Can breathing gases be analyzed without a mouth mask? Proof-of-concept and concurrent validity of a newly developed design with a mask-less headset:Proof-of-concept and concurrent validity of a newly developed design with a mask-less headset

A portable headset has been developed to analyze breathing gases and establish the energetic workload of physically active workers. This proof-of-concept study aimed to investigate the following: (1) the validity of the headset compared to indirect calorimetry using a mouth mask; (2) the validity of the headset compared to the validity of oxygen consumption (V̇O2) estimated on the basis of heart rate; (3) the influence of wind on validity; and (4) user experiences of the headset. Fifteen subjects performed a submaximal cycling test twice, once with the headset, and once with a mouth mask and heartrate monitor. Concurrent validity of the headset was analyzed using an intraclass correlation coefficient (ICC). Across all phases, a good correlation between the headset and mouth mask was observed for V̇O2, carbon dioxide production (V̇CO2) and exhaled volume (V̇E) (ICC≥0.72). The headset tended to underestimate V̇O2, V̇CO2 and V̇E at low intensities and to overestimate it at higher intensities. The headset was more valid for estimating V̇O2 (ICC = 0.39) than estimates based on heart rate (ICC = 0.11) (n = 7). Wind flow caused an overestimation (md ≥ 18.4 ± 16.9%) and lowered the correlation of V̇O2 between the headset and the mouth mask to a moderate level (ICC = 0.48). The subjects preferred the headset over the mouth mask because it was more comfortable, did not hinder communication and had lower breathing resistance. The headset appears to be useable for monitoring development of the energetic workloads of physically active workers, being more valid than heart rate monitoring and more practical than indirect calorimetry with a mouth mask. Proof-of-concept was confirmed. Another design step and further validation studies are needed before implementation in the workplace

Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle

AbstractPKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Gö-6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Gö-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Gö-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD

New Insights into the Structure of (1→3,1→6)-β-D-Glucan Side Chains in the Candida glabrata Cell Wall

β-glucan is a (1→3)-β-linked glucose polymer with (1→6)-β-linked side chains and a major component of fungal cell walls. β-glucans provide structural integrity to the fungal cell wall. The nature of the (1–6)-β-linked side chain structure of fungal (1→3,1→6)-β-D-glucans has been very difficult to elucidate. Herein, we report the first detailed structural characterization of the (1→6)-β-linked side chains of Candida glabrata using high-field NMR. The (1→6)-β-linked side chains have an average length of 4 to 5 repeat units spaced every 21 repeat units along the (1→3)-linked polymer backbone. Computer modeling suggests that the side chains have a bent curve structure that allows for a flexible interconnection with parallel (1→3)-β-D-glucan polymers, and/or as a point of attachment for proteins. Based on these observations we propose new approaches to how (1→6)-β-linked side chains interconnect with neighboring glucan polymers in a manner that maximizes fungal cell wall strength, while also allowing for flexibility, or plasticity

Four Design Criteria for Any Future Contractarian Theory of Business Ethics

This article assesses the quality of Integrative Social Contracts Theory (ISCT) as a social contract argument. For this purpose, it embarks on a comparative analysis of the use of the social contract model as a theory of political authority and as a theory of social justice. Building on this comparison, it then develops four criteria for any future contractarian theory of business ethics (CBE). To apply the social contract model properly to the domain of business ethics, it should be: (1) self-disciplined, i.e., not aspire results beyond what the contract model can realistically establish; (2) argumentative, i.e., it should seek to provide principles that are demonstrative results of the contractarian method; (3) task-directed, i.e., it should be clear what the social contract thought-experiment is intended to model; and (4) domain-specific, i.e., the contractarian choice situation should be tailored to the defining problems of business ethics

Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels

The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer's disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.Fil: Navas Guimaraes, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Lopez Blanco, Roi. Universidad de Santiago de Compostela; EspañaFil: Correa, Juan. Universidad de Santiago de Compostela; EspañaFil: Fernandez Villamarin, Marcos. Universidad de Santiago de Compostela; EspañaFil: Bistue Millon, Maria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Kumar, Vijay. University of Colorado; Estados UnidosFil: Wempe, Michael F.. University of Colorado; Estados UnidosFil: Cuello, A. C.. McGill University; CanadáFil: Fernandez Megia, Eduardo. Universidad de Santiago de Compostela; EspañaFil: Bruno, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentin

Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.Peer reviewe

Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms

Recent studies have revealed an important role for LTBP-4 in elastogenesis. Its mutational inactivation in humans causes autosomal recessive cutis laxa type 1C (ARCL1C), which is a severe disorder caused by defects of the elastic fiber network. Although the human gene involved in ARCL1C has been discovered based on similar elastic fiber abnormalities exhibited by mice lacking the short Ltbp-4 isoform (Ltbp4S(-/-)), the murine phenotype does not replicate ARCL1C. We therefore inactivated both Ltbp-4 isoforms in the mouse germline to model ARCL1C. Comparative analysis of Ltbp4S(-/-) and Ltbp4-null (Ltbp4(-/-)) mice identified Ltbp-4L as an important factor for elastogenesis and postnatal survival, and showed that it has distinct tissue expression patterns and specific molecular functions. We identified fibulin-4 as a previously unknown interaction partner of both Ltbp-4 isoforms and demonstrated that at least Ltbp-4L expression is essential for incorporation of fibulin-4 into the extracellular matrix (ECM). Overall, our results contribute to the current understanding of elastogenesis and provide an animal model of ARCL1C.Peer reviewe

Discovery and characterization of small molecules that target the Ral GTPase

The Ras-like GTPases RalA and B are important drivers of tumor growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here, we used protein structure analysis and virtual screening to identify drug-like molecules that bind a site on the GDP-form of Ral. Compounds RBC6, RBC8 and RBC10 inhibited Ral binding to its effector RalBP1, Ral-mediated cell spreading in murine fibroblasts and anchorage-independent growth of human cancer cell lines. Binding of RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasma resonance and 15N-HSQC NMR. RBC8 and BQU57 show selectivity for Ral relative to Ras or Rho and inhibit xenograft tumor growth similar to depletion of Ral by siRNA. Our results show the utility of structure-based discovery for development of therapeutics for Ral-dependent cancers