Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP.

STING (stimulator of interferon genes) is an important innate immune protein, but its homeostatic regulation at the resting state is unknown. Here, we identified TOLLIP as a stabilizer of STING through direct interaction to prevent its degradation. Tollip deficiency results in reduced STING protein in nonhematopoietic cells and tissues, and renders STING protein unstable in immune cells, leading to severely dampened STING signaling capacity. The competing degradation mechanism of resting-state STING requires IRE1α and lysosomes. TOLLIP mediates clearance of Huntington's disease-linked polyQ protein aggregates. Ectopically expressed polyQ proteins in vitro or endogenous polyQ proteins in Huntington's disease mouse striatum sequester TOLLIP away from STING, leading to reduced STING protein and dampened immune signaling. Tollip-/- also ameliorates STING-mediated autoimmune disease in Trex1-/- mice. Together, our findings reveal that resting-state STING protein level is strictly regulated by a constant tug-of-war between 'stabilizer' TOLLIP and 'degrader' IRE1α-lysosome that together maintain tissue immune homeostasis.

A "KU" new sensor for cytosolic DNA in T cells.

Adaptive immune cells are usually not equipped with pattern recognition receptors. In this issue of Immunity, Wang et al. revealed an "innate-like" cytosolic DNA-sensing mechanism by the KU complex in aged CD4+ T cells, which exacerbates aging-related autoimmunity.

Interferon-Independent Activities of Mammalian STING Mediate Antiviral Response and Tumor Immune Evasion.

Type I interferon (IFN) response is commonly recognized as the main signaling activity of STING. Here, we generate the Sting1S365A/S365A mutant mouse that precisely ablates IFN-dependent activities while preserving IFN-independent activities of STING. StingS365A/S365A mice protect against HSV-1 infection, despite lacking the STING-mediated IFN response. This challenges the prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis reveals widespread IFN-independent activities of STING in macrophages and T cells, and STING activities in T cells are predominantly IFN independent. In mouse tumor models, T cells in the tumor experience substantial cell death that is in part mediated by IFN-independent activities of STING. We found that the tumor induces STING-mediated cell death in T cells to evade immune control. Our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive immunity.

Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.

The classic mode of STING activation is through binding the cyclic dinucleotide 2'3'-cyclic GMP-AMP (cGAMP), produced by the DNA sensor cyclic GMP-AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann-Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 'primes' STING signalling by physically linking or 'tethering' STING to SREBP2 trafficking. Loss of NPC1 protein also 'boosts' STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1-/- mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1-/- mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.

STING trafficking activates MAPK-CREB signaling to trigger regulatory T cell differentiation.

The Type-I interferon (IFN-I) response is the major outcome of stimulator of interferon genes (STING) activation in innate cells. STING is more abundantly expressed in adaptive T cells; nevertheless, its intrinsic function in T cells remains unclear. Intriguingly, we previously demonstrated that STING activation in T cells activates widespread IFN-independent activities, which stands in contrast to the well-known STING-mediated IFN response. Here, we have identified that STING activation induces regulatory T cells (Tregs) differentiation independently of IRF3 and IFN. Specifically, the translocation of STING from the endoplasmic reticulum to the Golgi activates mitogen-activated protein kinase (MAPK) activity, which subsequently triggers transcription factor cAMP response element-binding protein (CREB) activation. The activation of the STING-MAPK-CREB signaling pathway induces the expression of many cytokine genes, including interleukin-2 (IL-2) and transforming growth factor-beta 2 (TGF-ß2), to promote the Treg differentiation. Genetic knockdown of MAPK p38 or pharmacological inhibition of MAPK p38 or CREB markedly inhibits STING-mediated Treg differentiation. Administration of the STING agonist also promotes Treg differentiation in mice. In the Trex1-/- autoimmune disease mouse model, we demonstrate that intrinsic STING activation in CD4+ T cells can drive Treg differentiation, potentially counterbalancing the autoimmunity associated with Trex1 deficiency. Thus, STING-MAPK-CREB represents an IFN-independent signaling axis of STING that may have profound effects on T cell effector function and adaptive immunity.

Advances in Mechanism of HIV-1 Immune Reconstitution Failure: Understanding Lymphocyte Subpopulations and Interventions for Immunological Nonresponders.

In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.

Subthalamic Nucleus Stimulation Modulates Cognitive Theory of Mind in Parkinson's Disease.

BACKGROUND: Theory of mind (ToM), the ability to infer others' mental state, is essential for social interaction among human beings. It has been widely reported that both cognitive (inference of knowledge) and affective (inference of emotion) components of ToM are disrupted in Parkinson's disease (PD). Previous studies usually focused on the involvement of the prefrontal cortex. OBJECTIVE: This study investigated the causal role of the subthalamic nucleus (STN), a key hub of the fronto-basal ganglia loops, in ToM. METHODS: Thirty-four patients with idiopathic PD (15 women, aged 62.2 ± 8.3 years) completed a Yoni task with deep brain stimulation (DBS) ON and OFF. The Yoni task was designed to separate the cognitive and affective components of ToM. Volumes of tissue activated (VTA) were computed for three subregions of the STN. RESULTS: DBS showed insignificant effects on ToM inference costs at the group level, which may be due to the large interindividual variability. The associative VTA correlated with the cognitive inference cost change but not the affective inference cost change. Patients with greater associative STN stimulation infer more slowly on cognitive ToM. Stimulating associative STN can adversely affect cognitive ToM in PD patients, especially in patients with a wide range of stimulation (≥0.157) or cognitive decline (Montreal Cognitive Assessment < 26). CONCLUSIONS: The associative STN plays a causal role in cognitive ToM in patients with PD. However, stimulating the associative STN likely impairs cognitive ToM and potentially leads to social interaction deficits in PD. © 2024 International Parkinson and Movement Disorder Society.

Long Noncoding RNA PSMB8-AS1 Mediates the Tobacco-Carcinogen-Induced Transformation of a Human Bronchial Epithelial Cell Line by Regulating Cell Cycle.

Lung cancer is the main cause of cancer deaths around the world. Nitrosamine 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen of lung cancer. Abundant evidence implicates long noncoding RNAs (lncRNAs) in tumorigenesis. Yet, the effects and mechanisms of lncRNAs in NNK-induced carcinogenesis are still unclear. In this study, we discovered that NNK-induced transformed Beas-2B cells (Beas-2B-NNK) showed increased cell migration and proliferation while decreasing rates of apoptosis. RNA sequencing and differentially expressed lncRNAs analyses showed that lncRNA PSMB8-AS1 was obviously upregulated. Interestingly, silencing the lncRNA PSMB8-AS1 in Beas-2B-NNK cells reduced cell proliferation and migration and produced cell cycle arrest in the G2/M phase along with a decrease in CDK1 expression. Conclusively, our results demonstrate that lncRNA PSMB8-AS1 could promote the malignant characteristics of Beas-2B-NNK cells by regulating CDK1 and affecting the cell cycle, suggesting that it may supply a new prospective epigenetic mechanism for lung cancer.

The role of epithelial cells in fibrosis: Mechanisms and treatment.

Fibrosis is a pathological process that affects multiple organs and is considered one of the major causes of morbidity and mortality in multiple diseases, resulting in an enormous disease burden. Current studies have focused on fibroblasts and myofibroblasts, which directly lead to imbalance in generation and degradation of extracellular matrix (ECM). In recent years, an increasing number of studies have focused on the role of epithelial cells in fibrosis. In some cases, epithelial cells are first exposed to external physicochemical stimuli that may directly drive collagen accumulation in the mesenchyme. In other cases, the source of stimulation is mainly immune cells and some cytokines, and epithelial cells are similarly altered in the process. In this review, we will focus on the multiple dynamic alterations involved in epithelial cells after injury and during fibrogenesis, discuss the association among them, and summarize some therapies targeting changed epithelial cells. Especially, epithelial mesenchymal transition (EMT) is the key central step, which is closely linked to other biological behaviors. Meanwhile, we think studies on disruption of epithelial barrier, epithelial cell death and altered basal stem cell populations and stemness in fibrosis are not appreciated. We believe that therapies targeted epithelial cells can prevent the progress of fibrosis, but not reverse it. The epithelial cell targeting therapies will provide a wonderful preventive and delaying action.

Synthesis of Fe-N doped porous carbon/silicate composites regulated by minerals in coal gasification fine slag for synergistic electrocatalytic treatment of phenolic wastewater.

Coal gasification fine slag (CGFS), as a difficult-to-dispose solid waste in the coal chemical industry, consists of minerals and residual carbon. Due to the aggregate structure of minerals blocking pores and encapsulating active substances, the high-value utilization of CGFS still remains a challenge. Based on the intrinsic characteristics of CGFS, this study synthesized Fe-N doped porous carbon/silicate composites (Fe-NC) by alkali activation and pyrolysis for electrocatalytic degradation of phenolic wastewater. Meanwhile, minerals were utilized to regulate the surface chemical and pore structure, turning their disadvantages into advantages, which caused a sharp increase in m-cresol mineralization. The positive effect of minerals on composite properties was investigated by characterization techniques, electrochemical analyses and density functional theory (DFT) calculations. It was found that the mesoporous structure of the mineral-regulated composites was further developed, with more carbon defects and reactive substances on its surface. Most importantly, silicate mediated iron conversion through strong interaction with H2O2, high work function gradient with electroactive iron, and excellent superoxide radical (•O2-) production capacity. It effectively improved the reversibility and kinetics of the entire electrocatalytic reaction. Within the Fe-NC311 electrocatalytic system, the m-cresol removal rate reached 99.55 ± 1.24%, surpassing most reported Fe-N-doped electrocatalysts. In addition, the adsorption and electrooxidation experiment confirmed that the synergistic effect of Fe-N doped porous carbon and silicate simultaneously promoted the capture of pollutants and the transformation of electroactive molecules, and hence effectively shortened the diffusion path of short-lived radicals, which was further supported by molecular dynamics simulation. Therefore, this research provides new insights into the problem of mineral limitations and opens an innovative approach for CGFS recycling and environmental remediation.

Risk factors and intervention of caregiver burden in Parkinson's disease: a systematic review and meta-analysis.

PURPOSE: This study summarized characteristics and risk factors of caregiver burden in PD patients and used meta-analysis to verify the effectiveness of the intervention on caregiver burden. METHODS: Systematic review and meta-analysis were conducted. RESULTS: Forty-nine articles that involved 5387 caregivers of patients with PD were included in this study. Results of systematic review indicated that Zarit burden Inventory (ZBI) was the most used scale to measure the caregiver burden. All scales revealed caregivers of PD patients had mild to moderate caregiver burden. For the PD patients with longer disease duration, severer disease severity, more negative emotion and cognition impairment, their caregivers intended to have higher caregiver burden. The caregiver with negative emotion and who spent more time on caregiving indicated higher caregiver burden than the others. The caregiver burden was not improved after deep brain stimulation (DBS). Meta-analysis showed that cognitive behavior therapy and palliative care had no significant effect to reduce caregiver burden in PD patients' caregiver. CONCLUSION: Caregivers of PD patients experienced mild to moderate caregiver burden. Demographic factor, diseased-related factor and negative emotional factor were the risk factors of caregiver burden. Health education and care support for long-term management after DBS surgery should be provided for patients and caregivers to decrease caregiver burden.

Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

BACKGROUND: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. METHODS: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). RESULTS: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. CONCLUSIONS: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

CTRP13 Mitigates Endothelial Cell Ferroptosis via the AMPK/KLF4 Pathway: Implications for Atherosclerosis Protection.

BACKGROUND C1q/tumor necrosis factor-related protein 13 (CTRP13) preserves endothelial function and possesses anti-oxidation activity. However, its effects on ferroptosis of human umbilical vein endothelial cells (HUVECs) remain unclear. We investigated the effects of CTRP13 on HUVEC ferroptosis induced by oxidized low-density lipoprotein (ox-LDL) and explored the underlying mechanisms of CTRP13 against ferroptosis via the AMPK/KLF4 pathway. MATERIAL AND METHODS Cell Counting Kit-8 assay was used to evaluate cell viability. Lactate dehydrogenase activity and malondialdehyde content analysis were performed to evaluate the cell membrane integrity and lipid peroxidation. Mito-Tracker, JC-1, and 2',7'-dichlorofluorescein di-acetate were used to evaluate the biological activity of mitochondria, mitochondrial membrane potential, and reactive oxygen species (ROS) in endothelial cells. The ferroptosis indicator expressions, recombinant solute carrier family 7, member 11, glutathione peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 were examined using real-time reverse transcription-polymerase chain reaction and Western blot. Immunofluorescence staining detected GPX4 location in endothelial cells. RESULTS The results demonstrate that CTRP13 (450 ng/mL) prevented HUVEC ferroptosis by inhibiting ROS overproduction and mitochondrial dysfunction, and CTRP13 accelerated antioxidant enzyme expression levels, such as heme oxygenase 1, superoxide dismutase 1, and superoxide dismutase 2, compared with the ox-LDL (100 µg/mL) group for 48 h. Additionally, CTRP13 treatment increased p-AMPK/AMPK expression by 47.65% (P<0.05) while decreasing Krüppel-like factor 4 expression by 37.43% (P<0.05) in ox-LDL-induced HUVECs and elucidated the protective effect on endothelial dysfunction from ferroptosis. CONCLUSIONS These findings provide new insights for understanding the effects and mechanism of CTRP13 on preventing endothelial cell ferroptosis.

Carotid Ultrasound Combined with Plasma Atherosclerosis Index (AIP) in the Severe Analysis of Coronary Heart Disease Treated with Atorvastatin.

Background: Atherosclerotic coronary heart disease (CHD) stands as a paramount cardiovascular concern and the primary cause of mortality. To underscore the significance of our study, it is crucial to highlight the existing gaps in current diagnostic methods and prognostic assessments of CHD. By addressing these gaps, our research aims to contribute valuable insights and advancements in the understanding and management of this prevalent cardiovascular condition. Objective: The primary objective of this study is to investigate the correlation between carotid ultrasound, the Atherogenic Index of Plasma (AIP), and the severity of CHD. Methods: We enrolled 59 patients diagnosed with coronary heart disease and categorized them into two groups (multi-vessel and single-vessel disease groups) based on disease severity. The study employed carotid ultrasound, which measures Intima-Media Thickness (IMT) and carotid artery stenosis, among other indicators. Additionally, we calculated the AIP. This approach allowed us to thoroughly analyze the correlation between these key indicators and the severity of coronary heart disease lesions. Results: The study included 59 patients, 38 with single-vessel disease and 21 with multi-vessel disease. In the multivessel disease group, we observed significantly elevated levels of AIP, IMT, and carotid stenosis compared to the single-vessel disease group. Specifically, AIP, IMT, and carotid stenosis levels were higher in the multi-vessel group. Furthermore, our analysis revealed a positive correlation between AIP and IMT (r = 0.038, P = .003), while no significant correlation was found between AIP and carotid stenosis. Additionally, there was a moderate correlation between IMT and carotid stenosis. Conclusion: The combined assessment of AIP and carotid ultrasonography emerges as a promising approach for evaluating the severity of CHD. Notably, the multi-vessel disease group exhibited higher AIP levels compared to the single-vessel disease group, along with increased IMT and carotid artery stenosis. Our findings highlight a positive correlation between AIP and IMT, as well as between IMT and the degree of carotid stenosis. These associations underscore the potential of AIP, in conjunction with carotid ultrasonography parameters, as valuable indicators for gauging CHD severity. The clinical implications of these findings warrant further exploration, particularly in their potential integration into existing diagnostic or prognostic models for CHD. This integrated approach may offer enhanced precision in distinguishing between single-vessel and multi-vessel disease, contributing to more informed clinical decision-making.

Assessment of vegetation net primary productivity variation and influencing factors in the Beijing-Tianjin-Hebei region.

Exploring the spatiotemporal variations of vegetation net primary productivity (NPP) and analyzing the relationships between NPP and its influencing factors are vital for ecological protection in the Beijing-Tianjin-Hebei (BTH) region. In this study, we employed the CASA model in conjunction with spatiotemporal analysis techniques to estimate and analyze the spatiotemporal variations of NPP in BTH and different ecological function sub-regions over the past two decades. Subsequently, we established three scenarios (actual, climate-driven and land cover-driven) to assess the influencing factors and quantify their relative contributions. The results indicated that the overall NPP in BTH exhibited a discernible upward trend from 2000 to 2020, with a growth rate of 3.83 gC·m-2a-1. Furthermore, all six sub-regions exhibited an increase. The Bashang Plateau Ecological Protection Zone (BP) exhibited the highest growth rate (5.03 gC·m-2a-1), while the Low Plains Ecological Restoration Zone (LP) exhibited the lowest (2.07 gC·m-2a-1). Geographically, the stability of NPP exhibited a spatial pattern of gradual increase from west to east. Climate and land cover changes collectively increased NPP by 0.04 TgC·a-1 and 0.07 TgC·a-1, respectively, in the BTH region. Climate factors were found to have the greatest influence on NPP variations, contributing 40.49% across the BTH region. This influence exhibited a decreasing trend from northwest to southeast, with precipitation identified as the most influential climatic factor compared to temperature and solar radiation. Land cover change has profound effects on ecosystems, which is an important factor on NPP. From 2000 to 2020, 15.45% area of the BTH region underwent land cover type change, resulting in a total increase in NPP of 1.33 TgC. The conversion of grass into forest brought about the 0.89 TgC increase in NPP, which is the largest of all change types. In the area where land cover had undergone change, the land cover factor has been found to be the dominant factor influencing variations in NPP, with an average contribution of 49.37%. In contrast, in the south-central area where there has been no change in land cover, the residual factor has been identified as the most influential factor influencing variations in NPP. Our study highlights the important role of land cover change in influencing NPP variations in BTH. It also offers a novel approach to elucidating the influences of diverse factors on NPP, which is crucial for the scientific assessment of vegetation productivity and carbon sequestration capacity.

Effects of Tannic Acid Supplementation of a High-Carbohydrate Diet on the Growth, Serum Biochemical Parameters, Antioxidant Capacity, Digestive Enzyme Activity, and Liver and Intestinal Health of Largemouth Bass, Micropterus salmoides.

We investigated the effects of dietary tannic acid (TA) supplementation of a high-carbohydrate diet on growth, feed utilization, whole-body proximate composition, serum biochemical indicators, antioxidant capacity, digestive enzyme activity, and liver and intestinal health of juvenile largemouth bass, Micropterus salmoides (initial mean weight: 8.08 ± 0.08 g). Five diets were prepared, including a positive control (dietary carbohydrate level, 16%, LC0), a negative control (dietary carbohydrate level, 21%, HC0), and three TA-supplementation diets based on the negative control diet with TA addition at 200, 400, and 800 mg/kg, respectively. After 8 weeks of feeding, the results showed that compared with the LC0 diet, 400-800 mg/kg dietary TA significantly improved the survival rate of largemouth bass (P < 0.05) while significantly reducing its weight-gain rate and specific growth rate (P < 0.05). Compared with the HC0 diet, 400 mg/kg dietary TA significantly increased serum catalase activity (P < 0.05), and significantly decreased serum malondialdehyde, liver glycogen, lightness (L ∗), and yellowness (b ∗) (P < 0.05). Moreover, compared with the HC0 diet, 200-400 mg/kg dietary TA effectively improved the vacuolation of hepatocytes caused by the high-carbohydrate diet and reduced the occurrence of intestinal epithelial cell vacuolation and necrosis. In turn, 800 mg/kg dietary TA significantly inhibited protease activity in the pyloric caecum and intestine (P < 0.05). In conclusion, dietary supplementation with TA inhibited protease activity, which resulted in decreased growth performance in largemouth bass. However, it was also found that 200-400 mg/kg TA enhanced the antioxidant capacity of largemouth bass in the case of the high-carbohydrate diet, reduced liver glycogen levels, and improved liver and intestinal health. Finally, it should be noted that, when the dietary TA level exceeded 800 mg/kg, TA appeared to play a pro-oxidation role in the liver, which may cause oxidative stress in the liver.

Association of cardio-renal biomarkers and mortality in the U.S.: a prospective cohort study.

OBJECTIVE: Diabetes poses a significant threat to human health. There is a lack of large-scale cohort studies to explore the association between mortality risk and indicators beyond blood glucose monitoring in diabetic populations. METHODS: Multivariable Cox proportional hazards regression models were performed to investigate the association of 13 blood biomarkers with mortality risk in the National Health and Nutrition Examination Survey (NHANES) and biomarker levels were log-transformed and correlated with mortality. RESULTS: During a median follow-up of 7.42 years, 1783 diabetic patients were enrolled. Compared to traditional risk factors, the addition of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin biomarkers increased the predictive ability for all-cause mortality by 56.4%, 29.5%, 38.1%, 18.8%, 35.7%, and 41.3%, respectively. However, the inclusion of blood glucose monitoring had no impact on the prediction of all-cause mortality. Compared with the 1st quartiles of creatinine and Cystatin C, the risk of diabetes mortality were higher in the highest quartiles (HR: 5.16, 95% CI: 1.87-14.22; HR: 10.06, 95% CI: 4.20-24.13). CONCLUSIONS: In the diabetic population, elevated plasma levels of hs-cTnT, hs-cTnI, NT-proBNP, creatinine, cystatin C, and ß-2 microglobulin serve as robust and straightforward predictors of long-term mortality compared to blood glucose levels and HbA1c values. Creatinine and cystatin C stand out as more precise markers for predicting diabetes mortality prior to blood glucose monitoring.

Knockdown of circ-ADAM9 inhibits malignant phenotype and enhances radiosensitivity in breast cancer cells via acting as a sponge for miR-383-5p.

BACKGROUND: Circular RNA (circRNA) has been proven to play a critical role in breast cancer progression. Therefore, this study was designed to clarify the role and underlying molecular mechanisms of circ-disintegrin and metalloproteinase 9 (circ-ADAM9) in breast cancer. METHODS: A quantitative real-time polymerase chain reaction (RT-qPCR) was conducted to assess the expression levels of circ-ADAM9, microRNA-383-5p (miR-383-5p), and profilin 2 (PFN2). Cellular growth curves of breast cancer cells were determined by colony-forming assay. Cell viability and apoptosis were measured by MTT and flow cytometry, respectively. The protein expression level was analyzed by western blot. Cell migration and invasion were evaluated by wound healing and Transwell assays. A xenograft experiment was established to clarify the functional role of circ-ADAM9 inhibition in vivo. The interactions among circ-ADAM9, miR-383-5p, and PFN2 were analyzed by dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. RESULTS: We found that circ-ADAM9 was upregulated in breast cancer tissues and cells compared to controls. Inhibition of circ-ADAM9 expression impaired proliferation, migration, and invasion, but increased radiosensitivity and apoptosis in breast cancer cells; besides, radiotherapy combined with circ-ADAM9 inhibition showed significant inhibitory effects on tumor growth. The functional effects of circ-ADAM9 were related to miR-383-5p, a target of circ-ADAM9. Overexpression of miR-383-5p-mediated malignant behaviors and radiosensitivity of breast cancer cells were dependent on PFN2. CONCLUSION: Circ-ADAM9 was found to participate in breast cancer progression through targeting the miR-383-5p/PFN2 axis.

Dopaminergic damage pattern predicts phenoconversion time in isolated rapid eye movement sleep behavior disorder.

PURPOSE: The exact phenoconversion time from isolated rapid eye movement (REM) sleep behavior disorder (iRBD) to synucleinopathies remains unpredictable. This study investigated whole-brain dopaminergic damage pattern (DDP) with disease progression and predicted phenoconversion time in individual patients. METHODS: Age-matched 33 iRBD patients and 20 healthy controls with 11C-CFT-PET scans were enrolled. The patients were followed up 2-10 (6.7 ± 2.0) years. The phenoconversion year was defined as the base year, and every 2 years before conversion was defined as a stage. Support vector machine with leave-one-out cross-validation strategy was used to perform prediction. RESULTS: Dopaminergic degeneration of iRBD was found to occur about 6 years before conversion and then abnormal brain regions gradually expanded. Using DDP, area under curve (AUC) was 0.879 (90% sensitivity and 88.3% specificity) for predicting conversion in 0-2 years, 0.807 (72.7% sensitivity and 83.3% specificity) in 2-4 years, 0.940 (100% sensitivity and 84.6% specificity) in 4-6 years, and 0.879 (100% sensitivity and 80.7% specificity) over 6 years. In individual patients, predicted stages correlated with whole-brain dopaminergic levels (r = - 0.740, p < 0.001). CONCLUSION: Our findings suggest that DDP could accurately predict phenoconversion time of individual iRBD patients, which may help to screen patients for early intervention.