Aging microglia.

Microglia are the tissue-resident macrophage population of the brain, specialized in supporting the CNS environment and protecting it from endogenous and exogenous insults. Nonetheless, their function declines with age, in ways that remain to be fully elucidated. Given the critical role played by microglia in neurodegenerative diseases, a better understanding of the aging microglia phenotype is an essential prerequisite in designing better preventive and therapeutic strategies. In this review, we discuss the most recent literature on microglia in aging, comparing findings in rodent models and human subjects.

Orthostatic Hypotension Promotes the Progression From Mild Cognitive Impairment to Dementia in Type 2 Diabetes Mellitus.

CONTEXT: In type 2 diabetes mellitus (T2DM), orthostatic hypotension (OH) is associated with cognition, but the mechanisms governing the link between OH and cognition are still unclear. OBJECTIVE: We sought to analyze Alzheimer's disease (AD) biomarkers and the part of complement proteins in modulating the association of OH with cognitive impairment and examine whether OH could accelerate the clinical progression of mild cognitive impairment (MCI) to dementia in T2DM. METHODS: We recruited patients with T2DM with MCI and collected general healthy information and blood samples. Complement proteins of astrocyte-derived exosomes were isolated and AD biomarkers of neuronal cell-derived exosomes isolated were quantified by enzyme-linked immunosorbent assay. Cognitive assessments were performed at patient enrollment and follow-up. RESULTS: Mediation analysis showed that the influence of OH on cognition in T2DM was partly mediated by baseline AD biomarkers and complement proteins. Cox proportional-hazards regression proved the OH group had a higher risk of developing dementia compared to the T2DM without OH group. CONCLUSION: In T2DM with MCI patients, AD biomarkers and complement proteins mediate the effects of OH on cognitive impairment and OH may be a risk factor of progression from MCI to dementia in T2DM.

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Power Enhancement of 265 nm DUV-LED Flip-Chip by HVPE-AlN High-Temperature Annealing.

In this paper, the X-ray diffraction full width at half the maximum (XRD FWHM) of a 3.5 µm-thick hydride vapor phase epitaxy-aluminum nitride (HVPE-AlN) (002) face after high-temperature annealing was reduced to 129 arcsec. The tensile strain in the HVPE-AlN samples gradually released with the increasing annealing temperature. When the annealing temperature exceeded 1700 °C, an aluminum oxynitride (AlON) region was generated at the contact interface between HVPE-AlN and sapphire, and the AlON structure was observed to conform to the characteristics of Al5O6N by high-resolution transmission electron microscopy (HRTEM). A 265 nm light-emitting diode (LED) based on an HVPE-AlN template annealed at 1700 °C achieved a light output power (LOP) of 4.48 mW at 50 mA, which was approximately 57% greater than that of the original sample.

Long noncoding RNA ENST00000436340 promotes podocyte injury in diabetic kidney disease by facilitating the association of PTBP1 with RAB3B.

Dysfunction of podocytes has been regarded as an important early pathologic characteristic of diabetic kidney disease (DKD), but the regulatory role of long noncoding RNAs (lncRNAs) in this process remains largely unknown. Here, we performed RNA sequencing in kidney tissues isolated from DKD patients and nondiabetic renal cancer patients undergoing surgical resection and discovered that the novel lncRNA ENST00000436340 was upregulated in DKD patients and high glucose-induced podocytes, and we showed a significant correlation between ENST00000436340 and kidney injury. Gain- and loss-of-function experiments showed that silencing ENST00000436340 alleviated high glucose-induced podocyte injury and cytoskeleton rearrangement. Mechanistically, we showed that fat mass and obesity- associate gene (FTO)-mediated m6A induced the upregulation of ENST00000436340. ENST00000436340 interacted with polypyrimidine tract binding protein 1 (PTBP1) and augmented PTBP1 binding to RAB3B mRNA, promoted RAB3B mRNA degradation, and thereby caused cytoskeleton rearrangement and inhibition of GLUT4 translocation to the plasma membrane, leading to podocyte injury and DKD progression. Together, our results suggested that upregulation of ENST00000436340 could promote podocyte injury through PTBP1-dependent RAB3B regulation, thus suggesting a novel form of lncRNA-mediated epigenetic regulation of podocytes that contributes to the pathogenesis of DKD.

Complement proteins in serum astrocyte-derived exosomes are associated with mild cognitive impairment in type 1 diabetes mellitus patients.

BACKGROUND: The complement system plays a crucial role in cognitive impairment. The aim of this study is to investigate the correlation between the complement proteins levels in serum astrocyte-derived exosomes (ADEs) and mild cognitive impairment (MCI) in type 1 diabetes mellitus (T1DM) patients. METHODS: In this cross-sectional study, the patients with immune-mediated T1DM were enrolled. Healthy subjects matched for age and sex with T1DM patients were selected as controls. The cognitive function was evaluated by a Beijing version of the Montreal Cognitive Assessment (MoCA) questionnaire. The complement proteins including C5b-9, C3b and Factor B in serum ADEs were measured by ELISA kits. RESULTS: This study recruited 55 subjects immune-mediated T1DM patients without dementia, including 31 T1DM patients with MCI, 24 T1DM patients without MCI. 33 healthy subjects were enrolled as controls. The results showed higher complement proteins including C5b-9, C3b and Factor B levels in ADEs from T1DM patients with MCI than those in the controls (P < 0.001, P < 0.001, P = 0.006) and T1DM patients without MCI (P = 0.02, P = 0.02, P = 0.03). The C5b-9 levels in ADEs were independently associated with MCI in T1DM patients(OR: 1.20, 95% CI: 1.00-1.44, P = 0.04). The C5b-9 levels in ADEs were significantly correlated with global cognitive scores (ß = -0.360, P＜0.001) and visuo-executive (ß = -0.132, P＜0.001), language(ß = -0.036, P = 0.026) and delayed recall score (ß = -0.090,P = 0.007). There was no correlation between the C5b-9 levels in ADEs and the fasting glucose, HbA1c, fasting c-peptide and GAD65 antibody in T1DM patients. Furthermore, the C5b-9, C3b and Factor B levels in ADEs exhibited a fair combined diagnostic value for MCI, with an area under the curve of 0.76 (95% CI: 0.63-0.88, P = 0.001). CONCLUSION: The elevated C5b-9 levels in ADEswere significantly associated with theMCI in T1DM patients. The C5b-9 in ADEs may be used as a marker of MCI in T1DM patients.

T cells and their products in diabetic kidney disease.

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease and has gradually become a public health problem worldwide. DKD is increasingly recognized as a comprehensive inflammatory disease that is largely regulated by T cells. Given the pivotal role of T cells and T cells-producing cytokines in DKD, we summarized recent advances concerning T cells in the progression of type 2 diabetic nephropathy and provided a novel perspective of immune-related factors in diabetes. Specific emphasis is placed on the classification of T cells, process of T cell recruitment, function of T cells in the development of diabetic kidney damage, and potential treatments and therapeutic strategies involving T cells.

Inhibition of the lncRNA 585189 prevents podocyte injury and mitochondria dysfunction by promoting hnRNP A1 and SIRT1 in diabetic nephropathy.

Podocyte dysfunction has been identified as a crucial pathological characteristic of diabetic nephropathy (DN). However, the regulatory effects of long non-coding RNAs (lncRNAs) in this process have not been fully elucidated. Here, we performed an unbiased RNA-sequencing (RNA-seq) analysis of renal tissues and identified a significantly upregulated long non-coding RNA, ENST00000585189.1 (lncRNA 585189), in patients with DN. Furthermore, lncRNA 585189 was positively correlated with renal insufficiency and was upregulated in both DN patients and high-glucose-induced human podocytes. Gain- and loss-of-function experiments revealed that silencing lncRNA 585189 decreased the production of ROS, rescued aberrant mitochondrial morphology and membrane potential, and alleviated podocyte damage caused by high glucose. Mechanistically, bioinformatics analysis predicted an interaction between lncRNA 585189 and hnRNP A1, which was subsequently confirmed by RIP, pull-down, and EMSA assays. Further investigation revealed that lncRNA 585189 destabilizes the hnRNP A1 protein, leading to the downregulation of its expression. Conversely, hnRNP A1 promoted the expression of lncRNA 585189. Moreover, both RIP and pull-down assays demonstrated a direct interaction between hnRNP A1 and SIRT1, which enhanced SIRT1 mRNA stability. Our findings suggest that lncRNA 585189 suppresses SIRT1 through hnRNP A1, thereby hindering the recovery from mitochondrial abnormalities and podocyte damage. In summary, targeting lncRNA 585189 is a promising strategy for reversing mitochondrial dysfunction and treating DN.