Trending Advancements in Technologies Pertinent to Therapeutical Pharmacodynamics

It is omniscient that pharmacodynamics of a drug is understood as its effect on body by interacting with the structure of targets to either activate or inhibit their function/action. Based on the activity of the drug to the target binding site they have been classified into different types. Physiological, cellular, molecular, biochemical, and toxicological effects individually have a significant role in drug’s effect and response. The mechanism of action, dosage and its response, therapeutic index are some of the noteworthy parameters to be considered in drug pharmacodynamics. This chapter comprehends the above-mentioned concepts, their importance in pharmacodynamics of drug, and the impact of recently developed methods like genome-wide or transcriptome-wide sequencing, chronopharmacodynamics, systems biology, pharmacometabolomics, etc., in different stages of drug discovery process, and how the digitization of therapeutics and healthcare direct the path to personalized medicine. The integration of bioinformatics, systems biology, and big data related approaches like ML & AI with the pharmacological (PK/PD) study highly benefits the patients’ therapeutics

Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a ‘fat-burning’ phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders

Review on Various Types of Geopolymer Materials with the Environmental Impact Assessment

The development of green technology in the construction industry since 10 years ago is something to be proud of Malaysia. Several alternative geopolymer materials were invented in Malaysia such as fly ash, POFA, kaolin, metakaolin, and dolomite based geopolymer materials to achieve sustainable development especially in the building and construction sector. Those alternative materials are very important to replace the application of OPC, which is said to be the main cause of global warming. A review on the content of the chemical differences with the environmental impact resulting from the production of geopolymer is carried out in this study. In conclusion, fly ash based geopolymer material showed the best performance in terms of aluminosilicate content and also it is the best practice in the environmental protection applications for the moment. However, when compared with the OPC, fly ash geopolymer concrete was still able to reduce the effects of global warming potentials, but it is rather gave a negative impact on some aspects of the environment such as abiotic depletions, human toxicity, freshwater ecotoxicity, terrestrial ecotoxicity and acidification

Integrated Proteomics Unveils Nuclear PDE3A2 as a Regulator of Cardiac Myocyte Hypertrophy

Background: Signaling by cAMP is organized in multiple distinct subcellular nanodomains regulated by cAMP-hydrolyzing PDEs (phosphodiesterases). Cardiac β-adrenergic signaling has served as the prototypical system to elucidate cAMP compartmentalization. Although studies in cardiac myocytes have provided an understanding of the location and properties of a handful of cAMP subcellular compartments, an overall view of the cellular landscape of cAMP nanodomains is missing. Methods: Here, we combined an integrated phosphoproteomics approach that takes advantage of the unique role that individual PDEs play in the control of local cAMP, with network analysis to identify previously unrecognized cAMP nanodomains associated with β-adrenergic stimulation. We then validated the composition and function of one of these nanodomains using biochemical, pharmacological, and genetic approaches and cardiac myocytes from both rodents and humans. Results: We demonstrate the validity of the integrated phosphoproteomic strategy to pinpoint the location and provide critical cues to determine the function of previously unknown cAMP nanodomains. We characterize in detail one such compartment and demonstrate that the PDE3A2 isoform operates in a nuclear nanodomain that involves SMAD4 (SMAD family member 4) and HDAC-1 (histone deacetylase 1). Inhibition of PDE3 results in increased HDAC-1 phosphorylation, leading to inhibition of its deacetylase activity, derepression of gene transcription, and cardiac myocyte hypertrophic growth. Conclusions: We developed a strategy for detailed mapping of subcellular PDE-specific cAMP nanodomains. Our findings reveal a mechanism that explains the negative long-term clinical outcome observed in patients with heart failure treated with PDE3 inhibitors

Lifespan extension in a semelparous chordate occurs via developmental growth arrest just prior to meiotic entry

It is proposed that the ageing process is linked to signaling from the germline such that the rate of ageing can be adjusted to the state of the reproductive system, allowing these two processes to co-evolve. Mechanistic insight into this link has been primarily derived from iteroparous reproductive models, the nematode C. elegans, and the arthropod Drosophila. Here, we examined to what extent these mechanisms are evolutionarily conserved in a semelparous chordate, Oikopleura dioica, where we identify a developmental growth arrest (GA) in response to crowded, diet-restricted conditions, which can extend its lifespan at least three-fold. Under nutritional stress, the iteroparative models sacrifice germ cells that have entered meiosis, while maintaining a reduced pool of active germline stem cells (GSCs). In contrast, O. dioica only entered GA prior to meiotic entry. Stress conditions encountered after this point led to maturation in a normal time frame but with reduced reproductive output. During GA, TOR signaling was inhibited, whereas MAPK, ERK1/2 and p38 pathways were activated, and under such conditions, activation of these pathways was shown to be critical for survival. Direct inhibition of TOR signaling alone was sufficient to prevent meiotic entry and germline differentiation. This inhibition activated the p38 pathway, but did not activate the ERK1/2 pathway. Thus, the link between reproductive status and lifespan extension in response to nutrientlimited conditions is interpreted in a significantly different manner in these iteroparative versus semelparous models. In the latter case, meiotic entry is a definitive signal that lifespan extension can no longer occur, whereas in the former, meiotic entry is not a unique chronological event, and can be largely erased during lifespan extension in response to nutrient stress, and reactivated from a pool of maintained GSCs when conditions improve

Lifespan extension in a semelparous chordate Oikopleura dioica via developmental growth arrest : Roles of Target of Rapamycin (TOR) signaling and D type cyclins

All living organisms experience ageing during the course of their lifespan. The science of ageing has emerged into an enthralling area of research. Our knowledge of the mechanisms of ageing and reproduction has been mainly derived from iteroparous model organisms such as C. elegans and D. melanogaster. The mechanisms governing lifespan are linked to signaling from the reproductive tissues. In this study, we examined to what extent these mechanisms are evolutionarily conserved in a semelparous model organism 0ikopleura dioica. This marine chordate is a dioecious species that belongs to the sister group of vertebrates. Rapid growth occurs by increasing the size of somatic endocycling cells. The pre-meiotic gonad consists of mitotic germline nuclei which proliferate asynchronously in a common cytoplasm (syncytium). We identify a reversible developmental growth arrest (GA) in 0. dioica in response to high-density, nutrient-limited conditions, which extends its lifespan up to three-fold. Iteroparous models, sacrifice germ cells that have already entered meiosis, and maintain a reduced number of active germline stem cells (GSCs) under starvation. In contrast, the post-meiotic germline of 0. dioica does not maintain GSCs and GA only occurs prior to meiotic entry. Nutrient limitation encountered after the meiotic entry led to production of reduced numbers of progeny. During GA, nutrient-dependent Target of Rapamycin (TOR) signaling activity was reduced whereas MAPK stress signaling ERK1/2 and p38 and their common downstream effector MSK1 pathways were activated. Chemical inhibition of TOR signaling alone was sufficient to prevent meiotic entry and germline differentiation. Under GA conditions, both ERK1/2 and p38 pathways were activated and shown to be critical for survival. However, chemical inhibition of TOR signaling only activated p38-MSK1, but not the ERK1/2 pathway. TOR signaling differentially regulated mitotic and endocycling cell cycles during GA. Somatic endocycles immediately ceased upon entry into GA, whereas mitotic germline nuclei and intestinal cells gradually arrested over time. This was mirrored on release from GA, mitotic germline cell cycle resumed first, followed by mitotic intestinal cell cycles, and finally, somatic endocycles. Unlike C. elegans and Drosophila GSCs, 0. dioica germline nuclei have a distinct G1 phase and D-type cyclins play a major role in cell cycle regulation. TOR signaling differentially regulated endocycling and mitotic germ nuclei by altering the expression of D-type cyclins, E2Fs and Cyclin-dependent Kinase Inhibitor a (CKIa). Under GA/TOR inhibition, levels of Cyclin Dd and E2F1 were reduced immediately in arrested endocycling cells, whereas they declined more gradually in proliferating germ nuclei. Simultaneously, increased expression of negative cell cycle regulators, CKIa and E2F7, was observed during somatic endocycling cell arrest. CKIa-mediated cell cycle arrest in proliferating germline nuclei was delayed through cytoplasmic sequestration of CKIa by increased levels of the Cyclin Dbf3 splice variant (lacking phosphodegron and Retinoblastoma-binding motifs) in the syncytial cytoplasm. Overall in this investigation, we interpret that the single event of meiotic entry is a definitive signal that lifespan extension can no longer occur in 0. dioica. Moreover, we demonstrated that TOR signaling integrates environmental cues such as nutrient limitation, to differentially regulate cell cycle variants and promote lifespan extension, in response to adverse environmental conditions

Experimental investigations of vibration and acoustics signals in milling process using kapok oil as cutting fluid

Vegetable oils are found as the feasible alternative for conventional minerals oils. There has been many environmental and health issues which are spotted with the use of conventional cutting fluids. There has been a great demand for developing new environmentally friendly vegetable based cutting fluids to reduce these harmful effects. In this present study, vegetable based kapok oil is used as a cutting fluid during milling to study its consequences over other conventional oils. The process parameters such as spindle speed, depth of cut and feed rate were optimized with respect to the flank wear (Vb) and surface roughness (Ra) respectively with the use of central composite design in response surface methodology (RSM). Further an attempt has been made to monitor the tool condition by measuring the cutting force, vibration and sound pressure simultaneously. Three different tool conditions such as dull, fresh and working were analyzed and their consequences were also reported. Also, the performance of the kapok oil is compared with the palm oil and mineral oil (SAE 20W 40). The feed rate has the major contribution for surface roughness and flank wear. It is found that the cutting force (F), sound pressure (p) and vibration (V) increases with the tool wear

A Chaotic Search-Based Hybrid Optimization Technique for Automatic Load Frequency Control of a Renewable Energy Integrated Power System

In this work, a chaotic search-based hybrid Sperm Swarm Optimized-Gravitational Search Algorithm (CSSO-GSA) is proposed for automatic load frequency control (ALFC) of a hybrid power system (HPS). The HPS model is developed using multiple power sources (thermal, bio-fuel, and renewable energy (RE)) that generate power to balance the system’s demand. To regulate the frequency of the system, the control parameters of the proportional-integral-derivative (PID) controller for ALFC are obtained by minimizing the integral time absolute error of HPS. The effectiveness of the proposed technique is verified with various combinations of power sources (all sources, thermal with bio-fuel, and thermal with RE) connected into the system. Further, the robustness of the proposed technique is investigated by performing a sensitivity analysis considering load variation and weather intermittency of RE sources in real-time. However, the type of RE source does not have any severe impact on the controller but the uncertainties present in RE power generation required a robust controller. In addition, the effectiveness of the proposed technique is validated with comparative and stability analysis. The results show that the proposed CSSO-GSA strategy outperforms the SSO, GSA, and hybrid SSO-GSA methods in terms of steady-state and transient performance indices. According to the results of frequency control optimization, the main performance indices such as settling time (ST) and integral time absolute error (ITAE) are significantly improved by 60.204% and 40.055% in area 1 and 57.856% and 39.820% in area 2, respectively, with the proposed CSSO-GSA control strategy compared to other existing control methods

Evaluation of a new single parameter for characterising the compressional properties of weft-knitted fabrics

242-247An attempt has been made to formulate a new single parameter of compression (Compression Value) using the least squares method. Computation of the new measure is done by means of an analysis of the Kawabata pressure-thickness curve. A ‘C’ program has been formulated for the purpose. The new single parameter is validated by correlating it with the percentage compression results to establish that it is a simple, reliable, sensitive and more consistent method for characterization of the compressional properties of weft-knitted fabrics. The compressional properties of weft-knitted fabrics have also been studied

Growth arrest in <i>Oikopleura dioica</i>.

<p>A) At standard densities <i>O. dioica</i> completes its life cycle in 6 days at which point it spawns and dies. At higher culture densities <i>O. dioica</i> undergoes growth arrest (GA) and the animal can exhibit a 3-fold increase in lifespan, albeit, with increasing mortality up to day 18. B) At high culture densities GA animals undergo very limited increase in body length compared to control animals at standard culture densities (significant differences: *p<0.05, **p<0.01). The morphology of surviving GA animals throughout the 18–day period remained similar to that of day 3 animals cultured under standard conditions. Error bars indicate standard errors in A and B. C) A rapid post-day 3 reduction in IdU incorporation (S phase marker) was observed in somatic endocycling cells in animals cultured under dense conditions. IdU incorporation persisted longer in mitotically proliferating germ nuclei in these same animals but eventually diminished as growth arrest persisted (D3 <i>d</i> = day 3 dense etc.). Scale bars = 50 μm.</p