Progenius

Hydrocephalus is a clinical manifestation of cerebrospinal fluid (CSF) accumulation, leading to ventriculomegaly and increased intracranial pressure. Diuretics and other pharmacotherapies have failed to treat hydrocephalus in the human population; therefore, treatment options remain exclusively surgical. The need to develop pharmacotherapies for the treatment of hydrocephalus remains an unmet clinical need and paramount to this need is the study of brain fluid regulation. Previous studies in our laboratory identified the transient receptor potential vanilloid 4 (TRPV4) channel as a potential regulatory hub protein in the choroid plexus responsible, in part, for the regulation of CSF production. Antagonists of the TRPV4 channel were shown to ameliorate hydrocephalus in a genetic rat model. The current studies highlight a novel drug target: serum‐ and glucocorticoid‐induced kinase 1 (SGK1) in the choroid plexus. A specific small molecular weight, membrane permeant inhibitor of SGK1, SI113, has shown promising results in cancer and metabolic research in recent years. In other tissues, SGK1 has been shown to phosphorylate and activate TRPV4 at the membrane, indicating SGK1 as an important upstream regulatory kinase. SI113 blocked TRPV4‐mediated transepithelial ion flux and barrier conductance increases in a cell culture model of human choroid plexus epithelia (HIBCPP line), and ameliorated ventriculomegaly in the genetic rat model. In hydrocephalic animals, there is an increased apical membrane signal in the choroid plexus epithelial cells via immunofluorescent localization of p‐SGK1 and TRPV4, but not of pan‐SGK1. This is not accompanied by a significant increase in either protein or transcript abundance as measured by western blotting or qPCR, respectively. The change in localization is, however, attenuated by treatment with SI113. Animals treated with SI113 show no change in amounts of TRPV4 or total SGK1, but do show significantly reduced levels of p‐SGK1. Thus, phosphorylation of SGK1 appears to be crucial for the activation of TRPV4 which is, in turn, a channel protein that is activated during the development of hydrocephalus. Like Trpv4‐/‐mice, Sgk1‐/‐mice do not show overt phenotypes, indicating pharmacological antagonism of the kinase would have minimal off‐target effects. Overall, these data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.

Cerebrospinal fluid (CSF) secretion into the brain ventricular system is an active process via the choroid plexus (CP) - a specialized convoluted epithelial sheet surrounding a fenestrated capillary bed which is fed from the cerebral arterioles. The final CSF composition differs from a simple plasma filtrate implicating the CP as an important regulatory site controlling CSF composition and volume. Flux across this blood-CSF barrier is tightly controlled by ion and water transport proteins. Transient Receptor Potential Vanilloid 4 (TRPV4) is a polymodal, non-selective cation channel which functions as a regulatory hub protein in epithelia, including the CP. Our previous studies have shown that TRPV4-selective antagonists were effective at reducing ventriculomegaly in a genetic rat model of severe postnatal hydrocephalus. In CP, we found that activation of TRPV4 caused the influx of both Ca2+ and Na+ ions, and entry of both of these ions was selectively blocked by a TRPV4 antagonist. Systemic treatment with TRPV4 antagonists reduced TRPV4 mRNA expression in the CP in hydrocephalic rats, but not in normal rats, indicating a role for TRPV4 as part of a regulatory pathway in CSF production. To study the mechanism of CSF secretion by the CP, we utilized two continuous, high resistance CP cell lines: the porcine choroid plexus – Reims (PCP-R) and the human choroid plexus papilloma (HIBCPP) cells. The current experiments utilize Ussing chamber electrophysiological techniques, western blotting, qRT-PCR, and fluorescent immunolabeling. Immunolabeling and mRNA expression demonstrate a robust abundance for TRPV4 and other well-characterized CP membrane proteins in both cell lines. In both lines, TRPV4 activation stimulates a large change in short circuit current (ISC), a measure of net electrogenic ion flux. This change in ISCis coupled with a substantial change in transepithelial membrane conductance, a measure of cellular permeability. The transepithelial membrane transport changes due to TRPV4 activation in human and porcine cells are similar in overall effect, but differ in baseline, duration, and magnitude, indicating species-specific CP transport mechanisms. In both cases, these responses can be inhibited by either pre- or post-incubation with TRPV4 antagonists, substantiating the specificity to TRPV4 activation. The human cells, but not the porcine cells, demonstrate a substantial baseline transepithelial transport which is dependent on K+, Na+, and Cl- gradients. Furthermore, in both the porcine and human cells, the TRPV4 response is dependent upon K+ secretion, Cl- absorption, and Na+ secretion. These data confirm a role for TRPV4 in regulating ionic gradients, modulating both electrogenic and electroneutral transporters, and controlling CSF production. The promising results of these studies, coupled with published data from other investigators suggesting a role for TRPV4 in blood-brain-barrier permeability and astrocyte volume regulation, shows the importance of TRPV4 as a regulatory hub protein in brain fluid volume regulation.

Now-a-days, sustainability of power quality is a major concern. Speed control of an AC motor is required for several industrial applications, but is often difficult to achieve as the AC motor runs at fixed speed. Hence, power electronic devices are introduced in the system. Due to the development in power electronic devices with improved dependability and cheaper cost, results in the growth of modern variable frequency drive (VFD) which can control the speed of an induction motor by adjusting the frequency of the machine [8]. They produce harmonic components and distort the supply mains, which in turn adversely affect the power quality. To outlive the difficulty, a technique named multi-pulse rectifier is developed. The main objective of this work is to reduce the impact of harmonic distortion using variable frequency drives (VFDs). Modeling, simulation and performance analysis of VFD is done based on Total harmonic distortion (THD) [8]. The proposed topology deals with the THD comparison for 6, 12 and 24 pulses. All the simulations are carried out in MATLAB/Simulink.

Mainly in more electric aircraft (MEA) electric power capacity is increasing rapidly. And so due to the advent of electric power system (EPS) all pneumatic, hydraulics & bleed engines are removed. Hence the consumption of fuel is reduced. Disturbances caused by various components in electrical system can inject harmonics into the system and thereby Transformer Rectifier Unit (TRU) is used for harmonic mitigation and to improve the power quality of the system. So TRU is used in MEA for the conversion of AC electrical power to DC electrical power. The phase-shifting transformers are designed to obtain the necessary phase displacement. In this paper the analysis of multi-pulse rectifier, their THD comparison on MATLAB and hardware is presented and further, the simulation of TRU with an inverter is also shown for different topologies like 6, 12 and 24 pulses.