• Christoffersen Lohmann opublikował 1 rok, 3 miesiące temu

    Marburg virus (MARV) is a lipid-enveloped negative sense single stranded RNA virus, which can cause a deadly hemorrhagic fever. MARV encodes seven proteins, including VP40 (mVP40), a matrix protein that interacts with the cytoplasmic leaflet of the host cell plasma membrane. VP40 traffics to the plasma membrane inner leaflet, where it assembles to facilitate the budding of viral particles. VP40 is a multifunctional protein that interacts with several host proteins and lipids to complete the viral replication cycle, but many of these host interactions remain unknown or are poorly characterized. In this study, we investigated the role of a hydrophobic loop region in the carboxy-terminal domain (CTD) of mVP40 that shares sequence similarity with the CTD of Ebola virus VP40 (eVP40). These conserved hydrophobic residues in eVP40 have been previously shown to be critical to plasma membrane localization and membrane insertion. An array of cellular experiments and confirmatory in vitro work strongly suggests proper orientation and hydrophobic residues (Phe281, Leu283, and Phe286) in the mVP40 CTD are critical to plasma membrane localization. In line with the different functions proposed for eVP40 and mVP40 CTD hydrophobic residues, molecular dynamics simulations demonstrate large flexibility of residues in the EBOV CTD whereas conserved mVP40 hydrophobic residues are more restricted in their flexibility. This study sheds further light on important amino acids and structural features in mVP40 required for its plasma membrane localization as well as differences in the functional role of CTD amino acids in eVP40 and mVP40.In this paper, we reported on four cases of severe pulmonary active tuberculosis in patients with multiple sclerosis (MS) undergoing interferon beta-1b (IFNβ-1b) therapy. Disease-modifying therapies (DMTs) in MS may increase the risk of developing active tuberculosis (TB) due to their impact on cellular immunity. Screening for latent infection with Mycobacterium tuberculosis (LTBI) should be performed, not only for the newer DMTs (alemtuzumab, ocrelizumab) but also for IFNβ-1b, alongside better supervision of these patients.The possibilities of metallurgical preparation of 40Nb-60Al and 15W-85Al intermetallic compounds (in at.%) by plasma arc melting (PAM) and vacuum induction melting (VIM) were studied. Both methods allow easy preparation of Nb-Al alloys; however, significant evaporation of Al was observed during the melting, which affected the resulting chemical composition. The preparation of W-Al alloys was more problematic because there was no complete re-melting of W during PAM and VIM. However, the combination of PAM and VIM allowed the preparation of W-Al alloy without any non-melted parts. The microstructure of Nb-Al alloys consisted of Nb2Al and NbAl3 intermetallic phases, and W-Al alloys consisted mainly of needle-like WAl4 intermetallic phase and Al matrix. The effects of melting conditions on chemical composition, homogeneity, and microstructure were determined. Differential thermal analysis was used to determine melting and phase transformation temperatures of the prepared alloys.In view of the urgent need for intelligent rehabilitation equipment for some disabled people, an intelligent, upper limb rehabilitation training robot is designed by applying the theories of artificial intelligence, information, control, human-machine engineering, and more. A new robot structure is proposed that combines the use of a flexible rope with an exoskeleton. By introducing environmentally intelligent ergonomics, combined with virtual reality, multi-channel information fusion interaction technology and big-data analysis, a collaborative, efficient, and intelligent remote rehabilitation system based on a human’s natural response and other related big-data information is constructed. For the multi-degree of the freedom robot system, optimal adaptive robust control design is introduced based on Udwdia-Kalaba theory and fuzzy set theory. The new equipment will help doctors and medical institutions to optimize both rehabilitation programs and their management, so that patients are more comfortable, safer, and more active in their rehabilitation training in order to obtain better rehabilitation results.Deficiencies in iron and vitamin D are frequently observed in athletes. Therefore, we examined whether different baseline vitamin D3 levels have any impact on post-exercise serum hepcidin, IL-6 and iron responses in ultra-marathon runners. In this randomized control trial, the subjects (20 male, amateur runners, mean age 40.75 ± 7.15 years) were divided into two groups experimental (VD) and control (CON). The VD group received vitamin D3 (10,000 UI/day) and the CON group received a placebo for two weeks before the run. Venous blood samples were collected on three occasions-before the run, after the 100 km ultra-marathon and 12 h after the run-to measure iron metabolism indicators, hepcidin, and IL-6 concentration. After two weeks of supplementation, the intervention group demonstrated a higher level of serum 25(OH)D than the CON group (27.82 ± 5.8 ng/mL vs. 20.41 ± 4.67 ng/mL; p less then 0.05). There were no differences between the groups before and after the run in the circulating hepcidin and IL-6 levels. The decrease in iron concentration immediately after the 100-km ultra-marathon was smaller in the VD group than CON (p less then 0.05). These data show that various vitamin D3 status can affect the post-exercise metabolism of serum iron.Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.Chondrosarcomas (CHS) are malignant cartilaginous neoplasms with diverse morphological features, characterized by resistance to chemo- and radiation therapies. In this study, we investigated the role of tumor-associated macrophages (TAM)s in tumor tissues from CHS patients by immunohistochemistry. Three-dimensional organotypic co-cultures were set up in order to evaluate the contribution of primary human CHS cells in driving an M2-like phenotype in monocyte-derived primary macrophages, and the capability of macrophages to promote growth and/or invasiveness of CHS cells. Finally, with an in vivo model of primary CHS cells engrafted in nude mice, we tested the ability of a potent peptide inhibitor of cell migration (Ac-d-Tyr-d-Arg-Aib-d-Arg-NH2, denoted RI-3) to reduce recruitment and infiltration of monocytes into CHS neoplastic lesions. We found a significant correlation between alternatively activated M2 macrophages and intratumor microvessel density in both conventional and dedifferentiated CHS human tissues, suggesting a link between TAM abundance and vascularization in CHS. In 3D and non-contact cu-culture models, soluble factors produced by CHS induced a M2-like phenotype in macrophages that, in turn, increased motility, invasion and matrix spreading of CHS cells. Finally, we present evidence that RI-3 successfully prevent both recruitment and infiltration of monocytes into CHS tissues, in nude mice.The functions of the annexin family of proteins involve binding to Ca2+, lipid membranes, other proteins, and RNA, and the annexins share a common folded core structure at the C terminus. Annexin A11 (AnxA11) has a long N-terminal region, which is predicted to be disordered, binds RNA, and forms membraneless organelles involved in neuronal transport. Mutations in AnxA11 have been linked to amyotrophic lateral sclerosis (ALS). We studied the structure and stability of AnxA11 and identified a short stabilising segment in the N-terminal end of the folded core, which links domains I and IV. The crystal structure of the AnxA11 core highlights main-chain hydrogen bonding interactions formed through this bridging segment, which are likely conserved in most annexins. The structure was also used to study the currently known ALS mutations in AnxA11. Three of these mutations correspond to buried Arg residues highly conserved in the annexin family, indicating central roles in annexin folding. The structural data provide starting points for detailed structure-function studies of both full-length AnxA11 and the disease variants being identified in ALS.Saudi Arabia is witnessing a drastic rise in adult obesity. Geographic limitations hamper somatic activities to counter this rise. Parental physical inactivity in the region has never been addressed. This study’s purpose is to determine the differences between parent and adult child (the subjects here) levels of physical activity (PA) and screen time (ST) between normal weight and obese adults in the Saudi Arabian population. Two hundred and forty adult subjects (18 to 35 years) were screened for their body mass index (BMI) values (18.5 ≤ 25 as normal and 25 ≤ 30) or above as overweight/obese), followed by their congregation into normal weight (N) (n = 150) and overweight/obese (Ov/Ob) (n = 90) groups. A self-reported questionnaire assessed parenting practices, while a physical activity record diary calculated existing levels of PA and ST. Statistical significance was determined by a chi-squared test (p less then 0.01) and BMI correlation was found by Pearson’s correlation coefficient. Maternal age (87.8% ≤ 20 years in the Ov/Ob group (Gp) and consanguineous marriage (88.9% in the Ov/Ob Gp) showed significant differences. A high prevalence of inactivity was observed among families (father 53.3%, mother 53.3%, subject 80.0%) in the Ov/Ob Gp. Higher amounts of ST (76.7% ≥ 9 h/day) were found in the Ov/Ob Gp, which significantly differed. Differences in the parent and child levels of PA and ST exist between normal weight and obese Saudi Arabian adults. Physically active parents having adult children inspire them to develop healthy physical behaviors which counter the development of obesity. Consanguineous marriage and early maternal age may be associated with progressive adult obesity.

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