Resetting of the 24-nt siRNA landscape in rice zygotes.

The zygote, a totipotent stem cell, is crucial to the life cycle of sexually reproducing organisms. It is produced by the fusion of two differentiated cells-the egg and sperm, which in plants have radically different siRNA transcriptomes from each other and from multicellular embryos. Owing to technical challenges, the epigenetic changes that accompany the transition from differentiated gametes to totipotent zygote are poorly understood. Because siRNAs serve as both regulators and outputs of the epigenome, we characterized small RNA transcriptomes of zygotes from rice. Zygote small RNAs exhibit extensive maternal carryover and an apparent lack of paternal contribution, indicated by absence of sperm signature siRNAs. Zygote formation is accompanied by widespread redistribution of 24-nt siRNAs relative to gametes, such that ∼70% of the zygote siRNA loci do not overlap any egg cell siRNA loci. Newly detected siRNA loci in zygote are gene-proximal and not associated with centromeric heterochromatin, similar to canonical siRNAs, in sharp contrast to gametic siRNA loci that are gene-distal and heterochromatic. In addition, zygote but not egg siRNA loci are associated with high DNA methylation in the mature embryo. Thus, the zygote begins transitioning before the first embryonic division to an siRNA profile that is associated with future RdDM in embryogenesis. These findings indicate that, in addition to changes in gene expression, the transition to totipotency in the plant zygote is accompanied by resetting of the epigenetic reprogramming that occurred during gamete formation.

Single-cell multi-omics in the medicinal plant Catharanthus roseus.

Advances in omics technologies now permit the generation of highly contiguous genome assemblies, detection of transcripts and metabolites at the level of single cells and high-resolution determination of gene regulatory features. Here, using a complementary, multi-omics approach, we interrogated the monoterpene indole alkaloid (MIA) biosynthetic pathway in Catharanthus roseus, a source of leading anticancer drugs. We identified clusters of genes involved in MIA biosynthesis on the eight C. roseus chromosomes and extensive gene duplication of MIA pathway genes. Clustering was not limited to the linear genome, and through chromatin interaction data, MIA pathway genes were present within the same topologically associated domain, permitting the identification of a secologanin transporter. Single-cell RNA-sequencing revealed sequential cell-type-specific partitioning of the leaf MIA biosynthetic pathway that, when coupled with a single-cell metabolomics approach, permitted the identification of a reductase that yields the bis-indole alkaloid anhydrovinblastine. We also revealed cell-type-specific expression in the root MIA pathway.

Quantitative Single-Cell Mass Spectrometry Provides a Highly Resolved Analysis of Natural Product Biosynthesis Partitioning in Plants.

Plants produce an extraordinary array of natural products (specialized metabolites). Notably, these structurally complex molecules are not evenly distributed throughout plant tissues but are instead synthesized and stored in specific cell types. Elucidating both the biosynthesis and function of natural products would be greatly facilitated by tracking the location of these metabolites at the cell-level resolution. However, detection, identification, and quantification of metabolites in single cells, particularly from plants, have remained challenging. Here, we show that we can definitively identify and quantify the concentrations of 16 molecules from four classes of natural products in individual cells of leaf, root, and petal of the medicinal plant Catharanthus roseus using a plate-based single-cell mass spectrometry method. We show that identical natural products show substantially different patterns of cell-type localization in different tissues. Moreover, we show that natural products are often found in a wide range of concentrations across a population of cells, with some natural products at concentrations of over 100 mM per cell. This single-cell mass spectrometry method provides a highly resolved picture of plant natural product biosynthesis partitioning at a cell-specific resolution.

Enhancement of PRMT6 binding to a novel germline GATA1 mutation associated with congenital anemia.

Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1's target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function, and the role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis.

Walking pace and microvascular complications among individuals with type 2 diabetes: A cohort study from the UK Biobank.

INTRODUCTION: Walking pace is associated with various health-related outcomes. The aim of this study was to investigate the association between self-reported walking pace and the incidences of diabetic microvascular complications among participants with type 2 diabetes (T2D). METHODS: Self-reported walking pace was classified as brisk, average, or slow. The outcomes were the incidences of diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. COX proportional hazards models adjusted for sociodemographic, lifestyle, and health-related factors were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: A total of 14 518 participants with T2D in the UK Biobank (mean age 59.7 ± 7.0 years, 5028 [34.6%] women) were included. During a median follow-up of 12.5 (interquartile range: 11.6-13.4) years, 2980 participants developed diabetic microvascular complications. After adjusting for confounding factors, and compared with brisk walkers, slow walkers had a multivariable-adjusted HR of 1.98 (95% CI 1.58, 2.47) for composite diabetic microvascular complications, 1.54 (95% CI 1.11, 2.14) for diabetic retinopathy, 3.26 (95% CI 2.08, 5.11) for diabetic neuropathy, and 2.32 (95% CI 1.91, 2.82) for diabetic nephropathy. Average walking pace was associated with a higher risk for diabetic nephropathy (HR 1.51, 95 CI% 1.27-1.79) compared with brisk walking. Additionally, ≥1 diabetic microvascular complication occurred in 447 (14.7%) of participants with brisk walking pace, 1702 (19.5%) with average walking pace, and 831 (30.4%) with slow walking pace. Time from study recruitment to first diagnosis was shorter in participants who reported a slow walking pace, compared with brisk or average walkers. Among participants who had diabetic nephropathy as their first diagnosis, slow walking pace was associated with subsequent risk of a second diabetic microvascular complication (HR 3.88, 95 CI% 2.27-6.60). CONCLUSIONS: Self-reported slow walking pace is associated with a higher risk of diabetic microvascular complications among participants with T2D in this population-based cohort study.

Loneliness and social isolation are associated with an increased risk of glaucoma: a UK Biobank cohort study.

BACKGROUND: Loneliness and social isolation have been found to be associated with various health-related outcomes. Our study aimed to evaluate the association of loneliness and social isolation with the risk of glaucoma. METHODS: A total of 373,330 participants from the UK Biobank without glaucoma at recruitment were included in this study. Self-reported questionnaires were used to define loneliness and social isolation. Incident glaucoma events were identified by hospital inpatient admissions and self-reported data. COX proportional hazards models adjusted for sociodemographic, lifestyle, and health-related factors were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During a median follow-up of 13.1 (interquartile range: 12.3-13.9) years, 6,489 participants developed glaucoma. After adjusting for confounding factors, loneliness (yes vs. no: adjusted HR: 1.16; 95% CI: 1.04-1.30; P = 0.009) and social isolation (yes vs. no: adjusted HR: 1.08; 95% CI: 1.01-1.16; P = 0.033) were associated with an increased risk of glaucoma. CONCLUSIONS: In this population-based prospective cohort study, loneliness and social isolation were associated with a higher risk of glaucoma.

Modifiable lifestyle, mental health status and diabetic retinopathy in U.S. adults aged 18-64 years with diabetes: a population-based cross-sectional study from NHANES 1999-2018.

BACKGROUND: The relationship between integrated lifestyles, mental status and their impact on overall well-being has attracted considerable attention. This study aimed to evaluate the association between lifestyle factors, depression and diabetic retinopathy (DR) in adults aged 18-64 years. METHODS: A cohort of 3482 participants diagnosed with diabetes was drawn from the National Health and Nutrition Examination Survey (NHANES) spanning the years 1999-2018. DR was defined based on self-reported diabetic retinopathy diagnoses by professional physicians, relying on Diabetes Interview Questionnaires. Subgroup analysis was employed to assess lifestyle and psychological factors between participants with DR and those without, both overall and stratified by diabetic duration. Continuous variables were analyzed using the student's t test, while weighted Rao-Scott χ2 test were employed for categorical variables to compare characteristics among the groups. RESULTS: Of the 3482 participants, 767 were diagnosed with diabetic retinopathy, yielding a weighted DR prevalence of 20.8%. Patients with DR exhibited a higher prevalence of heavy drinking, depression, sleep deprivation, and insufficient physical activity compared to those without DR. Furthermore, multivariable logistic regression analysis revealed that sleeping less than 5 h (OR = 3.18, 95%CI: 2.04-4.95, p < 0.001) and depression (OR = 1.35, 95%CI:1.06-1.64, p = 0.025) were associated with a higher risk of DR, while moderate drinking (OR = 0.49, 95%CI: 0.32-0.75, p = 0.001) and greater physical activity (OR = 0.64, 95%CI: 0.35-0.92, p = 0.044) were identified as protective factors. CONCLUSIONS: Adults aged 18-64 years with DR exhibited a higher prevalence of lifestyle-related risk factors and poorer mental health. These findings underscore the need for concerted efforts to promote healthy lifestyles and positive emotional well-being in this population.

Genome-wide redistribution of 24-nt siRNAs in rice gametes.

Gametes constitute a critical stage of the plant life cycle during which the genome undergoes reprogramming in preparation for embryogenesis. Here, we examined genome-wide distributions of small RNAs in the sperm and egg cells of rice. We found that 24-nt siRNAs, which are a hallmark of RNA-directed DNA methylation (RdDM) in plants, were depleted from heterochromatin boundaries in both gametes relative to vegetative tissues, reminiscent of siRNA patterns in DDM1-type nucleosome remodeler mutants. In sperm cells, 24-nt siRNAs were spread across heterochromatic regions, while in egg cells, 24-nt siRNAs were concentrated at a smaller number of heterochromatic loci throughout the genome, especially at loci which also produced siRNAs in other tissues. In both gametes, patterns of CHH methylation, typically a strong indicator of RdDM, were similar to vegetative tissues, although lower in magnitude. These findings indicate that the small RNA transcriptome undergoes large-scale redistribution in both male and female gametes, which is not correlated with recruitment of DNA methyltransferases in gametes and suggestive of unexplored regulatory activities of gamete small RNAs.

Transient receptor potential channel 6 knockdown prevents high glucose-induced Müller cell pyroptosis.

BACKGROUND: Transient receptor potential channel 6 (TRPC6) is reported to be involved in the pathogenesis of diabetic complications, but its role in diabetic retinopathy (DR) remains unknown. The aim of our study was to determine the role and mechanism of TRPC6 in DR. METHODS: High glucose was used to construct a DR cell model using rat retinal Müller cells (rMC-1). Intracellular Ca2+, reactive oxygen species (ROS) and cell pyroptosis were evaluated by flow cytometry. Protein levels of NLRP3, pro-caspase-1, active caspase-1, gasdermin D (GSDMD), GSDMD-N, TRPC6 and H3K27ac were detected by Western blot. mRNA levels of EP300 and TRPC6 were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Levels of IL-1ß and IL-18 were estimated by enzyme linked immunosorbent assay (ELISA). The interaction between EP300 and TRPC6 was validated by a chromatin immunoprecipitation assay. RESULTS: The knockdown of TRPC6 reduced inflammation and cell pyroptosis in HG induced rMC-1 cells, whereas overexpression of TRPC6 had the opposite effects. The inhibition of ROS and NLRP3 reversed TRPC6-mediated cell pyroptosis in the DR cell model. In addition, EP300 increased the expression of H3K27ac and TRPC6 to promote cell pyroptosis, which was suppressed by the knockdown of TRPC6. CONCLUSIONS: Our study revealed a novel EP300/H3K27ac/TRPC6 signaling pathway that may contribute to HG induced Müller cell pyroptosis. TRPC6 played a novel role in Müller cell pyroptosis triggered by HG, and may be a potential target for DR treatment in the future.

Diamond: a multi-modal DIA mass spectrometry data processing pipeline.

SUMMARY: Currently, various software tools are used to support two mainstream workflows for data-independent acquisition (DIA) mass spectrometry (MS) data processing, namely, spectrum-centric scoring (SCS) and peptide-centric scoring (PCS). However, a fully automatic, easily reproducible and freely accessible pipeline that simultaneously integrates SCS and PCS strategies and supports both library-free and library-based modes is absent. We developed Diamond, a Nextflow-based, containerized, multi-modal DIA-MS data processing pipeline for peptide identification and quantification. Diamond integrated two mainstream workflows for DIA data analysis, namely, SCS and PCS, for use cases both with and without assay libraries. This multi-modal pipeline serves as a versatile, easy-to-use and easily extendable toolbox for large-scale DIA data processing. AVAILABILITY: Diamond is hosted on GitHub (https://github.com/xmuyulab/Diamond) and is released under the highly permissive MIT license to encourage further customization and modification. The Docker image for Diamond is freely accessible at https://hub.docker.com/r/zeroli/diamond.

ß-arrestin 2 is essential for fluoxetine-mediated promotion of hippocampal neurogenesis in a mouse model of depression.

Over the last decade, the roles of ß-arrestins in the treatment of neuropsychological diseases have become increasingly appreciated. Fluoxetine is the first selective serotonin reuptake inhibitor developed and is approved for the clinical treatment of depression. Emerging evidence suggests that fluoxetine can directly combine with the 5-HT receptor, which is a member of the G protein-coupled receptor (GPCR) family, in addition to suppressing the serotonin transporter. In this study, we prepared a chronic mild stress (CMS)-induced depression model with ß-arrestin2-/- mice and cultured adult neural stem cells (ANSCs) to investigate the involvement of the 5-HT receptor-ß-arrestin axis in the pathogenesis of depression and in the therapeutic effect of fluoxetine. We found that ß-arrestin2 deletion abolished the fluoxetine-mediated improvement in depression-like behaviors and monoamine neurotransmitter levels, although ß-arrestin2 knockout did not aggravate CMS-induced changes in mouse behaviors and neurotransmitters. Notably, the ß-arrestin2-/- mice had a shortened dendritic length and reduced dendritic spine density, as well as decreased neural precursor cells, compared to the WT mice under both basal and CMS conditions. We further found that ß-arrestin2 knockout decreased the number of proliferating cells in the hippocampal dentate gyrus and suppressed the proliferative capability of ANSCs in vitro. Moreover, ß-arrestin2 knockout aggravated the impairment of cell proliferation induced by corticosterone and further blocked the fluoxetine-mediated promotion of mouse hippocampal neurogenesis. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-PI3K/Akt axis is essential to maintain the modulation of hippocampal neurogenesis in depressed mice. Our study may provide a promising target for the development of new antidepressant drugs.

High frequency in vitro regeneration of adventitious shoots in daylilies (Hemerocallis sp) stem tissue using thidiazuron.

BACKGROUND: Daylilies are a lucrative crop used for its floral beauty, medicinal proprieties, landscaping, fire prevention, nutritional value, and research. Despite the importance, daylilies remain extremely challenging for multiplying in vitro. The response difficulty is exacerbated because a few good protocols for daylilies micropropagation are generally difficult to reproduce across genotypes. An efficient strategy, currently applied at Langston University, is to systematically explore individual tissues or organs for their potential to micropropagation. This article is a partial report of the investigation carried out under room environmental conditions and focuses on developing an efficient daylilies in vitro propagation protocol that uses the stem tissue as the principal explant. RESULTS: In less than three months, using thidiazuron, the use of the stem tissue as the in vitro experimental explant was successful in inducing multiple shoots several folds greater than current daylilies shoot organogenesis protocols. The study showed that tissue culture can be conducted successfully under unrestricted room environmental conditions as well as under the controlled environment of a growth chamber. It also showed that splitting lengthwise stem explants formed multiple shoots several folds greater than cross-sectioned and inverted explants. Shoot conversion rate was mostly independent of the number of shoots formed per explants. The overall response was explant and genotype-dependent. Efficient responses were observed in all thidiazuron treatments. CONCLUSION: An efficient protocol, which can be applied for mass multiple shoots formation using the daylilies stem tissue as the main explant, was successfully developed. This could lead to a broad and rapid propagation of the crop under an array of environmental conditions to meet the market demand and hasten exogenous gene transfer and breeding selection processes.

Reproductive Long Intergenic Noncoding RNAs Exhibit Male Gamete Specificity and Polycomb Repressive Complex 2-Mediated Repression.

Long noncoding RNAs (lncRNAs) have been characterized extensively in animals and are involved in several processes, including homeobox gene expression and X-chromosome inactivation. In comparison, there has been much less detailed characterization of plant lncRNAs, and the number of distinct lncRNAs encoded in plant genomes and their regulation by developmental and epigenetic mechanisms remain largely unknown. Here, we analyzed transcriptome data from Asian rice (Oryza sativa) and identified 6,309 long intergenic noncoding RNAs (lincRNAs), focusing on their expression in reproductive tissues and organs. Most O. sativa lincRNAs were expressed in a highly tissue-specific manner, with an unexpectedly high fraction specifically expressed in male gametes. Mutation of a component of the Polycomb Repressive Complex2 (PRC2) resulted in derepression of another large class of lincRNAs, whose expression is correlated with H3K27 trimethylation in developing panicles. Overlap with the sperm cell-specific lincRNAs suggests that epigenetic repression of lincRNAs in the panicles was partially relieved in the male germline. Expression of a subset of lincRNAs also showed modulation by drought in reproductive tissues. Comparison with other cereal genomes showed that the lincRNAs generally have low levels of conservation at both the sequence and structural levels. Use of a novelty detection support vector machine model enabled the detection of nucleotide sequence and structural homology in ∼10% and ∼4% of the lincRNAs in genomes of purple false brome (Brachypodium distachyon) and maize (Zea mays), respectively. This is the first study to report on a large number of lncRNAs that are targets of repression by PRC2 rather than mediating regulation via PRC2. That the vast majority of the lincRNAs reported here do not overlap with those of other rice studies indicates that these are a significant addition to the known lincRNAs in rice.

Leonurine Exerts Antidepressant-Like Effects in the Chronic Mild Stress-Induced Depression Model in Mice by Inhibiting Neuroinflammation.

Background: Leonurine is an active alkaloid that is extracted from Traditional Chinese Medicine Herba leonuri. Emerging evidence indicates that leonurine produces neuroprotective effects in ischemic stroke, Parkinson's disease, and Alzheimer's disease. However, the effect of leonurine in neuropsychiatric disorders, especially in major depression, remains unknown. Methods: We used the chronic mild stress mouse model to explore the antidepressant effects of leonurine and the potential mechanisms. Behavioral tests including sucrose preference test, forced swimming test, and tail suspension test were taken to evaluate depression symptoms. Moreover, the contents of monoamine neurotransmitters in hippocampus and prefrontal cortex were measured by high-performance liquid chromatography. Neuronal morphology was detected by transmission electron microscopy. Results: Administration of leonurine (60 mg/kg) for 4 weeks significantly alleviated depression-like behaviors of chronic mild stress mice, including increased sucrose preference and reduced immobility time in forced swimming test and tail suspension test. We further found that leonurine (60 mg/kg) effectively restored the levels of 5-hydroxytryptamine, noradrenaline, and dopamine in the hippocampus and prefrontal cortex of chronic mild stress mice, accompanied by amelioration of hippocampal neuronal damage. Furthermore, leonurine (60 mg/kg) significantly inhibited the production of proinflammatory cytokine interleukin-1ß, interleukin-6 and TNF-α, and suppressed the nuclear factor kappa B signaling pathway. Conclusions: These findings demonstrate that leonurine exerts antidepressant-like effects, which may be mediated, at least in part, by improving monoamine neurotransmitters and inhibiting neuroinflammation. Our study provides insight into the potential of leonurine in depression therapy.

Immunotherapy efficacy prediction through a feature re-calibrated 2.5D neural network.

BACKGROUND AND OBJECTIVE: Lung cancer continues to be a leading cause of cancer-related mortality worldwide, with immunotherapy emerging as a promising therapeutic strategy for advanced non-small cell lung cancer (NSCLC). Despite its potential, not all patients experience benefits from immunotherapy, and the current biomarkers used for treatment selection possess inherent limitations. As a result, the implementation of imaging-based biomarkers to predict the efficacy of lung cancer treatments offers a promising avenue for improving therapeutic outcomes. METHODS: This study presents an automatic system for immunotherapy efficacy prediction on the subjects with lung cancer, facilitating significant clinical implications. Our model employs an advanced 2.5D neural network that incorporates 2D intra-slice feature extraction and 3D inter-slice feature aggregation. We further present a lesion-focused prior to guide the re-calibration for intra-slice features, and a attention-based re-calibration for the inter-slice features. Finally, we design an accumulated back-propagation strategy to optimize network parameters in a memory-efficient fashion. RESULTS: We demonstrate that the proposed method achieves impressive performance on an in-house clinical dataset, surpassing existing state-of-the-art models. Furthermore, the proposed model exhibits increased efficiency in inference for each subject on average. To further validate the effectiveness of our model and its components, we conducted comprehensive and in-depth ablation experiments and discussions. CONCLUSION: The proposed model showcases the potential to enhance physicians' diagnostic performance due to its impressive performance in predicting immunotherapy efficacy, thereby offering significant clinical application value. Moreover, we conduct adequate comparison experiments of the proposed methods and existing advanced models. These findings contribute to our understanding of the proposed model's effectiveness and serve as motivation for future work in immunotherapy efficacy prediction.

Imaging-based body fat distribution and diabetic retinopathy in general US population with diabetes: an NHANES analysis (2003-2006 and 2011-2018).

BACKGROUND: Limited studies have investigated the correlation between fat distribution and the risk of diabetic retinopathy (DR) in the general population with diabetes. The relationship between obesity and DR remains inconclusive, possibly due to using simple anthropometric measures to define obesity. This study investigates the relationships between the android-to-gynoid fat ratio (A/G ratio, measured using dual-energy X-ray absorptiometry) and DR within the US population with diabetes. METHODS: The study used a population-based, cross-sectional approach based on the 2003-2006 and 2011-2018 data of the National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression analyses were performed on participants with diabetes to evaluate the contribution of body mass index (BMI), waist-to-height ratio (WHtR), and A/G ratio to the prevalence of DR. RESULTS: The prevalence of DR was 22.2, 21.2, and 17.6% among participants with A/G ratios <1.0, 1.0-1.2, and ≥1.2, respectively. After adjusting sex, age, ethnicity, diabetes duration, hemoglobin A1c level, blood pressure level, and non-high-density lipoprotein cholesterol level, a higher A/G ratio (≥1.2) was independently associated with decreased odds of DR (odds ratio [OR], 0.565; 95% CI: 0.372-0.858) compared with the A/G ratio of 1.0-1.2. Associations between a higher A/G ratio and DR remained statistically significant after adjusting for BMI (OR, 0.567; 95% CI: 0.373-0.861) and WHtR (OR, 0.586; 95% CI: 0.379-0.907). Moreover, these associations remained statistically significant in analyses using the ethnic-specific tertiles for the A/G ratio. In sex-stratified models, these correlations remained in males. There was a significant inverse association between the A/G ratio and diabetes duration in males, which persisted after multivariable adjustments (p < 0.05). CONCLUSIONS: A novel finding indicates that a higher A/G ratio is associated with a reduced likelihood of DR in males with diabetes. The results from NHANES underscore the importance of considering imaging-based fat distribution as a critical indicator in clinical practice.

Diabetes-Related Macrovascular Complications Are Associated With an Increased Risk of Diabetic Microvascular Complications: A Prospective Study of 1518 Patients With Type 1 Diabetes and 20 802 Patients With Type 2 Diabetes in the UK Biobank.

BACKGROUND: Diabetic vascular complications share common pathophysiological mechanisms, but the relationship between diabetes-related macrovascular complications (MacroVCs) and incident diabetic microvascular complications remains unclear. We aimed to investigate the impact of MacroVCs on the risk of microvascular complications. METHODS AND RESULTS: There were 1518 participants with type 1 diabetes (T1D) and 20 802 participants with type 2 diabetes from the UK Biobank included in this longitudinal cohort study. MacroVCs were defined by the presence of macrovascular diseases diagnosed after diabetes at recruitment, including coronary heart disease, peripheral artery disease, stroke, and ≥2 MacroVCs. The primary outcome was incident microvascular complications, a composite of diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy. During a median (interquartile range) follow-up of 11.61 (5.84-13.12) years and 12.2 (9.50-13.18) years, 596 (39.3%) and 4113 (19.8%) participants developed a primary outcome in T1D and type 2 diabetes, respectively. After full adjustment for conventional risk factors, Cox regression models showed significant associations between individual as well as cumulative MacroVCs and the primary outcome, except for coronary heart disease in T1D (T1D: diabetes coronary heart disease: 1.25 [0.98-1.60]; diabetes peripheral artery disease: 3.00 [1.86-4.84]; diabetes stroke: 1.71 [1.08-2.72]; ≥2: 2.57 [1.66-3.99]; type 2 diabetes: diabetes coronary heart disease: 1.59 [1.38-1.82]; diabetes peripheral artery disease: 1.60 [1.01-2.54]; diabetes stroke: 1.50 [1.13-1.99]; ≥2: 2.66 [1.92-3.68]). Subgroup analysis showed that strict glycemic (glycated hemoglobin <6.5%) and blood pressure (<140/90 mm Hg) control attenuated the association. CONCLUSIONS: Individual and cumulative MacroVCs confer significant risk of incident microvascular complications in patients with T1D and type 2 diabetes. Our results may facilitate cost-effective high-risk population identification and development of precise prevention strategies.

RNA-binding protein LSM7 facilitates breast cancer metastasis through mediating alternative splicing of CD44.

AIMS: The RNA-binding protein LSM7 is essential for RNA splicing, acting as a key component of the spliceosome complex; however, its specific role in breast cancer (BC) has not been extensively investigated. MATERIALS AND METHODS: LSM7 expression in BC samples was evaluated through bioinformatics analysis and immunohistochemistry. The impact of LSM7 on promoting metastatic tumor characteristics was examined using transwell and wound healing assays, as well as an orthotopic xenograft model. Additionally, the involvement of LSM7 in alternative splicing of CD44 was explored via RNA immunoprecipitation and third-generation sequencing. The regulatory role of TCF3 in modulating LSM7 gene expression was further elucidated using luciferase reporter assays and chromatin immunoprecipitation. KEY FINDINGS: Our findings demonstrate that LSM7 was significantly overexpressed in metastatic BC tissues and was associated with poor prognostic outcomes in patients with BC. LSM7 overexpression markedly increased the migratory and invasive capabilities of BC cells in vitro and significantly promoted spontaneous lung metastasis in vivo. Furthermore, RIP-seq analysis revealed that LSM7 binded to CD44 RNA, enhancing the expression of its alternatively spliced isoform CD44s, thereby driving BC metastasis and invasion. Additionally, the transcription factor TCF3 was found to activate LSM7 transcription by directly binding to its promoter. SIGNIFICANCE: In summary, this study highlights the pivotal role of LSM7 in the production of the CD44s isoform and the promotion of breast cancer metastasis. Targeting the TCF3/LSM7/CD44s axis may offer a promising therapeutic strategy for breast cancer treatment.

RANKL/RANK signaling recruits Tregs via the CCL20-CCR6 pathway and promotes stemness and metastasis in colorectal cancer.

TNF receptor superfamily member 11a (TNFRSF11a, RANK) and its ligand TNF superfamily member 11 (TNFRSF11, RANKL) are overexpressed in many malignancies. However, the clinical importance of RANKL/RANK in colorectal cancer (CRC) is mainly unknown. We examined CRC samples and found that RANKL/RANK was elevated in CRC tissues compared with nearby normal tissues. A higher RANKL/RANK expression was associated with a worse survival rate. Furthermore, RANKL was mostly produced by regulatory T cells (Tregs), which were able to promote CRC advancement. Overexpression of RANK or addition of RANKL significantly increased the stemness and migration of CRC cells. Furthermore, RANKL/RANK signaling stimulated C-C motif chemokine ligand 20 (CCL20) production by CRC cells, leading to Treg recruitment and boosting tumor stemness and malignant progression. This recruitment process was accomplished by CCL20-CCR6 interaction, demonstrating a connection between CRC cells and immune cells. These findings suggest an important role of RANKL/RANK in CRC progression, offering a potential target for CRC prevention and therapy.

The differences of metabolic profiles, socioeconomic status and diabetic retinopathy in U.S. working-age and elderly adults with diabetes: results from NHANES 1999-2018.

AIMS: Controlled metabolic factors and socioeconomic status (SES) was crucial for prevention of diabetic retinopathy (DR). The study aims to assess the metabolic factors control and SES among working-age adults (18-64 years) with diabetes compared to older adults (65 years and older). METHODS: Totals of 6738 participants with self-reported diagnosed diabetes from National Health and Nutrition Examination Survey were included, of whom 3482 were working-age and 3256 were elderly. The prevalence of DR, metabolic factors control, and the impact of SES and diabetic duration on DR was estimated. Subgroup analysis among working-age adults was employed across different diabetic duration and SES level. RESULTS: The prevalence of DR was 20.8% among working-age adults and 20.6% in elderly adults. Further, working-age adults possessed suboptimal control on glycemia (median HbA1c: 7.0% vs. 6.8%, p < 0.001) and lipids (Low-density lipoprotein < 100 mg/dL: 46.4% vs. 63.5%, p < 0.001), but better blood pressure control (< 130/80 mmHg: 53.5% vs. 37.5%, p < 0.001) compared to the elderly, judging based on age-specific control targets. Prolonged diabetic duration didn't improve glycemic and composite factors control. SES like education and income impacted metabolic factors control and adults with higher SES were more likely to control well. Diabetic duration was a significant risk factor (OR = 4.006, 95%CI= (2.752,5.832), p < 0.001) while higher income (OR = 0.590, 95%CI= (0.421,0.826), p = 0.002) and educational level (OR = 0.637, 95%CI= (0.457,0.889), p = 0.008) were protective against DR. CONCLUSIONS: Working-age adults with diabetes demonstrate suboptimal metabolic profile control, especially glycemia and lipids. Additional efforts are needed to improve metabolic factor control and reduce DR risk, particularly for those with longer diabetes duration, less education, and lower incomes.