Factors regulating the transcription of eukaryotic protein coding genes and their mechanism of action- a review

Protein factors play a crucial role in establishing gene-specific and cell-specific regulation of the process of transcription. These include general transcription factors which recognize TATA and CCAAT boxes and which form components of the RNA polymerase II system. Specific transcription factors interact with characteristic promoter elements of individual genes. Some of the examples are SP1, glucocorticoid receptor, GCN4, GAL4 and many others. Transcription factors have a DNA binding domain demarcated from the transcription activation domain. Some factors may have an additional ligand (small molecule) binding domain. Typical structural features such as helix-turn-helix motif, zinc finger and leucine zipper have been recognized in the DNA binding domain of the transcription factors. The acidic domain of the protein factors is involved in the transcription activation process. It appears that activation is the result of the combined action of several regulatory proteins binding at different regions of the promoter. Interaction between proteins bound to DNA but seperated by long stretches of nucleotides is facilitated by DNA bending. Functional specificity as well as diversity are feasible with a limited number of transcription factors through alterations in the architecture of interaction between a group of proteins bound to promoter elements

Drugs and drug targets against malaria

The development of resistance by the parasite against first line and second line antimalarial drugs, has underscored the importance to develop new drug targets and pharmacophores to treat the disease. The absence of a vaccine for protection and the availability of artemisinin and its derivatives as the only option has made the situation rather serious. With the availability of increased support for malaria research, a variety of drug targets and candidate molecules are now available for further development. However, the success rate of a candidate molecule to become a drug is very low and it does become necessary to start with a large basket, identified on a rational basis. This review focuses on the present efforts to identify a variety of drug targets in the malaria parasite and to develop candidate drug molecules

Dexamethasone negatively regulates phenobarbitone-activated transcription but synergistically enhances cytoplasmic levels of cytochrome P-450b/e messenger RNA

Dexamethasone has a potentiating effect on phenobarbitone mediated induction of cytochrome P-450b + e mRNAs in adult rat liver. However, the glucocorticoid inhibits phenobarbitone-activated transcription of cytochrome P-450b + e mRNAs by 60-70s. This inhibitory effect is evident in run-off transcription of the endogenous genes as well as in the transcription of an added cloned gene fragment. Dexamethasone inhibits the phenobarbitone-mediated increase in the binding of a transcription factor(s) to the upstream region of the gene as evidenced by gel retardation and Southwestern blot analysis. The glucocorticoid does not stabilize the phenobarbitone-induced polyribosomal cytochrome P-450b + e mRNAs but appears to stabilize the nuclear transcripts. It is proposed that a negative element may mediate the action of dexamethasone at the level of nuclear transcription and stabilization of the nuclear transcript may account for the potentiating effect of the glucocorticoid on phenobarbitone-mediated increase in cytochrome P-450b + e mRNAs in the cytoplasm of the adult rat liver. However, the cytochrome P-450b protein levels are slightly lower in phenobarbitone+dexamethasone treatment than in phenobarbitone-treated liver microsomes

Artemisinin-based combination with curcumin adds a new dimension to malaria therapy

Malaria afflicts 300 million people worldwide, with over a million deaths every year. With no immediate prospect of a vaccine against the disease, drugs are the only choice to treat it. Unfortunately, the parasite has become resistant to most antimalarials, restricting the option to use artemisinins (ARTs) for effective cure. With the use of ARTs as the front-line antimalarials, reports are already available on the possible resistance development to these drugs as well. Therefore, it has become necessary to use ART-based combination therapies to delay emergence of resistance. It is also necessary to discover new pharmacophores to eventually replace ART. Studies in our laboratory have shown that curcumin not only synergizes with ART as an antimalarial to kill the parasite, but is also uniquely able to prime the immune system to protect against parasite recrudescence in the animal model. The results indicate a potential for the use of ART- curcumin combination against recrudescence/relapse in falciparum and vivax malaria. In addition, studies have also suggested the use of curcumin as an adjunct therapy against cerebral malaria. In this review we have attempted to highlight these aspects as well as the studies directed to discover new pharmacophores as potential replacements for ART

The role of mechanical environment in regulating vascular network formation

Introduction: The integration of engineered tissues after implantation is limited due to the lack of a vascular network. When vascular networks are included, they generally are not organized, or lose their initial organization fast1. Due to the ability of cells to sense their environment by mechanotransduction, signaling, maturation, organization and cell survival is regulated. The objective of this study is to analyze the combinatory effect of substrate stiffness and fluid flow on vascular organization and maturation to find the basic parameters for pre-vascularization of engineered tissue. Methods A microfluidic PDMS framed system was used, which makes it possible to investigate different hydrogel compositions in parallel. Pre-glycation by D-(-)-Ribose allowed for the use of one type of hydrogel in the same concentration but with different modulated mechanical properties. During the polymerization process of the hydrogels, needles were integrated into the gels to create hollow channels by their removing afterwards. The down and top side of the system were sealed with thin cover glasses to ensure the visibility of the inner system. The fluid-flow channels were coated with 0.1% Gelatin to improve the cell attachment and seeded with Smooth muscle cells. Afterwards Human Umbilical Vein Endothelial Cells (HUVECs) were seeded on top of the smooth muscle cells to mimic the physiological blood vessel structure. An additional channel was filled with VEGF (50 ng/mL), which is known as one of the main angiogenic factors which diffuse into the hydrogel over time2. Different fluid-flow profiles were applied to the cell seeded channels. The newly formed capillary network was analyzed by ImageJ. Results: The pre-glycation by incubation of different concentrations of D-(-)-Ribose resulted in an increase of stiffness of the same type of hydrogel by additionally crosslinking of the different hydrogels components. The use of different modulated hydrogels allowed for the simultaneous analysis of the effect of fluid flow on the vascular sprouting into the hydrogels triggered by the diffused VEGF. Different mechanical properties in combination with different fluid flow patterns affected the ability of HUVEC to migrate and organize into the hydrogels and show differences in the sprouting morphology. Outlook: To mimic the physiological state, different Endothelial cell types (e.g. HUVECs, HMECs, HIAEC) will be integrated into the fluid flow channels. This will allow us to see if different endothelial cell origins leads to a different sprouting behavior or if the already described endothelial plasticity leads to similar results

A State-of-the-Art review on the drive of renewables in Gujarat, State of India: Present situation, barriers and future initiatives

Given the recent increasing public focus on climate change issues, the share of electricity generation by renewable energy resources is increasing day by day. Increased renewables share will give us robust, sustainable, and climate-friendly energy systems for the future. Renewable energy penetration with the current power systems needs substantial research, planning and development which are now the primary focus throughout the world. In this study, a global renewable energy scenario is explained in detail in contrast with India, considering a case study elucidating the comprehensive review of the Gujarat state in India. The primary focus is on Gujarat state’s actions plans to pertain to harvest renewable energy and maximizing its share in the energy mix. This study examines the actions and the policies adopted by the Gujarat government to overcome the potential barriers in order to support non-conventional as well as renewable energy development. It also investigates the numerous techno-economic and social constraints with possible solutions in promoting the deployment of upcoming renewable energy resources across Gujarat. This study can be used as a guideline for the government, policymakers, utilities, stakeholders and researchers to promote an increased renewable energy share in Gujarat as well as at other places around the globe

Examination of the Mechanical, Corrosion, and Tribological Behavior of Friction Stir Welded Aluminum Alloy AA8011

Aluminum alloy AA8011 is emerging as a promising material for modern engineering applications in which improved tensile strength, hardness, corrosion-resistance, and wear-resistance of materials are required. Typically, AA8011 alloys are utilized in air-conditioning ducts and heat exchanger fins in ships, leisure boats, luxury vessels, workboats, fishing vessels, and patrol boats. However, the conventional welding of AA8011 is a challenging procedure. In this context, this paper focuses on the development of an effective solid-state welding methodology for AA8011 alloy welding. The AA8011 alloy was friction stir welded by varying the tool rotation speed, traverse speed, and shoulder diameter. The microhardness, tensile strength, joint efficiency, elongation, corrosion rate, and wear rate of the friction stir welded specimens were compared with the base material. Fractography analysis was conducted after the tensile test and surface morphology analysis after corrosion and wear tests, using scanning electron microscopy. The compositional elements in the corroded and worn section of the specimens were analyzed using energy-dispersive X-ray spectroscopy. Based on the joint efficiency as a primary constraint, the optimum process parameters for friction stir welding of aluminum alloy AA8011 have been established as follows: tool rotation speed of 1200 rpm, tool traverse speed of 45 mm/min, and tool shoulder diameter of 21 mm

Maximum power point tracking implementation by Dspace controller integrated through Z-Source inverter using particle swarm optimization technique for photovoltaic applications

Maximum Power Point Tracking (MPPT) technique is used to extract maximum power from the photovoltaic system. This paper involves working on an enhanced Particle Swarm Optimization (PSO) based MPPT method for the photovoltaic (PV) system integrated through Z-Source inverter. The main benefit of the proposed method is the diminishing of the steady-state oscillation when the maximum power point (MPP) is located. Additionally, during an extreme environmental condition, such as partial shading and large fluctuations of irradiance and temperature, the proposed method has the capability to track the MPP. This algorithm is implemented in dspace 1104 controller. MATLAB simulations are carried out under varying irradiance and temperature conditions to evaluate its effectiveness. Its performance is compared with a conventional method like Perturb and observe (P&O) method

Validity of the diagnosis of pneumonia in hospitalised patients with COPD.

Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) and pneumonia are two of the most common reasons for acute hospital admissions. Acute exacerbations and pneumonia present with similar symptoms in COPD patients, representing a diagnostic challenge with a significant impact on patient outcomes. The objectives of this study were to compare the prevalence of radiographic consolidation with the discharge diagnoses of hospitalised COPD patients. Methods: COPD patients admitted to three UK hospitals over a 3-year period were identified. Participants were included if they were admitted with an acute respiratory illness, COPD was confirmed by spirometry and a chest radiograph was performed within 24 h of admission. Pneumonia was defined as consolidation on chest radiograph reviewed by two independent observers. Results: There were 941 admissions in 621 patients included in the final analysis. In 235 admissions, consolidation was present on chest radiography and there were 706 admissions without consolidation. Of the 235 admissions with consolidation, only 42.9% had a discharge diagnosis of pneumonia; 90.7% of patients without consolidation had a discharge diagnosis of COPD exacerbation. The presence of consolidation was associated with increased rate of high-dependency care admission, increased mortality and prolonged length of stay. Inhaled corticosteroid use was associated with recurrent pneumonia. Conclusions: Pneumonia is underdiagnosed in patients with COPD. Radiographic consolidation is associated with worse outcomes and prolonged length of stay. Incorrect diagnosis could result in inappropriate use of inhaled corticosteroids. Future guidelines should specifically address the diagnosis and management of pneumonia in COPD