Regulation of the Late Onset alzheimer’s Disease Associated HLA-DQA1/DRB1 Expression

(Genome-wide Association Studies) GWAS have identified ∼42 late-onset Alzheimer’s disease (LOAD)-associated loci, each of which contains multiple single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD) and most of these SNPs are in the non-coding region of human genome. However, how these SNPs regulate risk gene expression remains unknown. In this work, by using a set of novel techniques, we identified 6 functional SNPs (fSNPs) rs9271198, rs9271200, rs9281945, rs9271243, and rs9271247 on the LOAD-associated HLA-DRB1/DQA1 locus and 42 proteins specifically binding to five of these 6 fSNPs. As a proof of evidence, we verified the allele-specific binding of GATA2 and GATA3, ELAVL1 and HNRNPA0, ILF2 and ILF3, NFIB and NFIC, as well as CUX1 to these five fSNPs, respectively. Moreover, we demonstrate that all these nine proteins regulate the expression of both HLA-DQA1 and HLA-DRB1 in human microglial cells. The contribution of HLA class II to the susceptibility of LOAD is discussed

Hnf4α is involved in the regulation of vertebrate LC-PUFA biosynthesis: insights into the regulatory role of Hnf4α on expression of liver fatty acyl desaturases in the marine teleost Siganus canaliculatus

Long chain polyunsaturated fatty acid (LC-PUFA) biosynthesis is an important metabolic pathway in vertebrates, especially fish, considering they are the major source of n-3 LC-PUFA in the human diet. However, most fish have only limited capability for biosynthesis of LC-PUFA. The rabbitfish (Siganus canaliculatus) is able to synthesize LC-PUFA as it has all the key enzyme activities required including Δ6Δ5 Fads2, Δ4 Fads2, Elovl5 and Elovl4. We previously reported a direct interaction between the transcription factor Hnf4α and the promoter regions of Δ4 and Δ6Δ5 Fads2, which suggested that Hnf4α was involved in the transcriptional regulation of fads2 in rabbitfish. For further functionally investigating it, a full-length cDNA of 1736 bp encoding rabbitfish Hnf4α with 454 amino acids was cloned, which was highly expressed in intestine, followed by liver and eyes. Similar to the expression characteristics of its target genes Δ4 and Δ6Δ5 fads2, levels of hnf4α mRNA in liver and eyes were higher in fish reared at low salinity than those reared in high salinity. After the rabbitfish primary hepatocytes were respectively incubated with Alverine, Benfluorex or BI6015, which were anticipated agonists or antagonist for Hnf4α, the mRNA level of Δ6Δ5 and Δ4 fads2 displayed a similar change tendency with that of hnf4α mRNA. Furthermore, when the mRNA level of hhf4α was knocked down using siRNA, the expression of Δ6Δ5 and Δ4 fads2 also decreased. Together, these data suggest that Hnf4α is involved in the transcriptional regulation of LC-PUFA biosynthesis, specifically, by targeting Δ4 and Δ6Δ5 fads2 in rabbitfish

MHC class I-presented tumor antigen appraisable for T-cell responses against ovarian cancer

The purpose of this study is to assess whether MHC class I-presented tumor antigen is appraisable for T-cell responses against ovarian cancer. In ovarian cancer cell, human leukocyte antigen A2 (HLA-A2) associated with peptides was used to promote the activation of naive T cells so as to activate antigen-specific T cells. 7 or 4 patients were observed grade 1 or 2 injection site reactions, respectively. 5, 2 or 1 patients were observed grade 1, 2 or 3 pain reactions, respectively. 4 or 1 patients were observed grade 1 or 2 induration reactions. Total number mean value of patients experiencing response to the particular peptide was 7.73, and total number mean value of peptides to which the patients responded was 7.45. MHC class I-presented tumor antigen is appraisable for T-cell responses against ovarian cancer in China

Pharmacodynamics, metabolomics and pathological studies on mechanisms of traditional benefits of Angelica sinensis in blood circulation

Angelica sinensis is a rich source of medically important active molecules that need in-depth understanding on its action mechanisms. Therefore, through pharmacodynamics, metabolomics, and network pharmacology, the traditional benefits of A. sinensis in blood circulation was studied using 24 randomly selected Sprague-Dawley (SD) rats. Measurement of the blood rheological parameters for whole blood viscosity (WBV) and plasma viscosity (PV), and inspection of the heart and lung tissues pathological changes were undertaken using molecular and bioinformatic techniques. Multivariate statistical analysis and establishment of the model of the relationship between metabolite expression and sample categories to test the prediction of sample categories were performed. Screening was undertaken to find the potential metabolites for A. sinensis to treat blood stasis syndrome and find related metabolic pathways. Active ingredients of A. sinensis and targets and building of an “effect component-target” network was undertaken, A. sinensis was confirmed to improve blood stasis syndrome in rats and improve heart and lung pathology to varying degrees. Compared with the blood stasis model group, A. sinensis significantly reduced WBV and PV in hemorheology (p<0.05, p<0.01) and regulated blood stasis-induced changes in 22 metabolites including alpha-D-glucose, L-isoleucine, creatine and acetylcarnitine, which are involved in the metabolism of linoleic acid, linolenic acid, phenylalanine, ascorbic acid and uronic acid. Using the network pharmacology to build a "component-target-pathway" network of A. sinensis, 62 active ingredients, 169 active proteins and 18 metabolic pathways were obtained, among which linoleic acid metabolism, ascorbic acid and uronic acid metabolism were consistent with the metabolic pathways obtained by metabolomics

Current evidence, clinical applications, and future directions of transcranial magnetic stimulation as a treatment for ischemic stroke

Transcranial magnetic stimulation (TMS) is a non-invasive brain neurostimulation technique that can be used as one of the adjunctive treatment techniques for neurological recovery after stroke. Animal studies have shown that TMS treatment of rats with middle cerebral artery occlusion (MCAO) model reduced cerebral infarct volume and improved neurological dysfunction in model rats. In addition, clinical case reports have also shown that TMS treatment has positive neuroprotective effects in stroke patients, improving a variety of post-stroke neurological deficits such as motor function, swallowing, cognitive function, speech function, central post-stroke pain, spasticity, and other post-stroke sequelae. However, even though numerous studies have shown a neuroprotective effect of TMS in stroke patients, its possible neuroprotective mechanism is not clear. Therefore, in this review, we describe the potential mechanisms of TMS to improve neurological function in terms of neurogenesis, angiogenesis, anti-inflammation, antioxidant, and anti-apoptosis, and provide insight into the current clinical application of TMS in multiple neurological dysfunctions in stroke. Finally, some of the current challenges faced by TMS are summarized and some suggestions for its future research directions are made

Krüppel-like factors in tumors: Key regulators and therapeutic avenues

Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research

Effect of Multiple Factors for the Roadway Excavation Process Stability in FLAC3D

Appropriate simulation set parameters are the precondition to obtain accurate results; while the simulation results are affected by multiple factors, it is thus crucial to investigate the sensibility of different factors. This paper first analyses the application situation of numerical simulation software in the field of geotechnical engineering and finds that Fast Lagrangian analysis of continua in three dimensions (FLAC3D) has been widely used on roadways or tunnels. Then, taking the roadway excavation process as the engineering background, FLAC3D was used to create 171 schemes of different simulation parameters and analyze the influence of different factors on the simulation results. The findings show that there is a considerable difference in the degree of effect of different parameters on the simulation results. Most of the factors have a remarkable effect on the numerical simulation results (displacement and stress), and only some factors (parameter uniformity and density) have almost no effect on the results. Meanwhile, the trend of displacement and stress is opposite in most cases. In addition, some neglected factors can also have a considerable effect on the simulation results, such as the zone amount; therefore, it is necessary to avoid the variation of nonstudy factors as possible when carrying out the numerical simulation. This study may significantly assist concerned engineers and technicians in developing a more organized and thorough grasp of the impacts of various parameters on simulation outcomes