System Analysis and Design for the Resonant Inductive Near-field Generation System (RINGS)

The Resonant Inductive Near-field Generation System (RINGS) is a technology demonstrator experiment which will allow for the first ever testing of electromagnetic formation flight (EMFF) algorithms in a full six degree of freedom environment on board the International Space Station (ISS). RINGS is a hybrid design, which, in addition to providing EMFF capabilities, also allows for wireless power transfer (WPT) via resonant inductive coupling. This thesis presents an overview of the mechanical and electrical design of the RINGS experiment, as well as simulation techniques used to model various system parameters in both EMFF and WPT operational modes. Also presented is an analytical and experimental investigation of the influence of the proximity effect on a multi-layer flat spiral coil made from ribbon wire

Human PLCG2 Haploinsufficiency Results in a Novel Immunodeficiency

NK cells are critical for the recognition and lysis of herpesvirus-infected cells. Patients with NK cell immunodeficiency may suffer from unusually severe and/or recurrent herpesvirus infections; however, the genetic cause is frequently unknown. PLCG2 encodes a signaling protein in NK cell and B cell receptor signaling, in which dominant-negative or gain-of-function mutations may cause cold urticaria, antibody deficiency, or autoinflammation. However, loss-of-function mutations and PLCG2 haploinsufficiency have never been reported in human disease. We examined 2 families with autosomal dominant NK cell immunodeficiency with dual high-dimensional techniques, mass cytometry and whole-exome sequencing, to identify the cause of disease. We identified two novel heterozygous loss-of-function mutations in PLCG2 that impaired NK cell function, including calcium flux, granule movement, and target killing. Although expression of mutant PLCG2 protein in vitro was normal, phosphorylation of both mutants was diminished. In contrast to PLAID and APLAID, B cell function remained intact. Plcg2+/- mice, as well as targeted CRISPR knock-in mice, also displayed impaired NK cell function with preserved B cell function, phenocopying human PLCG2 haploinsufficiency. We report the first known cases of PLCG2 haploinsufficiency, a clinically and mechanistically distinct syndrome from previously reported mutations. Therefore, these families represent a novel disease, highlighting a role for PLCG2 haploinsufficiency in herpesvirus-susceptible patients and expanding the spectrum of PLCG2-related disease

VP24-Karyopherin alpha binding affinities differ between Ebolavirus species, nfluencing interferon inhibition and VP24 stability

Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. These data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. IMPORTANCE The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis

Análisis comparativo de las propiedades físico-mecánicas del concreto f´c 210 kg/cm2, al remplazarle fibra de vidrio y plástico reciclado, Callao – 2021

La presente investigación tuvo como objetivo general evaluar la influencia en las propiedades físico-mecánicas del concreto F´c 210 kg/cm2, al remplazarle fibra de vidrio y plástico reciclado, Callao – 2021; Estableciéndose realizar ensayos de resistencia a compresión, flexión y consistencia. Formulando la siguiente metodología: Diseño de investigación experimental (cuasi), tipo explicativo, de enfoque cuantitativo. Los resultados según los objetivos específicos con el remplazo de F.V en 0.25%, 0.55% y 0.75% y PET en 2.5%, 5.5% y 7.5% fueron: El primero fue especificar la influencia en la resistencia a compresión, el cual se mejoró desde 284.7 kg/cm2 hasta 306.6 kg/cm2 con 0.75% F.V, con 7.5% PET se redujo hasta 212.0 kg/cm2; segundo fue indicar la influencia en la resistencia a la flexión del concreto, el cual se mejoró del 40.6 kg/cm2 al 42.7 kg/cm2 con 0.75% F.V, con 7.5% de PET se redujo hasta 33.4 kg/cm2; el tercero fue especificar la influencia en la consistencia, quien disminuyó del 5¾ hasta 4¾ con 0.75% F.V, con 7.5% PET disminuyó hasta 4''. Conclusión, con el remplazo de F.V incrementó la resistencia a compresión, flexión y redujo el slump; con el PET disminuyo todas estas propiedades

Myelodysplastic Syndrome and Histone Deacetylase Inhibitors: “To Be or Not to Be Acetylated”?

Myelodysplastic syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increasing risk of transformation into an acute myeloid leukaemia. Structured guidelines are developed for selective therapy based on prognostic subgroups, age, and performance status. Although many driving forces of disease phenotype and biology are described, the complete and possibly interacting pathogenetic pathways still remain unclear. Epigenetic investigations of cancer and haematologic diseases like MDS give new insights into the pathogenesis of this complex disease. Modifications of DNA or histones via methylation or acetylation lead to gene silencing and altered physiology relevant for MDS. First clinical trials give evidence that patients with MDS could benefit from epigenetic treatment with, for example, DNA methyl transferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi). Nevertheless, many issues of HDACi remain incompletely understood and pose clinical and translational challenges. In this paper, major aspects of MDS, MDS-associated epigenetics and the potential use of HDACi are discussed

Dysregulated NK cell PLCγ2 signaling and activity in juvenile dermatomyositis

Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and muscle weakness. To delineate signaling abnormalities in JDM, mass cytometry was performed with PBMCs from treatment-naive JDM patients and controls. NK cell percentages were lower while frequencies of naive B cells and naive CD4+ T cells were higher in JDM patients than in controls. These cell frequency differences were attenuated with cessation of active disease. A large number of signaling differences were identified in treatment-naive JDM patients compared with controls. Classification models incorporating feature selection demonstrated that differences in phospholipase Cγ2 (PLCγ2) phosphorylation comprised 10 of 12 features (i.e., phosphoprotein in a specific immune cell subset) distinguishing the 2 groups. Because NK cells represented 5 of these 12 features, further studies focused on the PLCγ2 pathway in NK cells, which is responsible for stimulating calcium flux and cytotoxic granule movement. No differences were detected in upstream signaling or total PLCγ2 protein levels. Hypophosphorylation of PLCγ2 and downstream mitogen-activated protein kinase-activated protein kinase 2 were partially attenuated with cessation of active disease. PLCγ2 hypophosphorylation in treatment-naive JDM patients resulted in decreased calcium flux. The identification of dysregulation of PLCγ2 phosphorylation and decreased calcium flux in NK cells provides potential mechanistic insight into JDM pathogenesis

Influence of Five Potential Anticancer Drugs on Wnt Pathway and Cell Survival in Human Biliary Tract Cancer Cells

Background: The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease

Paramagnetic Meissner effect in superconductors from self-consistent solutions of Ginzburg-Landau equations

The paramagnetic Meissner effect (PME) is observed in small superconducting samples, and a number of controversial explanations of this effect are proposed, but there is as yet no clear understanding of its nature. In the present paper PME is considered on the base of the Ginzburg-Landau theory (GL). The one-dimensional solutions are obtained in a model case of a long superconducting cylinder for different cylinder radii R, the GL-parameters \kappa and vorticities m. Acording to GL-theory, PME is caused by the presence of vortices inside the sample. The superconducting current flows around the vortex to screeen the vortex own field from the bulk of the sample. Another current flows at the boundary to screen the external field H from entering the sample. These screening currents flow in opposite directions and contribute with opposite signs to the total magnetic moment (or magnetization) of the sample. Depending on H, the total magnetization M may be either negative (diamagnetism), or positive (paramagnetism). A very complicated saw-like dependence M(H) (and other characteristics), which are obtained on the base of self-consistent solutions of the GL-equations, are discussed.Comment: 6 pages, 5 figures, RevTex, submitted to Phys. Rev.

Inhibition of DNA methyltransferase activity and expression by treatment with the pan-deacetylase inhibitor panobinostat in hepatocellular carcinoma cell lines

Background Hepatocellular carcinoma (HCC) still represents an unmet medical need. Epigenetic inactivation of tumor suppressor genes like RASSF1A or APC by overexpression of DNA methyltransferases (DNMTs) has been shown to be common in HCC and to be linked to the overall prognosis of patients. Inhibitors of protein and histone deacetylases (DACi) have been demonstrated to possess strong anti-tumor effects in HCC models. Methods We therefore investigated whether DACi also has any influence on the expression and activity of DNMTs and methylated target genes in HepG2 and Hep3B cell culture systems and in a xenograft model by immunohistochemistry, westernblotting, RT-qPCR and methylation-specific PCR. Results Our findings demonstrate a rapid inhibition of DNMT activity 6 h after treatment with 0.1 μM of the pan-DACi panobinostat. A downregulation of DNMT mRNAs and protein were also observed at later points in time. This loss of DNMT activity and expression was paralleled by a diminished methylation of the target genes RASSF1A and APC and a concomitant re-expression of APC mRNA and protein. Analysis of HepG2 xenograft specimens confirmed these results in vivo. Conclusion We suggest a dual mode of action of DACi on DNA methylation status: a rapid inhibition of enzyme activity due to interference with posttranslational acetylation and a delayed effect on transcriptional control of DNMT genes by HDAC or miRNA mechanisms