Elucidating the Mechanism of Radiation Therapy on Mesenchymal Cell Fate in Preventing Heterotopic Ossification.

Radiation therapy is a clinically proven, localized preventive measure for heterotopic ossification (HO). Despite its efficacy, there is a lack of standardization of radiation prescription dosing and fractionation, and the mechanism of the impact of radiation in HO prevention remains unknown. Here, using an established mouse model of traumatic HO induced by burn and tenotomy, we demonstrate that 7Gy in one fraction delivered to the injury site within 72 hours postoperatively significantly decreases HO formation and improves hindlimb range of motion. In-depth single-cell transcriptomic analyses, in combination with immunofluorescent staining, demonstrate decreased cellular numbers as well as aberrant endochondral differentiation and downregulation of associated upstream signaling pathways in irradiated mesenchymal progenitor cells. Our study provides the framework for future mechanistic and clinically relevant studies exploring radiation efficacy in preventing HO formation.

Sodium Crotonate Alleviates Diabetic Kidney Disease Partially Via the Histone Crotonylation Pathway.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, inflammation and fibrosis play an important role in its progression. Histone lysine crotonylation (Kcr) was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of sodium crotonate (NaCr) and histone Kcr in kidney diseases. However, the effects of NaCr and NaCr-induced Kcr on DKD remain unclear. In this study, db/db mice and high glucose-induced human tubular epithelial cells (HK-2) were used respectively, and exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention reagents, histone Kcr and DKD-related indicators were detected. The results confirmed that NaCr had an antidiabetic effect and decreased blood glucose and serum lipid levels and alleviated renal function and DKD-related inflammatory and fibrotic damage. NaCr also induced histone Kcr and histone H3K18 crotonylation (H3K18cr). However, NaCr and Cr-CoA-induced histone Kcr and protective effects were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300 in vitro. In summary, our data reveal that NaCr may mitigate DKD via an antidiabetic effect as well as through ACSS2 and P300-induced histone Kcr, suggesting that Kcr may be the potential molecular mechanism and prevention target of DKD.

Dynamic changes on sensory property, nutritional quality and metabolic profiles of green kernel black beans during Eurotium cristatum-based solid-state fermentation.

Eurotium cristatum, a unique probiotic in Fu brick tea, is widely used in food processing to enhance added values. Here, green kernel black beans (GKBBs) were solid-fermented with E. cristatum and dynamic changes in flavour, chemical composition and metabolites during fermentation were investigated. As results, E. cristatum fermentation altered aroma profiles and sensory attributes of GKBBs, especially reduced sourness. After fermentation, total polyphenolic and flavonoid contents in GKBBs were elevated, while polysaccharides, soluble proteins and short-chain fatty acids contents were decreased. E. cristatum fermentation also induced biotransformation of glycosidic isoflavones into sapogenic isoflavones. During fermentation, dynamic changes in levels of 17 amino acids were observed, in which 3 branched-chain amino acids were increased. Non-targeted metabolomics identified 51 differential compounds and 10 related metabolic pathways involved in E. cristatum fermentation of GKBBs. This study lays foundation for the development of green kernel black bean-based functional food products with E. cristatum fermentation.

Prevalence rate of primary osteoporosis in China: a meta-analysis.

BACKGROUND: Primary osteoporosis (POP) is recognized as a "silent disease" and often ignored. This meta-analysis aimed to determine the prevalence of POP in the Chinese population over the past 20 years to raise awareness of the disease's epidemiology, which is hoped to help prevent and treat the condition better. METHODS: Eight English and three Chinese language databases were searched systematically from January 2002 to December 2023. Relevant data were analysed using Stata 16.0. Meta-regression and subgroup analyses were performed to explore causes of heterogeneity. A funnel plot was further drawn in combination with Egger and Begg tests to determine publication bias. RESULTS: A total of 45 studies (241,813 participants) were included. The meta-analysis revealed that the overall prevalence of POP in the Chinese population was 18.2% (95% CI: 14.7-21.7%), showing a positive correlation with age. Specifically, prevalence rates were 23.4% (18.3-28.5%) in women and 11.5% (9.1-13.9%) in men. A notable increase was observed within the span of 20 years (16.9% before 2010 and 20.3% in 2011-2020). Notably, regional variations were observed, with southern China reporting a lower prevalence of 16.4% compared to 20.2% in northern China. Meta-regression suggested that sample size significantly influenced the estimation of point prevalence (P = 0.037). CONCLUSIONS: Over the past two decades, there has been an increase in the prevalence of POP within the Chinese population. The growing prevalence of older individuals and women further highlights the urgency for tailored disease prevention and control measures.

Mycoplasma pneumoniae detections in children with lower respiratory infection before and during the COVID-19 pandemic: a large sample study in China from 2019 to 2022.

BACKGROUND: Nonpharmaceutical interventions (NPIs) implemented to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have suppressed the spread of other respiratory viruses during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to explore the epidemiological trends and clinical characteristics of Mycoplasma pneumoniae (MP) infection among inpatient children with lower respiratory tract infection (LRTI) before and during the COVID-19 pandemic, and investigate the long-term effects of China's NPIs against COVID-19 on the epidemiology of MP among inpatient children with LRTI. METHODS: Children hospitalised for LRTI at the Department of Pulmonology, The Children's Hospital, Zhejiang University School of Medicine (Hangzhou, China) between January 2019 and December 2022 were tested for common respiratory pathogens, including Mycoplasma pneumoniae (MP), Chlamydia trachomatis (CT) and other bacteria. Clinical data on age, sex, season of onset, disease spectrum, and combined infection in children with MP-induced LRTI in the past 4 years were collected and analysed. RESULTS: Overall, 15909 patients were enrolled, and MP-positive cases were 1971 (34.0%), 73 (2.4%), 176 (5.8%), and 952 (20.6%) in 2019, 2020, 2021, and 2022, respectively, with a significant statistical difference in the MP-positive rate over the 4 years (p <0.001). The median age of these children was preschool age (3-6 years), except for 2022, when they were school age (7-12 years), with statistical differences. Comparing the positive rates of different age groups, the school-age children (7-12 years) had the highest positive rate, followed by the preschoolers (3-6 years) in each of the 4 years. Compared among different seasons, the positive rate of MP in children with LRTI was higher in summer and autumn, whereas in 2020, it was highest in spring. The monthly positive rate peaked in July 2019, remained low from 2020 to 2021, and rebounded until 2022. Regarding the disease spectrum, severe pneumonia accounted for the highest proportion (46.3%) pre-pandemic and lowest (0%) in 2020. CONCLUSION: Trends in MP detection in children with LRTIs suggest a possible correlation between COVID-19 NPIs and significantly reduced detection rates. The positivity rate of MP gradually rose after 2 years. The epidemic season showed some differences, but school-age children were more susceptible to MP before and during the COVID-19 pandemic.

Seasonal variation of serum potassium in hemodialysis patients: myth or reality? A narrative review of literature.

Research has shown that patients undergoing hemodialysis experience seasonal variations in their serum potassium levels. There was inconsistent seasonal fluctuation in serum potassium levels among the hemodialysis population across different locations. In the form of narrative review for the first time, the article discusses the seasonal changes of serum potassium in this population and its potential reasons, this article demonstrates that it is primarily attributable to seasonal dietary potassium intake. However, existing studies have not quantified seasonal dietary potassium intake, so the results are still speculative. Furthermore, future research ought to further expound upon the clinical implications of seasonal variations in serum potassium levels among dialysis patients, as well as other influencing mechanisms such as the pathophysiological causes of these seasonal changes, particularly those pertaining to dietary, geographical, and regional factors. These findings contribute to a more thorough interpretation of laboratory results in hemodialysis patients and provide important guidance for their individualized dietary management.

The effect of stir-frying on the aging of oat flour during storage: A study based on lipidomics.

In this study, we used the LC-ESI-MS/MS technique to elucidate the effects of stir-frying on the lipidomics of oat flour before and after storage. We detected 1540 lipids in 54 subclasses; triglycerides were the most abundant, followed by diacylglycerol, ceramide (Cer), digalactosyldiacylglycerol, cardiolipin, and phosphatidylcholine. Principal component analysis and orthogonal least squares discriminant analysis analyses showed that oat flour lipids were significantly different before and after storage in stir-fried oat flour and raw oat flour. After oat flour was stir-fried, most of the lipid metabolites in it were significantly downregulated, and the changes in lipids during storage were reduced. Sphingolipid metabolism and ether lipid metabolism were the key metabolic pathways, and Cer, PC, and lyso-phosphatidylcholine were the key lipid metabolites identified in the related metabolic pathways during oat flour storage. Frying inhibits lipid metabolic pathways during storage of oat flour, thereby improving lipid stability and quality during storage. This study laid the foundation for further investigating quality control and the mechanism of changes in lipids during the storage of oat flour.

Tea Consumption, Milk or Sweeteners Addition, Genetic Variation in Caffeine Metabolism, and Incident Venous Thromboembolism.

OBJECTIVE: The association between tea consumption and venous thromboembolism (VTE) remains unknown. We aimed to evaluate the association between tea consumption with different additives (milk and/or sweeteners) and incident VTE, and the modifying effects of genetic variation in caffeine metabolism on the association. METHODS: A total of 190,189 participants with complete dietary information and free of VTE at baseline in the UK Biobank were included. The primary outcome was incident VTE, including incident deep vein thrombosis and pulmonary embolism. RESULTS: During a median follow-up of 12.1 years, 4,485 (2.4%) participants developed incident VTE. Compared with non-tea drinkers, tea drinkers who added neither milk nor sweeteners (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.76-0.94), only milk (HR: 0.86; 95% CI: 0.80-0.93), and both milk and sweeteners to their tea (HR: 0.90; 95% CI: 0.81-0.99) had a lower risk of VTE, while those who added only sweeteners to their tea did not (HR: 0.94; 95% CI: 0.75-1.17). Moreover, there was an L-shaped relationship between tea consumption and incident VTE among tea drinkers who added neither milk nor sweeteners, only milk, and both milk and sweeteners to their tea, respectively. However, a nonsignificant association was found among tea drinkers who added only sweeteners to their tea. Genetic variation in caffeine metabolism did not significantly modify the association (p-interaction = 0.659). CONCLUSION: Drinking unsweetened tea, with or without added milk, was associated with a lower risk of VTE. However, there was no significant association between drinking tea with sweeteners and incident VTE.

Development of rapid nucleic acid testing techniques for common respiratory infectious diseases in the Chinese population.

Background: Most respiratory viruses can cause serious lower respiratory diseases at any age. Therefore, timely and accurate identification of respiratory viruses has become even more important. This study focused on the development of rapid nucleic acid testing techniques for common respiratory infectious diseases in the Chinese population. Methods: Multiplex fluorescent quantitative polymerase chain reaction (PCR) assays were developed and validated for the detection of respiratory pathogens including the novel coronavirus (SARS-CoV-2), influenza A virus (FluA), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). Results: The assays demonstrated high specificity and sensitivity, allowing for the simultaneous detection of multiple pathogens in a single reaction. These techniques offer a rapid and reliable method for screening, diagnosis, and monitoring of respiratory pathogens. Conclusion: The implementation of these techniques might contribute to effective control and prevention measures, leading to improved patient care and public health outcomes in China. Further research and validation are needed to optimize and expand the application of these techniques to a wider range of respiratory pathogens and to enhance their utility in clinical and public health settings.

The Arabidopsis SGN3/GSO1 receptor kinase integrates soil nitrogen status into shoot development.

The Casparian strip is a barrier in the endodermal cell walls of plants that allows the selective uptake of nutrients and water. In the model plant Arabidopsis thaliana, its development and establishment are under the control of a receptor-ligand mechanism termed the Schengen pathway. This pathway facilitates barrier formation and activates downstream compensatory responses in case of dysfunction. However, due to a very tight functional association with the Casparian strip, other potential signaling functions of the Schengen pathway remain obscure. In this work, we created a MYB36-dependent synthetic positive feedback loop that drives Casparian strip formation independently of Schengen-induced signaling. We evaluated this by subjecting plants in which the Schengen pathway has been uncoupled from barrier formation, as well as a number of established barrier-mutant plants, to agar-based and soil conditions that mimic agricultural settings. Under the latter conditions, the Schengen pathway is necessary for the establishment of nitrogen-deficiency responses in shoots. These data highlight Schengen signaling as an essential hub for the adaptive integration of signaling from the rhizosphere to aboveground tissues.

Potential rapid intraoperative cancer diagnosis using dynamic full-field optical coherence tomography and deep learning: A prospective cohort study in breast cancer patients.

An intraoperative diagnosis is critical for precise cancer surgery. However, traditional intraoperative assessments based on hematoxylin and eosin (H&E) histology, such as frozen section, are time-, resource-, and labor-intensive, and involve specimen-consuming concerns. Here, we report a near-real-time automated cancer diagnosis workflow for breast cancer that combines dynamic full-field optical coherence tomography (D-FFOCT), a label-free optical imaging method, and deep learning for bedside tumor diagnosis during surgery. To classify the benign and malignant breast tissues, we conducted a prospective cohort trial. In the modeling group (n = 182), D-FFOCT images were captured from April 26 to June 20, 2018, encompassing 48 benign lesions, 114 invasive ductal carcinoma (IDC), 10 invasive lobular carcinoma, 4 ductal carcinoma in situ (DCIS), and 6 rare tumors. Deep learning model was built up and fine-tuned in 10,357 D-FFOCT patches. Subsequently, from June 22 to August 17, 2018, independent tests (n = 42) were conducted on 10 benign lesions, 29 IDC, 1 DCIS, and 2 rare tumors. The model yielded excellent performance, with an accuracy of 97.62%, sensitivity of 96.88% and specificity of 100%; only one IDC was misclassified. Meanwhile, the acquisition of the D-FFOCT images was non-destructive and did not require any tissue preparation or staining procedures. In the simulated intraoperative margin evaluation procedure, the time required for our novel workflow (approximately 3 min) was significantly shorter than that required for traditional procedures (approximately 30 min). These findings indicate that the combination of D-FFOCT and deep learning algorithms can streamline intraoperative cancer diagnosis independently of traditional pathology laboratory procedures.

Beyond conventional bounds: Surpassing system limits for stereotactic ablative (SAbR) lung radiotherapy using CBCT-based adaptive planning system.

PURPOSE: Online adaptive radiotherapy relies on a high degree of automation to enable rapid planning procedures. The Varian Ethos intelligent optimization engine (IOE) was originally designed for conventional treatments so it is crucial to provide clear guidance for lung SAbR plans. This study investigates using the Ethos IOE together with adaptive-specific optimization tuning structures we designed and templated within Ethos to mitigate inter-planner variability in meeting RTOG metrics for both online-adaptive and offline SAbR plans. METHODS: We developed a planning strategy to automate the generation of tuning structures and optimization. This was validated by retrospective analysis of 35 lung SAbR cases (total 105 fractions) treated on Ethos. The effectiveness of our planning strategy was evaluated by comparing plan quality with-and-without auto-generated tuning structures. Internal target volume (ITV) contour was compared between that drawn from CT simulation and from cone-beam CT (CBCT) at time of treatment to verify CBCT image quality and treatment effectiveness. Planning strategy robustness for lung SAbR was quantified by frequency of plans meeting reference plan RTOG constraints. RESULTS: Our planning strategy creates a gradient within the ITV with maximum dose in the core and improves intermediate dose conformality on average by 2%. ITV size showed no significant difference between those contoured from CT simulation and first fraction, and also trended towards decreasing over course of treatment. Compared to non-adaptive plans, adaptive plans better meet reference plan goals (37% vs. 100% PTV coverage compliance, for scheduled and adapted plans) while improving plan quality (improved GI (gradient index) by 3.8%, CI (conformity index) by 1.7%). CONCLUSION: We developed a robust and readily shareable planning strategy for the treatment of adaptive lung SAbR on the Ethos system. We validated that automatic online plan re-optimization along with the formulated adaptive tuning structures can ensure consistent plan quality. With the proposed planning strategy, highly ablative treatments are feasible on Ethos.

Modified Zhenwu Tang delays chronic renal failure progression by modulating oxidative stress and hypoxic responses in renal proximal tubular epithelial cells.

Background: Tubulointerstitial fibrosis (TIF) is a critical pathological feature of chronic renal failure (CRF), with oxidative stress (OS) and hypoxic responses in renal proximal tubular epithelial cells playing pivotal roles in disease progression. This study explores the effects of Modified Zhenwu Tang (MZWT) on these processes, aiming to uncover its potential mechanisms in slowing CRF progression. Methods: We used adenine (Ade) to induce CRF in rats, which were then treated with benazepril hydrochloride (Lotensin) and MZWT for 8 weeks. Assessments included liver and renal function, electrolytes, blood lipids, renal tissue pathology, OS levels, the hypoxia-inducible factor (HIF) pathway, inflammatory markers, and other relevant indicators. In vitro, human renal cortical proximal tubular epithelial cells were subjected to hypoxia and lipopolysaccharide for 72 h, with concurrent treatment using MZWT, FM19G11, and N-acetyl-l-cysteine. Measurements taken included reactive oxygen species (ROS), HIF pathway activity, inflammatory markers, and other relevant indicators. Results: Ade treatment induced significant disruptions in renal function, blood lipids, electrolytes, and tubulointerstitial architecture, alongside heightened OS, HIF pathway activation, and inflammatory responses in rats. In vivo, MZWT effectively ameliorated proteinuria, renal dysfunction, lipid and electrolyte imbalances, and renal tissue damage; it also suppressed OS, HIF pathway activation, epithelial-mesenchymal transition (EMT) in proximal tubular epithelial cells, and reduced the production of inflammatory cytokines and collagen fibers. In vitro findings demonstrated that MZWT decreased apoptosis, reduced ROS production, curbed OS, HIF pathway activation, and EMT in proximal tubular epithelial cells, and diminished the output of inflammatory cytokines and collagen. Conclusion: OS and hypoxic responses significantly contribute to TIF development. MZWT mitigates these responses in renal proximal tubular epithelial cells, thereby delaying the progression of CRF.

Comparative metabolomics combined with genome sequencing provides insights into novel wolfberry-specific metabolites and their formation mechanisms.

Wolfberry (Lycium, of the family Solanaceae) has special nutritional benefits due to its valuable metabolites. Here, 16 wolfberry-specific metabolites were identified by comparing the metabolome of wolfberry with those of six species, including maize, rice, wheat, soybean, tomato and grape. The copy numbers of the riboflavin and phenyllactate degradation genes riboflavin kinase (RFK) and phenyllactate UDP-glycosyltransferase (UGT1) were lower in wolfberry than in other species, while the copy number of the phenyllactate synthesis gene hydroxyphenyl-pyruvate reductase (HPPR) was higher in wolfberry, suggesting that the copy number variation of these genes among species may be the main reason for the specific accumulation of riboflavin and phenyllactate in wolfberry. Moreover, the metabolome-based neighbor-joining tree revealed distinct clustering of monocots and dicots, suggesting that metabolites could reflect the evolutionary relationship among those species. Taken together, we identified 16 specific metabolites in wolfberry and provided new insight into the accumulation mechanism of species-specific metabolites at the genomic level.

Efficacy of targeted therapy in patients with non-small cell lung cancer harboring very rare mutations in EGFR exon 18.

Background: Somatic mutations in epidermal growth factor receptor (EGFR) exon 18 are classified as uncommon or rare mutations in non-small cell lung cancer (NSCLC), in this context, other than G719X or E709X exon 18 mutations are even more rare and heterogeneous. In such scenario, first line treatment options are still debated. The aim of this study was to investigate the response of NSCLC patients harboring very rare exon 18 mutations to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Methods: This retrospective descriptive study included 105 patients with NSCLC harboring mutations in EGFR exon 18 diagnosed at West China Hospital. The clinical response to EGFR-TKIs was evaluated according to different classifications of mutations in 45 NSCLC patients: 39 harboring G719X or E709X mutations and 6 harboring very rare mutations in EGFR exon 18. Results: Among 105 patients, 84% (88/105) harbored rare mutations in EGFR exon 18, including G719X and E709X mutations. The remaining 16% (17/105) had very rare mutations in EGFR exon 18, including E709_710delinsX and G724S. For the subsequent efficacy analysis of EGFR-TKI in 45 NSCLC patients, patients harboring very rare mutations achieved a favorable disease control rate (DCR) of 100% and had a median progression-free survival (PFS) of 17.2 months, which was not significantly different compared to patients harboring G719X or E709X (P=0.59). Conclusions: EGFR-TKIs showed great efficacy in terms of responses and survival in patients harboring exon 18 EGFR rare mutations. This may justify the use of targeted therapies as a potential treatment strategy for these patients.

Urine-derived stem cells genetically modified with IGF1 improve muscle regeneration.

OBJECTIVE: In this study we aimed to determine the impact of human urine derived stem cells (USC) and genetically modified USC that were designed to overexpress myogenic growth factor IGF1 (USCIGF), on the regenerative capacity of cardiotoxin (CTX)-injured murine skeletal muscle. METHODS: We overexpressed IGF1 in USC and investigated the alterations in myogenic capacity and regenerative function in cardiotoxin-injured muscle tissues. RESULTS: Compared with USC alone, USCIGF1 activated the IGF1-Akt-mTOR signaling pathway, significantly improved myogenic differentiation capacity in vitro, and enhanced the secretion of myogenic growth factors and cytokines. In addition, IGF1 overexpression increased the ability of USC to fuse with skeletal myocytes to form myotubes, regulated the pro-regenerative immune response and inflammatory cytokines, and increased myogenesis in an in vivo model of skeletal muscle injury. CONCLUSION: Overall, USC genetically modified to overexpress IGF1 significantly enhanced skeletal muscle regeneration by regulating myogenic differentiation, paracrine effects, and cell fusion, as well as by modulating immune responses in injured skeletal muscles in vivo. This study provides a novel perspective for evaluating the myogenic function of USC as a nonmyogenic cell source in skeletal myogenesis. The combination of USC and IGF1 expression has the potential to provide a novel efficient therapy for skeletal muscle injury and associated muscular defects in patients with urinary incontinence.

Predicting transcriptional activation domain function using Graph Neural Networks.

Analysis of factors that lead to the functionality of transcriptional activation domains remains a crucial and yet challenging task owing to the significant diversity in their sequences and their intrinsically disordered nature. Almost all existing methods that have aimed to predict activation domains have involved traditional machine learning approaches, such as logistic regression, that are unable to capture complex patterns in data or plain convolutional neural networks and have been limited in exploration of structural features. However, there is a tremendous potential in the inspection of the structural properties of activation domains, and an opportunity to investigate complex relationships between features of residues in the sequence. To address these, we have utilized the power of graph neural networks which can represent structural data in the form of nodes and edges, allowing nodes to exchange information among themselves. We have experimented with two kinds of graph formulations, one involving residues as nodes and the other assigning atoms to be the nodes. A logistic regression model was also developed to analyze feature importance. For all the models, several feature combinations were experimented with. The residue-level GNN model with amino acid type, residue position, acidic/basic/aromatic property and secondary structure feature combination gave the best performing model with accuracy, F1 score and AUROC of 97.9%, 71% and 97.1% respectively which outperformed other existing methods in the literature when applied on the dataset we used. Among the other structure-based features that were analyzed, the amphipathic property of helices also proved to be an important feature for classification. Logistic regression results showed that the most dominant feature that makes a sequence functional is the frequency of different types of amino acids in the sequence. Our results consistent have shown that functional sequences have more acidic and aromatic residues whereas basic residues are seen more in non-functional sequences.

Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy.

AIM: Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN. METHODS: The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR. RESULTS: ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN. CONCLUSION: Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.

Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer's Disease: A Multivariable Mendelian Randomization Study.

Background: Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored. Objective: Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods. Methods: We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence. Results: Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%). Conclusions: Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.

Gestational diabetes mellitus affects the differentiation of hematopoietic stem cells in neonatal umbilical cord blood.

PURPOSE: There are abundant hematopoietic stem cells (HSCs) in cord blood. It is known that HSCs continue to differentiate to CLP, CMP and erythroid progenitor cells (EPC), EPC ultimately differentiated to platelets and erythrocytes. It has been reported that the proportion of HSCs in cord blood was higher than that in healthy pregnant women, so as the incidence of neonatal polycythemia in gestational diabetes mellitus (GDM) patients. We aimed to investigate whether the hyperglycemic and/or hyperinsulin environment in GDM patients has effects on the differentiation of HSCs into erythrocytes in offspring cord blood. METHODS: In this study, we collected cord blood from 23 GDM patients and 52 healthy pregnant women at delivery. HSCs, CLP, CMP and EPCs in cord blood of the two groups were identified and quantified by flow cytometry. HSCs were sorted out and treated with glucose and insulin, respectively, and then, the changes of HSCs proliferation and differentiation were detected. RESULTS: Compared to healthy controls, HSCs, CMP and EPC numbers in cord blood from GDM group were significantly increased, while CLP cell number was decreased. The differentiation of HSCs into EPC was promoted after treatment with glucose or insulin. CONCLUSION: There were more HSCs in the cord blood of GDM group, and the differentiation of HSCs to EPCs was increased. These findings were probably caused by the high-glucose microenvironment and insulin medication in GDM patients, and the HSCs differentiation changes might be influencing factors of the high incidence of neonatal erythrocytosis in GDM patients.