Downregulation of protein kinase C-α enhances intracellular survival of Mycobacteria: role of PknG

Abstract Background Intracellular trafficking of mycobacteria is comprehensively dependent on the unusual regulation of host proteins. Recently, we have reported that infection of macrophages by Mycobacterium tuberculosis H37Rv (Rv) selectively downregulates the expression of PKCα while infection by Mycobacterium smegmatis (MS) does not. Results Based on our earlier study, we have extrapolated for the first time that knockdown of PKCα, impairs phagocytosis of mycobacteria by macrophages while their intracellular survival is drastically increased. Mycobacterium bovis BCG (BCG) and Mycobacterium tuberculosis H37Ra (Ra) have also been shown to downregulate the expression of PKCα during the infection. Since PknG is uniquely expressed in BCG, Ra, Rv but not in MS and has been reported to promote intracellular survival of mycobacteria, led us to believe that PknG may be involved in such downregulation of PKCα. THP-1 cells infected with recombinant MS expressing PknG (MS-G), showed significant reduction in PKCα expression. In normal THP-1 cells survival of MS-G was enhanced as compared to MS, while their behavior in PKCα deficient cells could not be distinguished. The results strongly demonstrate that pathogenic mycobacteria recognize and then inhibit PKCα to circumvent phagocytosis and the hostile environment of macrophages. We emphasize that, this inhibition is controlled by PknG. Conclusions All together, our data reveal a mechanism that shows substantial interdependence of PKCα with PknG, in sustaining mycobacterial infection.</p

Bruton\u27s Tyrosine Kinase Targeting in Multiple Myeloma.

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones\u27 hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton\u27s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones\u27 interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM

Dynamic Phenotypic Switching and Group Behavior Help Non-Small Cell Lung Cancer Cells Evade Chemotherapy

Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells, when co-cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit a \u27persister-like\u27 behavior and are attenuated by sensitive cells; they also appear to \u27educate\u27 sensitive cells to evade chemotherapy. Further, tolerant cells can switch phenotypes to become sensitive, especially at low cisplatin concentrations. Finally, switching treatment from continuous to an intermittent regimen can attenuate the emergence of tolerant cells, suggesting that intermittent chemotherapy may improve outcomes in lung cancer

Curcumin-Loaded Apotransferrin Nanoparticles Provide Efficient Cellular Uptake and Effectively Inhibit HIV-1 Replication In Vitro

Curcumin (diferuloylmethane) shows significant activity across a wide spectrum of conditions, but its usefulness is rather limited because of its low bioavailability. Use of nanoparticle formulations to enhance curcumin bioavailability is an emerging area of research.In the present study, curcumin-loaded apotransferrin nanoparticles (nano-curcumin) prepared by sol-oil chemistry and were characterized by electron and atomic force microscopy. Confocal studies and fluorimetric analysis revealed that these particles enter T cells through transferrin-mediated endocytosis. Nano-curcumin releases significant quantities of drug gradually over a fairly long period, ∼50% of curcumin still remaining at 6 h of time. In contrast, intracellular soluble curcumin (sol-curcumin) reaches a maximum at 2 h followed by its complete elimination by 4 h. While sol-curcumin (GI(50) = 15.6 µM) is twice more toxic than nano-curcumin (GI(50) = 32.5 µM), nano-curcumin (IC(50)<1.75 µM) shows a higher anti-HIV activity compared to sol-curcumin (IC(50) = 5.1 µM). Studies in vitro showed that nano-curcumin prominently inhibited the HIV-1 induced expression of Topo II α, IL-1β and COX-2, an effect not seen with sol-curcumin. Nano-curcumin did not affect the expression of Topoisomerase II β and TNF α. This point out that nano-curcumin affects the HIV-1 induced inflammatory responses through pathways downstream or independent of TNF α. Furthermore, nano-curcumin completely blocks the synthesis of viral cDNA in the gag region suggesting that the nano-curcumin mediated inhibition of HIV-1 replication is targeted to viral cDNA synthesis.Curcumin-loaded apotransferrin nanoparticles are highly efficacious inhibitors of HIV-1 replication in vitro and promise a high potential for clinical usefulness

Facile Hydrogen Evolution Reaction on WO3Nanorods

Tungsten trioxide nanorods have been generated by the thermal decomposition (450 °C) of tetrabutylammonium decatungstate. The synthesized tungsten trioxide (WO3) nanorods have been characterized by XRD, Raman, SEM, TEM, HRTEM and cyclic voltammetry. High resolution transmission electron microscopy and X-ray diffraction analysis showed that the synthesized WO3nanorods are crystalline in nature with monoclinic structure. The electrochemical experiments showed that they constitute a better electrocatalytic system for hydrogen evolution reaction in acid medium compared to their bulk counterpart

Meeting Future Energy Needs in the Hindu Kush Himalaya

As mentioned in earlier chapters, the HKH regions form the entirety of some countries, a major part of other countries, and a small percentage of yet others. Because of this, when we speak about meeting the energy needs of the HKH region we need to be clear that we are not necessarily talking about the countries that host the HKH, but the clearly delineated mountainous regions that form the HKH within these countries. It then immediately becomes clear that energy provisioning has to be done in a mountain context characterized by low densities of population, low incomes, dispersed populations, grossly underdeveloped markets, low capabilities, and poor economies of scale. In other words, the energy policies and strategies for the HKH region have to be specific to these mountain contexts

Microstructural features, electrical and optical properties of nanostructured InSb thin films deposited at 373 K

Thin films of InSb nanocrystals have been deposited onto KCl substrate Using a thermal evaporation technique Under high vacuum conditions (similar to 10(-6) torr). Ail intriguing microstructure consisted of moire fringes with variable spacings and a corresponding variety of electron diffraction patterns in reciprocal space are reported at the deposition temperature of 373 K. The nano-rains of InSb with preferred orientation and faceted morphology are delineated. A possible mechanism has been postulated to explain the evolution of such microstructures. It has been noticed that there is a peculiarity in the resistivity characteristics and infrared transmittance measurements obtained oil these films. A set of electron micrographs, diffraction patterns and properties have been evaluated and discussed to understand the role of nanocrystals constituting the thin film, and certain types of defects introduced in the microstructure while deposition, oil these properties

Microstructural features and mechanical properties of carbon nanotubes reinforced aluminum-based metal matrix composites

The composites of aluminum-carbon nanotubes, produc ed using catalytic chemical vapour deposition metho d, are prepared with initial composition of aluminum homog eneously mixed with 1, 2, 4 and 10wt% nanotubes and subsequently hot-pressed. TEMs and a STEM have been used to stud y the as prepared carbon nanotubes and their distri bution in aluminum matrix after reinforcement. A set of preli minary observations delineated that the yield of as produced nanotubes in carbonaceous is very high with an average diamet er of about 45 nm and with straight and spiral shap es. In composites, these tubes have been seen uniformly distributed in aluminum matrix without any significant dimensiona l alteration. An enormous increase in microhardness of aluminum – 10 wt% carbon nanotubes composites in contrast to pure aluminum has been a remarkable study. Some of the important micr oscopic details, electrical measurements and mechan ical properties in the nanotubes and their composites have been elucid ated and discussed