Major depressive disorder (MDD) and dementia psychiatric and neurological diseases that are clinically widespread, but whether there is a causal link between them is still unclear. In this study, ...bidirectional two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between MDD and dementia via a genome-wide association study (GWAS) database, containing samples from the European population.
We collected data on MDD and common clinical dementia subtypes from GWAS, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), and vascular dementia (VaD). A series of bidirectional two-sample MR studies and correlation sensitivity analysis were carried out.
In the study of the effect of MDD on dementia subtypes, no causal relationship was found between MDD and dementia subtypes other than VaD, inverse variance weighted (IVW) method: odds ratio (OR), 2.131; 95 % confidence interval (CI), 1.249–3.639, P = 0.006; MDD-AD: OR, 1.000; 95 % CI, 0.999–1.001, P = 0.537; MDD-FTD: OR, 1.476; 95 % CI, 0.471–4.627, P = 0.505; MDD-PDD: OR, 0.592; 95 % CI, 0.204–1.718, P = 0.335; MR–Egger method: MDD-DLB: OR, 0.582; 95 % CI, 0.021–15.962, P = 0.751. In reverse MR analyses, no dementia subtype was found to be a risk factor for MDD.
The results of this study may not be generalizable to non-European populations.
MDD was identified as a potential risk factor for VaD, but no dementia subtype was found to be a risk factor for MDD. These results suggest a new avenue for the prevention of VaD.
•Major depressive disorder and dementia are on the rise.•There may be a link between major depressive disorder and dementia.•The study included all clinically common subtypes of dementia.•Major depressive disorder is a potential risk factor for vascular dementia.•The results provide a new idea for the prevention of dementia from mental conditions.
Cyclic GMP-AMP synthase (cGAS) is an essential DNA virus sensor that triggers type I interferon (IFN) signaling by producing cGAMP to initiate antiviral immunity. However, post-translational ...regulation of cGAS remains largely unknown. We report that K48-linked ubiquitination of cGAS is a recognition signal for p62-depdendent selective autophagic degradation. The induction of TRIM14 by type I IFN accelerates cGAS stabilization by recruiting USP14 to cleave the ubiquitin chains of cGAS at lysine (K) 414. Knockout of TRIM14 impairs herpes simplex virus type 1 (HSV-1)-triggered antiviral responses in a cGAS-dependent manner. Due to impaired type I IFN production, Trim14−/− mice are highly susceptible to lethal HSV-1 infection. Taken together, our findings reveal a positive feedback loop of cGAS signaling generated by TRIM14-USP14 and provide insights into the crosstalk between autophagy and type I IFN signaling in innate immunity.
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•TRIM14 deficiency remarkably impairs cGAS-mediated type I interferon signaling•The ubiquitination of cGAS is a signal for p62-mediated autophagic degradation•TRIM14 recruits USP14 to cleave K48-linked ubiquitination of cGAS at K414•TRIM14 stabilizes cGAS by disrupting cGAS-p62 interaction in the autophagosome
Cyclic GMP-AMP synthase (cGAS) is an essential DNA sensor in innate immunity. Chen et al. (2016) report that TRIM14 recruits USP14 to cleave the lysine 48 (K48)-linked ubiquitin chains of cGAS at K414, thereby inhibiting p62-mediated autophagic degradation of cGAS to enhance the activation of type I interferon signaling.
Schistosome infection persists for decades. Parasites are in close contact with host peripheral blood immune cells, yet little is known about the regulatory interactions between parasites and these ...immune cells. Here, we report that extracellular vesicles (EVs) released from Schistosoma japonicum are taken up primarily by macrophages and other host peripheral blood immune cells and their miRNA cargo transferred into recipient cells. Uptake of S. japonicum EV miR-125b and bantam miRNAs into host cells increased macrophage proliferation and TNF-α production by regulating the corresponding targets including Pros1, Fam212b, and Clmp. Mice infected with S. japonicum exhibit an increased population of monocytes and elevated levels of TNF-α. Reduction of host monocytes and TNF-α level in S. japonicum infected mice led to a significant reduction in worm and egg burden and pathology. Overall, we demonstrate that S. japonicum EV miRNAs can regulate host macrophages illustrating parasite modulation of the host immune response to facilitate parasite survival. Our findings provide valuable insights into the schistosome-host interaction which may help to develop novel intervention strategies against schistosomiasis.
The spleen is the largest lymphoid organ that can affect the immunological microenvironment in the liver via the portal system. Patients with liver cancer, often develop hypersplenism and ...splenomegaly from underlying cirrhosis and portal hypertension. The malfunction of the spleen not only induces hepatic fibrogenesis, but also changes the immune responses in the liver, so that liver cirrhosis accelerates while liver regeneration subdues. As a result, the hepatic microenvironment and the rest of the immune system reach a “tumor progressing” or “tumor tolerant” state. Splenectomy has been shown to improve immune responses, liver function and general condition in patients with liver cancer. Hence, splenectomy may possibly improve the tolerance in live cancer patients for other anticancer treatments. However, the long-term benefits and effects on the overall survival of concomitant hepatectomy and splenectomy for liver cancer patients with portal hypertension and hypersplenism still remain controversial.
Elastic modulus is an important parameter in rock mechanics and engineering geology that determines the mechanical properties of rocks. To analyze the effect of temperature and dynamic loading ...conditions on the elastic modulus of typical rocks, data and results from international publications are classified, analyzed, discussed and summarized. The findings show that the elastic modulus of different rocks is correlated linearly and negatively with temperatures, which can be attributed to dehydration, phase transition, thermal expansion and thermal decomposition of minerals. The elastic modulus is significantly more sensitive to temperature than to strain rate. In addition, the elastic modulus of sedimentary rocks shows a significant strain rate effect, especially in sandstones, yet it is not observed in igneous and metamorphic rocks. The threshold temperature for peak stress degradation of limestone, sandstone, granite and marble is consistent with that of strain rate effect of elastic modulus. Thermal activation mechanism, Stefan effect, inertia effect and dislocations in crystals are the main contributing factors to the strain rate effect of the elastic modulus in rock materials.
Natural or artificially disturbed rocks containing massive fillings are frequently subjected to various sophisticated temperature and stress perturbations. To investigate the effects of temperature ...and filling angle on the dynamic mechanical characteristics and fracture patterns of red sandstone, thermal treatments at 25°C, 200°C, 400°C, 600°C, and 800°C were conducted on red sandstone samples containing single fracture filling angles at 0°, 30°, 60°, and 90°. Subsequently, the dynamic mechanical information and crack evolution of specimens after thermal treatment were tested and recorded utilizing a modified split Hopkinson pressure bar (SHPB) test system integrated with a high-speed camera, and the crack expansion modes were identified and analyzed. Meanwhile, X-ray diffraction (XRD), scanning electron microscopy (SEM), simulation and one-dimensional stress wave theory were employed to analyze and discuss the thermal damage and failure mechanism of the specimens in detail. The results demonstrate that temperature and filling angle have conspicuous effects on the elastic modulus, thermal expansion, mineral composition, dynamic compressive strength, strain rate effects, and crack expansion modes of the specimens. Tensile cracks dominate the fracture of the specimen during dynamic loading, while shear cracks tend to appear in thermal stress concentration area. Moreover, thermal damage, wave impedance and stress wave propagation path are the critical factors controlling the fracture evolution and dynamic mechanical properties of the specimens.
•Effects of thermal treatment on the dynamic behavior of fissure-filled red sandstone.•Fracture patterns of the specimen after the effect of temperature and filling angle are exhibited.•Damage parameters and simulation are employed to characterize the thermal damage.•Wave impedance and stress wave path control the dynamic mechanical response of the specimen.
Research on innate immune signaling and regulation has recently focused on pathogen recognition receptors (PRRs) and their signaling pathways. Members of PRRs sense diverse microbial invasions or ...danger signals, and initiate innate immune signaling pathways, leading to proinflammatory cytokines production, which, in turn, instructs adaptive immune response development. Despite the diverse functions employed by innate immune signaling to respond to a variety of different pathogens, the innate immune response must be tightly regulated. Otherwise, aberrant, uncontrolled immune responses will lead to harmful, or even fatal, consequences. Therefore, it is essential to better discern innate immune signaling and many regulators, controlling various signaling pathways, have been identified. In this review, we focus on the recent advances in our understanding of the activation and regulation of innate immune signaling in the host response to pathogens and cancer.
Psoriasis vulgaris is the most common form of the four clinical types. However, early diagnosis of psoriasis vulgaris is difficult due to the lack of effective biomarkers. The aim of this study was ...to screen potential biomarkers for the diagnosis of psoriasis. In our study, we downloaded the original data from GSE30999 and GSE41664, and the autophagy-related genes list from human autophagy database to identify differentially expressed autophagy-related genes (DERAGs) by R software. Then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for DERAGs. DERAGs were validated by the other four databases (GSE13355, GSE14905, GSE6710, and GSE55201) to screen biomarkers with high diagnostic value for the early diagnosis of psoriasis vulgaris. Finally, DERAGs were verified in our clinical blood samples by ELISA. A total of 12 DERAGs were identified between 123 paired non-lesional and lesional skin samples from patients with psoriasis vulgaris. GO and KEGG enrichment analysis indicated the TORC2 complex was more enriched and the NOD-like receptor signaling pathway was mostly enriched. Three autophagy-related genes (BIRC5, NAMPT and BCL2) were identified through bioinformatics analysis and verified by ELISA in clinical blood samples. And these genes showed high diagnostic value for the early diagnosis of psoriasis vulgaris. We identified three autophagy-related genes (BIRC5, NAMPT and BCL2) with high diagnostic value for the early diagnosis of psoriasis vulgaris through bioinformatics analysis and clinical samples. Therefore, we proposed that BIRC5, NAMPT and BCL2 may be as potential biomarkers for the early diagnosis of psoriasis vulgaris. In addition, BIRC5, NAMPT and BCL2 may affect the development of psoriasis by regulating autophagy.
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