The Natriuretic Peptide Uroguanylin Elicits Physiologic Actions Through 2 Distinct Topoisomers

The peptide uroguanylin regulates electrolyte transport in the intestine and kidney. Human uroguanylin has two conformations that can be stably isolated, owing to their slow interconversion rate. The A isomer potently activates the guanylate cyclase-C receptor found primarily in the intestine. The B isomer, by contrast, is a very weak agonist of this receptor, leading to a widely-held assumption that it is physiologically irrelevant. We show here, however, that human uroguanylin B has potent natriuretic activity in the kidney. Interestingly, uroguanylin A and B both induce saliuretic responses, but the activity profiles for the two peptides differ markedly. The uroguanylin B dose-response curve is sigmoidal with a threshold dose near 10 nmol/kg body weight, whereas uroguanylin A has a comparable threshold, but a bell-shaped dose-response curve. Additionally, our study indicates a unique interplay between the A and B isoforms, such that the A form at high concentrations antagonizes the natriuretic action of the B form. These data show that the kidney contains a uroguanylin receptor whose pharmacological profile does not match that of the well-defined intestinal uroguanylin receptor (guanylate cyclase-C), an observation consistent with previous studies showing that the kidney of the guanylate cyclase-C knockout mouse remains responsive to uroguanylin. The results presented here also support the unconventional notion that distinct conformations of a single endocrine peptide can elicit different responses in different tissues

Biodegradable PEG–dendritic block copolymers: synthesis and biofunctionality assessment as vectors of siRNA

One important drawback of most of the currently used dendrimers for biomedical applications is their high stability under physiological conditions that can result in cytotoxicity or complications induced by the accumulation of non-degradable synthetic materials in the organism. Particularly in the gene therapy field, vector stability can further hinder the intracellular release of the nucleic acid from the dendriplex, consequently leading to low transfection efficiencies. Therefore, biodegradable cationic dendritic structures have been eagerly awaited. However, the development of these dendritic nanocarriers is challenging because of the undesired and/or premature degradation observed during their synthesis and/or application. Here, we report new hybrid-biodegradable, biocompatible, non-toxic, and water-soluble azide-terminated PEG–GATGE dendritic block copolymers, based on a gallic acid (GA) core and triethylene glycol (TG) butanoate arms, incorporating ester bonds (E) at the dendritic arms/shell. Their successful functionalization by “click” chemistry with unprotected alkynated amines allowed complexation and delivery of siRNA. The hydrophobic character of the GATGE building unit confers to these hydrolyzable dendritic bionanomaterials a great ability to complex, protect and mediate the cellular internalization of siRNA. Moreover, the localization of the degradation points at the dendritic periphery, close to the complexed siRNA, was found to be important for nucleic acid release from the nanoparticles, rendering a significant improvement of the transfection efficiency compared to their hydrolytically stable PEG–GATG copolymer counterparts. The present study puts forward these biodegradable PEG–dendritic block copolymers not only as suitable vectors for nucleic acids, but also as new avenues for further developments exploring their use in theranosticsThe authors would like to acknowledge the FEDER funds through the Programa Operacional Factores de Competitividade – COMPETE and the Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia (PTDC/CTM-NAN/112428/2009 and PTDC/CTM-NAN/3547/2014) that supported this work and the FCT / MEC through National Funds and, when applicable, co-financed by the FEDER via the PT2020 Partnership Agreement under the 4293 Unit I&D. V. Leiro acknowledges the support by FCT (SFRH/BPD/69110/2010) and by the project NORTE-01-0145-FEDER-000012, financed by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). P.M.D. Moreno acknowledges the support from the Marie Curie Actions of the European Community’s Seventh Framework Program (PIEF-GA-2011-300485) and FCT fellowship (SFRH/BPD/108738/2015). This work was also financially supported by the Spanish Government (MINECO: CTQ2012-34790, CTQ2012-33436) and the Xunta de Galicia (CN2011/037)S

A system study on the switchgear plant operations of Total PowerBox Solutions, Inc.

Total Power Box Solutions, Inc. is a sector that provides solutions and products, innovation and high-end engineering services to the communication and energy industry. Total Power Box Solutions, Inc. offers customers a wide range of best value high quality electrical products, such as panelboards and switchgears, at a competitive cost with shorter delivery lead times, efficient technical support and services by closely working with them from the design stage to project completion. For the year 2018, switchgear products generated the greatest number of sales as opposed to panelboards that is why this study would only tackle to plant operations of the nine types of switchgears which begins with receiving of orders up until product delivery and warehousing. A SWOT analysis was done after documentation of the switchgear plant operations to determine any problems within the company. A WOT-SUG analysis was then performed to rank the issues and concerns found. The highest ranked problem that was found is that the finished goods inventory level per month exceeds the monthly allotted by I 14.64% for the months of July to November 2018, incurring an additional cost of Php64,391,539.60 for the year. To further analyze the problem, a why-why analysis was done in order to identify the root causes of the problem. The initial why-why was validated and further reconstructed to form the final why-why diagram or the final analysis of the system. The root causes identified were the use of FIFO as production schedule, and workers unaware whose task it is to talk to clients. Alternative solutions were then generated and a KTDA approach was used to identify which solutions should be selected. The selected solutions are the use of E-Kanban TKS and the use of MRP system such as SAP Business One. E-Kanban IKS would be the solution implemented for the root cause workers unaware whose task it is to talk to clients. The purpose of this is that it gives an automated email to respective departments as well as the client regarding the talus of the switchgear once the e-Kanban card is scanned by the supervisor of that specific process. To implement this solution, an orientation will be given to teach the employee how to make use of the system. The department heads will be the ones in charge of canning the e-kanban cards and the production team will be the ones to input the job orders into the system. The Use of MRP system such as SAP Business One would be implemented to solve the root cause use of FIFO as a production schedule. The purpose of using this system is to eliminate or minimize the products from being made too early. To implement this solution, an orientation will first be given to the production team because they will be in charge of the actual usage of SAP Business One. The production team will be the one to input into the system the job order of the client and the software will generate the bill of materials, master production schedule and the inventory records. These proposed solutions would result in a 95% reduction of the cost incurred due to high finished goods inventory. This would save the company a total amount of Php122,343,925.23 annually. Based on the cost-benefit analysis done the payback period of the proposed system would be 0.004 years or 1.46 days