Implementation of an End-to-End Standards-based Patient Monitoring Solution

A proof-of-concept design of a patient monitoring solution for intensive care unit environments has been presented. It is end-to-end standard-based, using ISO/IEEE 11073 (X73) in the bedside environment and EN13606 to communicate the information to an electronic healthcare record (EHR) server. At the bedside end, the system is a plug-and-play sensor network communicating with a gateway that collects medical information and sends the data to a monitoring server. The monitoring server transforms this information into an EN13606 extract to be stored on the EHR server. The system has been implemented to comply with the last X73 and EN13606 available versions and tested in a laboratory environment to demonstrate the feasibility of an end-to-end standard-based solution

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

info:eu-repo/semantics/acceptedVersion

Highly substituted benzene derivatives have been easily prepared in a regioselective way from readily available 1,3-hexadien-5-ynes through a gold(I)-catalyzed tandem reaction. The process involves an initial cyclization followed by a selective Wagner-Meerwein shift in which the migration preference seems to be determined by the ability to stabilize a positive chargeMinisterio de Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-15358 and CTQ2009-09949/BQU) and Junta de Castilla y Leon (BU021A09 and GR-172) for financial suport. A.M. S. thanks Junta de Castilla y Leon for a predoctoral fellowship. P.G.-G. and M.A.F.-R. thank MICINN for "Juan de la Cierva" and "Ramon y Cajal" contractsMinisterio de Ciencia e Innovacion (MICINN) and FEDER (CTQ2010-15358 and CTQ2009-09949/BQU) and Junta de Castilla y Leon (BU021A09 and GR-172) for financial suport. A.M. S. thanks Junta de Castilla y Leon for a predoctoral fellowship. P.G.-G. and M.A.F.-R. thank MICINN for "Juan de la Cierva" and "Ramon y Cajal" contractsThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic letters, copyright © American Chemical Society after peer review and technical editing by the publisher

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: <i>N</i>‑[3-[(Benzimidazol-2-yl)amino]propyl]amides

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kg⁻¹, respectively. The results presented encourage further investigations to identify the target of these highly active compounds

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (<i>Pf</i>), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (<b>1</b>), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of <b>1</b> led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue <b>44</b> displayed potent in vitro activity (IC₅₀ = 10 nM) and oral activity in a SCID mouse model of <i>Pf</i> infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kg⁻¹, respectively. The results presented encourage further investigations to identify the target of these highly active compounds

Case Study of Small Molecules As Antimalarials: 2‑Amino-1-phenylethanol (APE) Derivatives

Antiparasitic oral drugs have been associated to lipophilic molecules due to their intrinsic permeability. However, these kind of molecules are associated to numerous adverse effects, which have been extensively studied. Within the Tres Cantos Antimalarial Set (TCAMS) we have identified two small, soluble and simple hits that even presenting antiplasmodial activities in the range of 0.4–0.5 μM are able to show in vivo activity