Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers

Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors.     

A review of prospects and challenges of photocatalytic decomposition of volatile organic compounds (VOCs) under humid environment

Volatile organic compounds (VOCs) are harmful for humans and the surrounding ecosystem. Emissions from these pollutants have caused a significant reduction in air quality, which has an effect on people's health. Alkanes, alkenes, alcohols, aromatics, and other VOC pollutants have all been broken down by TiO₂ photocatalytic processes. Due to several operating inefficiencies and deactivation issues in humid environments, the practical application of photocatalysis has not been realized on a broader scale. The effectiveness of photo-oxidation of VOCs is impacted by a variety of environmental conditions. In the photocatalytic oxidation of the VOCs, relative humidity (RH) is critical. Therefore, it is important to review the recent findings on how humidity affects the photocatalytic breakdown of VOCs in air. To satisfy this need, this work provides a critical review of the related literature with focus on the fundamentals of photocatalysis, photocatalytic degradation of air pollutants, and the influence of humidity on the photocatalytic process degradation for selected air pollutants. It also highlights the kinetic models and typical photocatalytic reactor and supports for VOC removal.     

A novel multicarrier index keying-aided non-orthogonal multiple access systems in presence of uncertain channel state information

This paper investigates the performance of novel multicarrier index keying-aided non-orthogonal multiple access (MCIK-NOMA) system. Unlike the classical scheme, the proposed system sends the information through both index domain and constellation domain symbols thereby increases the spectral efficiency. The impact of channel state information (CSI) uncertainty on the system's performance is investigated. More specifically, the performance of MCIK-NOMA under three different CSI conditions is analyzed: perfect CSI, MMSE-based variable CSI, and fixed CSI uncertainty. This paper also discusses the optimum power difference needed for the successful separation of symbols at the SIC receiver by alternating the power ratio in the proposed system. The influence of selecting different active subcarriers and modulation techniques on the system's performance is studied in detail. The simulation results show that the proposed system achieves better BER and spectral efficiency and outperforms the existing systems.     

The political economy of metering agricultural tube wells in West Bengal,India

Unmetered electricity supply to agriculture has given rise to a unique and invidious water–energy–food nexus in India. Metering of agricultural consumers has been suggested as a way to break the nexus, but most states have not been able to meter farmers due to their opposition . The only exception is the state of West Bengal. Using primary data from a household survey conducted in 2010 when the metering process was still underway, this paper argues that farmers’ support for metering in West Bengal can be explained in terms of the economics of groundwater use and politics surrounding agriculture and groundwater in the state.     

Cross-layer based congestion detection and routing protocol using fuzzy logic for MANET

Mobile Ad hoc Networks (MANET) is made up of mobile devices which form an infrastructure-less network. In MANET, the devices can change its location and configure itself at any time. Hence, there is a possibility for the network to be prone to abnormal network events due to certain factors like error in the links, overflow in the buffers, layers, and so forth. So, in this paper, a cross-layer based congestion detection and routing protocol is proposed using Fuzzy logic. In this protocol, whenever a network event occurs, the kind of event occurring is recognized in order to handle it accordingly. Next, the alternate routes for data transmission are determined by applying the concept of fuzzy logic on some of the critical factors. Based on the fuzzy inference rules, appropriate routes are selected and data messages are transmitted successfully.     

The energy-irrigation nexus and its impact on groundwater markets in eastern Indo-Gangetic basin: Evidence from West Bengal, India

South Asia in general and India in particular is heavily dependent on groundwater for supporting its largely agrarian population. Informal pump irrigation services markets have played an important role in providing access to irrigation to millions of small and marginal farmers and had positive equity, efficiency and sustainable impacts in water-abundant regions such as West Bengal. Quite predictably, in such pump lift-based economy, fortunes of energy and irrigation sectors are closely entwined. This has often been called the ‘energy-irrigation’ nexus. There are two major sources of energy for pumping groundwater, viz. electricity and diesel. Most of the current discourse in the field has looked only at the ‘electricity-irrigation’ nexus to the exclusion of the ‘diesel-irrigation nexus’. This paper looks at both these aspects. In doing so, it makes two propositions. First, high flat-rate electricity tariff encourages development of water markets whereby the water buyers—who are mostly small and marginal farmers—benefit through access to irrigation. Second, low rate of rural electrification has forced majority of farmers to depend on diesel for groundwater pumping and the steep increase in diesel prices over the last few years has resulted in economic scarcity of groundwater. This in turn has had serious negative impacts on crop production and farm incomes. Using primary field data from West Bengal, India, this paper makes a case for rapid rural electrification and continuation of high flat-rate tariff, which would in turn support developed groundwater markets and provide access to irrigation to the poor and marginal farmers.     

Characterization of a calmodulin kinase II inhibitor protein in brain

Ca2+/calmodulin-dependent protein kinase II (CaM-KII) regulates numerous physiological functions, including neuronal synaptic plasticity through the phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. To identify proteins that may interact with and modulate CaM-KII function, a yeast two-hybrid screen was performed by using a rat brain cDNA library. This screen identified a unique clone of 1.4 kb, which encoded a 79-aa brain-specific protein that bound the catalytic domain of CaM-KII alpha and beta and potently inhibited kinase activity with an IC50 of 50 nM. The inhibitory protein (CaM-KIIN), and a 28-residue peptide derived from it (CaM-KIINtide), was highly selective for inhibition of CaM-KII with little effect on CaM-KI, CaM-KIV, CaM-KK, protein kinase A, or protein kinase C. CaM-KIIN interacted only with activated CaM-KII (i. e., in the presence of Ca2+/CaM or after autophosphorylation) by using glutathione S-transferase/CaM-KIIN precipitations as well as coimmunoprecipitations from rat brain extracts or from HEK293 cells cotransfected with both constructs. Colocalization of CaM-KIIN with activated CaM-KII was demonstrated in COS-7 cells transfected with green fluorescent protein fused to CaM-KIIN. In COS-7 cells phosphorylation of transfected alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors by CaM-KII, but not by protein kinase C, was blocked upon cotransfection with CaM-KIIN. These results characterize a potent and specific cellular inhibitor of CaM-KII that may have an important role in the physiological regulation of this key protein kinase.