Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor ...resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells. Importantly, Rpn11 expression directly correlates with poor patient survival. Loss-of-function studies show that Rpn11-siRNA knockdown decreases MM cell viability. Pharmacological inhibition of Rpn11 with O-phenanthroline (OPA) blocks cellular proteasome function, induces apoptosis in MM cells and overcomes resistance to proteasome inhibitor bortezomib. Mechanistically, Rpn11 inhibition in MM cells activates caspase cascade and endoplasmic stress response signaling. Human MM xenograft model studies demonstrate that OPA treatment reduces progression of tumor growth and prolongs survival in mice. Finally, blockade of Rpn11 increases the cytotoxic activity of anti-MM agents lenalidomide, pomalidomide or dexamethasone. Overall, our preclinical data provide the rationale for targeting DUB enzyme Rpn11 upstream of 20S proteasome to enhance cytotoxicity and overcome proteasome inhibitor resistance in MM.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The paper presents an algorithm for network reconfiguration based on fuzzy multi-objective approach. Multiple objectives are considered for load balancing among the feeders, minimum deviation of the ...nodes voltage, minimize the power loss and branch current constraint violation, while subject to a radial network structure in which all loads must be energized. These objectives are modeled with fuzzy sets to evaluate their imprecise nature and one can provide his or her anticipated value of each objective. These four objectives are first fuzzified and then a fuzzy satisfaction objective function is formed and maximized for each tie-switch operation. Heuristic rules are also incorporated in the algorithm for minimizing the number of tie-switch operation. The effectiveness of the proposed method is demonstrated through an example.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its ...long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This paper presents allocation of power losses to consumers connected to radial distribution networks before and after network reconfiguration in a deregulated environment. Loss allocation is made in ...a quadratic way and it is based on identifying the real and imaginary parts of current in each branch, and losses are allocated to consumers. The network reconfiguration algorithm is based on the fuzzy multiobjective approach and the max-min principle is adopted for the multiobjective optimization in a fuzzy framework. Multiple objectives are considered for real-power loss reduction in which nodes voltage deviation is kept within a range, and an absolute value of branch currents is not allowed to exceed their rated capacities. At the same time, a radial network structure is maintained with all loads energized. The three objectives considered are modeled with fuzzy sets to evaluate their imprecise nature and one can provide his or her anticipated value of each objective. A 69-node example is considered to demonstrate the effectiveness of the proposed method.
Chitosan-tripolyphosphate (CTPP) beads were prepared using in-liquid curing method and used for the adsorption of uranium from aqueous solution. Beads were prepared at two different cross-linking ...densities by adjusting the pH of the tripolyphosphate solution. The synthesized beads were characterized using FTIR spectroscopy before and after adsorption of uranium. Beads having higher cross-linking are found to have better adsorption capacity for uranium. Factors that influence the uranium adsorption onto CTPP beads such as solution pH, contact time and initial uranium concentration were studied in detail. The experimental results were fitted into Langmuir and Freundlich adsorption isotherms. From Langmuir adsorption model the adsorption capacity of CTPP beads for uranium is estimated as 236.9mg/g. Pseudo-first order, pseudo-second order and intraparticle diffusion model were applied to the observed kinetics data and the results shows that the pseudo-second order model is more suitable to explain the kinetics of adsorption of uranium on CTPP beads. FTIR spectroscopic characterization of the beads showed that the phosphate groups may be more responsible for the adsorption of uranium on CTPP beads.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Core–shell type nanostructures show exceptional properties due to their unique structure having a central solid core of one type and an outer thin shell of another type which draw immense attention ...among researchers. In this study, molecular dynamics simulations are carried out on single crystals of copper–silver core–shell nanowires having wire diameter ranging from 9 to 30 nm with varying core diameter, shell thickness, and strain velocity. The tensile properties like yield strength, ultimate tensile strength, and Young’s modulus are studied and correlated by varying one parameter at a time and keeping the other two parameters constant. The results obtained for a fixed wire size and different strain velocities were extrapolated to calculate the tensile properties like yield strength and Young’s modulus at standard strain rate of 1 mm/min. The results show ultra-high tensile properties of copper–silver core–shell nanowires, several times than that of bulk copper and silver. These copper–silver core–shell nanowires can be used as a reinforcing agent in bulk metal matrix for developing ultra-high strength nanocomposites.
Post-COVID-19 HSV encephalitis: a review Gupta, S; Dutta, A; Chakraborty, U ...
QJM : An International Journal of Medicine,
04/2022, Volume:
115, Issue:
4
Journal Article
Peer reviewed
Open access
Summary
Background
Herpes simplex virus encephalitis (HSVE) is one of the most common infectious causes of sporadic encephalitis. Coronavirus disease (COVID-19) has been associated with immune ...dysregulation of the host that might increase the risk of infections like HSVE following SARS-CoV-2 infection. There is paucity of literature on post COVID-19 HSVE. This study was conducted with the aim of analyzing the clinical presentation, brain imaging, and outcome of patients presenting with HSVE within 6 weeks of COVID-19 and providing a comprehensive review on the possible mechanisms of post-COVID-19 HSVE.
Methods
This observational study included patients who had laboratory-confirmed HSVE (type 1 or type 2) and a history of COVID-19 within the previous 6 weeks. Patients were followed up for 3 months.
Results
Eight patients were included and all of them had type 1 HSVE. The mean latency of onset of neurological symptoms from being diagnosed with COVID-19 is 23.87 days and a majority of the patients have received injectable steroids with a mean duration of 6.5 days. Behavioral abnormality was the commonest neurological presentation and typical brain imaging involved T2 FLAIR hyperintensities of the medial temporal lobes. All patients received intravenous acyclovir 10 mg/kg every eight hourly for atleast 14 days. One patient with concomitant rhinocerebral mucormycosis succumbed while the majority had a complete recovery.
Conclusion
Possible immune dysregulation in COVID-19 may increase the susceptibility of HSVE in patients with a history of recent SARS-CoV-2 infection. The clinical manifestations and laboratory findings of HSVE in such patients are similar to typical HSVE.
PbS/CdS and CdS/PbS core/shell (CS) nanoparticles (NPs) were synthesized by chemical method using glycerol, PVA and
l
-cysteine as capping agents. The structural properties of PbS/CdS and CdS/PbS ...core/shell (CS) nanoparticles (NPs) were studied using X-ray diffractometer (XRD) and transmission electron microscope (TEM). The optical properties were studied using UV–visible absorption and photoluminescence (PL) spectroscopy. XRD pattern clearly showed the difference in particle sizes for different capping agents. A cubic structure was seen for PbS/CdS while hexagonal for CdS/PbS CS NPs. The size of the samples was calculated using Scherer formula and Williamson–Hall (W–H) plots. Formation of core/shell nanoparticles was evident from the TEM micrographs. UV–visible absorption spectra exhibited a large blue shift of the absorption maxima as compared to their bulk, which confirmed the formation of core/shell nanoparticles for three different capping agents. Photoluminescence spectra showed the emission peak shift towards higher wavelength with increase in particle size. Among capped samples,
l
-cysteine capped core/shell nanoparticles showed maximum luminescence intensity as compared to that of glycerol and PVA capped nanoparticles.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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