulation of "Sibai"(ST2) and "Quanliao"(SI18) on excitatory neurons of sensorimotor cortex in mice. / 电针"四白"和"颧髎"æ¿€æ´»å°é¼ èº¯ä½“æ„Ÿè§‰è¿åŠ¨çš®å±‚çš„å ´å¥‹æ€§ç¥žç»å ƒ.

OBJECTIVES: To observe the activation state and neuronal types of somatosensory cortex and the primary motor cortex induced by electroacupuncture (EA) stimulation of "Sibai" (ST2) and "Quanliao" (SI18) acupoints in mice. METHODS: Male C57BL/6J mice were randomly divided into blank control and EA groups, with 6 mice in each group. Rats of the EA group received EA stimulation (2 Hz, 0.6 mA) at ST2 and SI18 for 30 minutes. Samples were collected after EA intervention, and immunofluorescence staining was performed to quantify the expression of the c-Fos gene (proportion of c-Fos positive cells) in the somatosensory cortex and primary motor cortex. The co-labelled cells of calcium/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) and gamma-aminobutyric acid (GABA) in the somatosensory cortex and primary motor cortex were observed and counted by using microscope after immunofluorescence staining. Another 10 mice were used to detect the calcium activity of excitatory neurons in the somatosensory cortex and primary motor cortex by fiber photometry. RESULTS: In comparison with the blank control group, the number of c-Fos positive cells, and the proportion of c-Fos and CaMKⅡ co-labelled cells in both the somatosensory cortex and primary motor cortex were significantly increased after EA stimulation (P<0.05). No significant changes were found in the proportion of c-Fos and GABA co-labeled cells in both the somatosensory cortex and primary motor cortex after EA. Results of fiber optic calcium imaging technology showed that the spontaneous calcium activity of excitatory neurons in both somatosensory cortex and primary motor cortex were obviously increased during EA compared with that before EA (P<0.01), and strikingly reduced after cessation of EA compared with that during EA (P<0.05). CONCLUSIONS: Under physiological conditions, EA of ST2 and SI18 can effectively activate excitatory neurons in the somatosensory cortex and primary motor cortex.

Radiomic signatures associated with tumor immune heterogeneity predict survival in locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The prognostic value of traditional clinical indicators for locally recurrent nasopharyngeal carcinoma (lrNPC) is limited due to their inability to reflect intratumor heterogeneity. We aimed to develop a radiomic signature to reveal tumor immune heterogeneity and predict survival in lrNPC. METHODS: This multicenter, retrospective study included 921 patients with lrNPC. A machine learning signature and nomogram based on pretreatment MRI features were developed for predicting overall survival (OS) in a training cohort and validated in two independent cohorts. A clinical nomogram and an integrated nomogram were constructed for comparison. Nomogram performance was evaluated by concordance index (C-index) and receiver operating characteristic curve analysis. Accordingly, patients were classified into risk groups. The biological characteristics and immune infiltration of the signature were explored by RNA sequencing (RNA-seq) analysis. RESULTS: The machine learning signature and nomogram demonstrated comparable prognostic ability to a clinical nomogram, achieving C-indexes of 0.729, 0.718, and 0.731 in the training, internal, and external validation cohorts, respectively. Integration of the signature and clinical variables significantly improved the predictive performance. The proposed signature effectively distinguished patients between risk groups with significantly distinct OS rates. Subgroup analysis indicated the recommendation of local salvage treatments for low-risk patients. Exploratory RNA-seq analysis revealed differences in interferon response and lymphocyte infiltration between risk groups. CONCLUSIONS: An MRI-based radiomic signature predicted OS more accurately. The proposed signature associated with tumor immune heterogeneity may serve as a valuable tool to facilitate prognostic stratification and guide individualized management for lrNPC patients.

Towards an actionable One Health approach.

BACKGROUND: Despite the increasing focus on strengthening One Health capacity building on global level, challenges remain in devising and implementing real-world interventions particularly in the Asia-Pacific region. Recognizing these gaps, the One Health Action Commission (OHAC) was established as an academic community for One Health action with an emphasis on research agenda setting to identify actions for highest impact. MAIN TEXT: This viewpoint describes the agenda of, and motivation for, the recently formed OHAC. Recognizing the urgent need for evidence to support the formulation of necessary action plans, OHAC advocates the adoption of both bottom-up and top-down approaches to identify the current gaps in combating zoonoses, antimicrobial resistance, addressing food safety, and to enhance capacity building for context-sensitive One Health implementation. CONCLUSIONS: By promoting broader engagement and connection of multidisciplinary stakeholders, OHAC envisions a collaborative global platform for the generation of innovative One Health knowledge, distilled practical experience and actionable policy advice, guided by strong ethical principles of One Health.