Hedehonore6958

Atherosclerotic plaque rupture followed by luminal thrombosis is recognized as the main cause of acute cardiovascular events, especially in patients with diabetes. Although previous studies identified stimulation of macrophages polarization with advanced glycation end products (AGEs) results in the rapid progression of atherosclerosis, the underlying mechanisms are not understood fully. The purpose of this study was to investigate the effect of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase 4 (PDK4), critical proteins for regulating glucose metabolism, on macrophages polarization in diabetic atherosclerosis, and relevant mechanisms involved. We found that there is an increased number of M1 macrophages in carotid atherosclerotic tissues of diabetic mice and in AGE-bovine serum albumin (BSA)-treated RAW264.7 cells. Furthermore, we observed that HIF-1α was upregulated in AGE-BSA-induced M1 polarization and that the HIF-1α knockdown reduced macrophage polarization to M1 phenotype caused by AGE-BSA via regulation of PDK4. Thus, our study identified the critical role of HIF-1α/PDK4 axis in AGE-BSA-induced M1 polarization, which reflected the potential association between energy metabolism and inflammation in macrophages.Flaviviruses replicate in membranous factories associated with the endoplasmic reticulum (ER). Significant levels of flavivirus polyprotein integration contribute to ER stress and the host cell may exhibit an Unfolded Protein Response (UPR) to this protein accumulation, stimulating appropriate cellular responses such as adaptation, autophagy or cell death. These different stress responses support other antiviral strategies initiated by infected cells and can help to overcome viral infection. In epithelial A549 cells, a model currently used to study the flavivirus infection cycle and the host cell responses, all three pathways leading to UPR are activated during infection by Dengue virus (DENV), Yellow Fever virus (YFV) or West Nile virus (WNV). In the present study, we investigated the capacity of ZIKA virus (ZIKV) to induce ER stress in A549 cells. We observed that the cells respond to ZIKV infection by implementing an UPR through activation of the IRE1 and PERK pathway without activation of the ATF6 branch. Epigenetic inhibitor By modulating the ER stress response, we found that UPR inducers significantly inhibit ZIKV replication. Interestingly, our findings provide evidence that ZIKV could manipulate the UPR to escape this host cell defence system by downregulating GRP78/BiP expression. This subversion of GRP78 expression could lead to unresolved and persistent ER stress which can be a benefit for virus growth.Chagas disease is one of seventeen neglected tropical diseases according to the World Health Organization (WHO). The histidine-glutamate metabolic pathway is an oxidative route that has shown to be relevant for the bioenergetics in Trypanosoma cruzi, the etiological agent for Chagas disease. Histidine ammonia-lyase participates in the first stage of the histidine catabolism, catalyzing the conversion of l-histidine into urocanate. This work presents the three-dimensional (3D) structure of Trypanosoma cruzi histidine ammonia-lyase enzyme (TcHAL) and some comparisons of it to homologous structures. The enzyme was expressed, purified and assayed for crystallization, what allowed the obtainment of crystals of sufficient quality to collect X-ray diffraction data up to 2.55 Å resolution. After refinement, some structural analyses indicated that the structure does not contain the active site protection domain, in opposition to previously known 3D structures from plants and fungi phenylalanine ammonia-lyase, therefore, it is the first structure of eukaryotic ammonia-lyases that lacks this domain.This is a review of recent work on how the physics of evolution accounts for the origin, changes and future of social systems. Evolution means the changes (spatial, temporal) that happen with discernible direction in time. Changes are everywhere because physical features of 'freedom to change' are in every moving and flowing system. With freedom comes evolution, and with evolution come all these visible things, movement, change, configurations, diversity, multiple scales, and the universality of social organization phenomena such as human settlements, hierarchy, economics, economies of scale and diminishing returns.Background and purpose To compare secondary malignancy risks of modern proton and photon therapy techniques for locally advanced breast cancer. Methods and materials We utilized dosimetric data from 34 [10 photon-VMAT, 10 photon-3DCRT, 14 pencil beam scanning proton (PBS)] breast cancer patients who received comprehensive nodal irradiation. Employing a model based on organ equivalent dose to account for both inhomogeneous organ dose distributions and non-linear functional dose relationships, we estimated excess absolute risk, excess relative risk, and lifetime attributable risk (LAR) for secondary malignancies. The model uses dose distribution, number of fractions, age at exposure, attained age, the linear-quadratic dose response relationship for cell survival, repopulation factor, as well as gender specific age dependencies, and initial slopes of dose response curves. Results The LAR for carcinoma at age 70 was estimated to be up to 3.64% for esophagus with an advantage of 3DCRT over PBS and VMAT. For the ipsilateral lung, risks were lowest for PBS (up to 5.56%), followed by 3DCRT (up to 6.54%) and VMAT (up to 7.7%). For the contralateral lung, there is a clear advantage of 3DCRT and PBS techniques (risk less then 0.86%) over VMAT (up to 4.4%). The risk for the contralateral breast is negligible for 3DCRT and PBS but was estimated as up to 1.2% for VMAT. Risks for the thyroid are overall negligible. Independently performed comparative treatment plans on 10 patients revealed that the risk for the contralateral lung and breast using VMAT can be more than an order of magnitude higher compared to PBS. Sarcoma risks were estimated as well showing similar trends but were overall lower compared to carcinoma. Conclusion Conventional (3DCRT) techniques led to the lowest estimated risks of, thyroid and esophageal secondary cancers while PBS demonstrated a benefit for secondary lung and contralateral breast cancer risks, with the highest risks overall associated with VMAT techniques.