On Model-Based Systems Engineering for Design, Management, and Governance of Protective Systems

PresentationProtective systems failure can be catastrophic, and originates in management failure. These systems rely on a document-based approach, which involves handling disjointed artifacts that are expensive to maintain and may become inconsistent and obsolete. We propose a framework for managing process safety that pioneers the modeling of protective systems according to the tenors of model-based systems engineering (MBSE). The framework embeds management and governance, and harmonizes regulations and inconsistent industry guidelines. Potential users include enterprises and regulators in the chemical process safety industry and the energy sector. The framework starts the development of more sophisticated standards to prevent catastrophic protective systems failures

Effect of a gum-based thickener on the safety of swallowing in patients with poststroke oropharyngeal dysphagia

Altres ajuts: This work has been supported by Danone Nutricia Research, Fundació Salut del Consorci Sanitari del Maresme, Furega (Fundació per a la Recerca en Gastroenterologia) and Centro de Investigación en Red en Enfermedades Hepáticas y Digestivas (CIBERehd).Background: Increasing viscosity with thickening agents is a valid therapeutic strategy for oropharyngeal dysphagia (OD). To assess the therapeutic effect of a xanthan gum-based thickener (Nutilis Clear) at six viscosities compared with thin liquid in poststroke OD (PSOD) patients. Methods: A total of 120 patients with PSOD were studied in this controlled, multiple-dose, fixed-order, and single-blind study using videofluoroscopy (VFSS). A series of boluses of 10 mL thin liquid and 2000, 1400, 800, 450, 250, and 150 mPa s viscosities were given in duplicate, interrupted in case of aspiration. We assessed the safety and efficacy of swallow and the kinematics of the swallow response. Key Results: A total of 41.2% patients had safe swallow at thin liquid which significantly increased for all viscosities from 71.9% at 150 mPa s to 95.6% at 1400 mPa s (P <.001). PAS score (3.7 ± 2.3) at thin liquid was also reduced by increasing bolus viscosity (P <.001). The prevalence of patients with aspiration at thin liquid was 17.5% and decreased at all viscosities (P <.01), except at 150 mPa s. Increasing viscosity shortened time to laryngeal vestibule closure (LVC) at all viscosities (P <.01) and reduced bolus velocity at ≥450 mPa s (P <.05). The prevalence of patients with pharyngeal residue at each viscosity 37.7%-44.7% was similar to that at thin liquid (41.2%). Conclusions and Inferences: The prevalence of unsafe swallow with thin liquids is very high in PSOD. Increasing shear bolus viscosity with this xanthan gum-based thickener significantly increased the safety of swallow in patients with PSOD in a viscosity-dependent manner without increasing the prevalence of pharyngeal residue

Human ClCa1 modulates anionic conduction of calcium-dependent chloride currents

Proteins of the CLCA gene family including the human ClCa1 (hClCa1) have been suggested to constitute a new family of chloride channels mediating Ca2+-dependent Cl− currents. The present study examines the relationship between the hClCa1 protein and Ca2+-dependent Cl− currents using heterologous expression of hClCa1 in HEK293 and NCIH522 cell lines and whole cell recordings. By contrast to previous reports claiming the absence of Cl− currents in HEK293 cells, we find that HEK293 and NCIH522 cell lines express constitutive Ca2+-dependent Cl− currents and show that hClCa1 increases the amplitude of Ca2+-dependent Cl− currents in those cells. We further show that hClCa1 does not modify the permeability sequence but increases the Cl− conductance while decreasing the GSCN−/GCl− conductance ratio from ∼2–3 to ∼1. We use an Eyring rate theory (two barriers, one site channel) model and show that the effect of hClCa1 on the anionic channel can be simulated by its action on lowering the first and the second energy barriers. We conclude that hClCa1 does not form Ca2+-dependent Cl− channels per se or enhance the trafficking/insertion of constitutive channels in the HEK293 and NCIH522 expression systems. Rather, hClCa1 elevates the single channel conductance of endogenous Ca2+-dependent Cl− channels by lowering the energy barriers for ion translocation through the pore

Single-cell RNA sequencing of liver fine-needle aspirates captures immune diversity in the blood and liver in chronic hepatitis B patients

Background and Aims: HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing. Approach and Results: We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S3 picowell-based and the 10× Chromium reverse-emulsion droplet–based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences. Conclusions: The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.</p

PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion in the huntingtin (htt) gene. We found that peroxisome proliferator-activated receptor delta (PPARδ) interacts with htt and that mutant htt represses PPARδ-mediated transactivation. Increased PPARδ transactivation ameliorated mitochondrial dysfunction and improved cell survival of HD neurons. Expression of dominant-negative PPARδ in CNS was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities, and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPARδ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR δ, using the agonist KD3010, improved motor function, reduced neurodegeneration, and increased survival. PPAR δ activation also reduced htt-induced neurotoxicity in vitro and in medium spiny-like neurons generated from human HD stem cells, indicating that PPAR δ activation may be beneficial in individuals with HD and related disorders

Planck pre-launch status : The Planck mission

Peer reviewe

7th Drug hypersensitivity meeting: part two

No abstract availabl

Análisis Económico de Tecnologías de Producción de Granos Básicos en Michoacán

Si bien es cierto que el TLC para América del Norte y el Neoliberalismo Social brindan oportunidades, cuando de alimentos se trata, es necesario considerar otros factores de política agropecuaria como la soberanía alimentaria y la generación de empleos para el medio rural, ya que está en juego la recuperación económica nacional.El análisis realizado por la SARH y el Colegio de Postgraduados (1992), indicaba que Michoacán no competía en la producción de granos a excepción del Bajío michoacano, donde se pueden obtener 6 toneladas en maíz y 8 toneladas en sorgo y trigo; pero ¿cuál es la alternativa para las más de 400 mil hectáreas que se siembran de maíz, trigo y sorgo en las zonas temporaleras del estado?Si actualizamos el estudio bajo las condiciones establecidas hoy (tipo de cambio, precios internacionales y escasez del granos) los resultados indican que no hay pérdidas financieras con la producción de maíz, trigo y sorgo, y sí generación de valor agregado por el uso de la mano de obra, aun en las tecnologías no competitivas; además evita la salida de divisas.En este trabajo se analizan 34 tecnologías de producción de maíz, trigo y sorgo (16 recomendadas por INIFAP y 18 aplicadas por productores) para las regiones de la Meseta Purépecha, Bajío y Oriente del estado por medio de la Matriz de Análisis de Política (MAP) (Monke A.E. and Pearson, S.R. 1989) a precios de mercado, para los ciclos de primavera-verano de 1995 y otoño-invierno de 1995-96, con la cual se obtienen indicadores como: costo, ingreso, ganancia, relación beneficio-costo, estructura del ingreso (consumo y valor agregado), empleo de mano de obra, horas máquina, consumo de combustible y la estructura del costo de producción (insumos comercializables y factores internos) con los cuales se formó una base de datos o matrices de coeficientes técnicos, de maquinaria y equipo de bombeo, matriz de precios de mercado de los insumos utilizados y matriz de presupuesto privado, analizando varios escenarios: con renta de la tierra y sin renta, con maquinaria propia y rentada, con tasa de interés cero, normal y sin seguro agrícola.Se presentan los principales indicadores financieros para el escenario más común en zonas productoras del estado: maquinaria rentada, con tierra propia y tasa de interés normal (40.75% para 1995).En el presente trabajo se clasifican los costos de producción en: insumos comerciables (fertilizantes, herbicidas, fungicidas, insecticidas, semilla y diesel); servicios contratados (labores mecanizadas principalmente); factores internos (labores manuales, labores mecanizadas, crédito, seguro, pago del agua, electricidad y renta de la tierra) e insumos indirectamente comerciables (tractor e implementos, equipo de bombeo y servicios)

Acute and subacute effects of oropharyngeal sensory stimulation with TRPV1 agonists in older patients with oropharyngeal dysphagia: a biomechanical and neurophysiological randomized pilot study

Background: Older people with oropharyngeal dysphagia (OD) present a decline in pharyngeal sensory function. The aim of this proof-of-concept study was to assess the biomechanical and neurophysiological effects of acute and subacute oropharyngeal sensory stimulation with transient receptor potential vanilloid 1 (TRPV1) agonists (capsaicinoids) in older patients with OD. Methods: We studied the effect of a single dose versus multiple doses (2 weeks) of oral capsaicin treatment (10 –5 M) or placebo in 28 older patients with OD (81.2 ± 4.6 years) using videofluoroscopy (penetration-aspiration scale [PAS], timing of swallow response) and electroencephalography (EEG) (latency and amplitude of pharyngeal event-related potential [ERP]). Results: Acute stimulation by capsaicinoids 10 –5 M did not improve swallow function and did not produce significant changes in pharyngeal ERP. In contrast, after 10 days of treatment, patients presented a clinically relevant and statistically significant reduction in the laryngeal vestibule closure (LVC) time (22.5%, p = 0.042), and in the PAS (24.2%, p = 0.038), compared with the placebo group. EEG results showed a reduction in the latency of the N1 peak (28.6%, p = 0.007) and an increase of the amplitude of the P1-N2 (59.4%, p = 0.038) and the N2-P2 (43.6%, p = 0.050) peaks. We observed a strong and significant correlation between the reduction in the latency of the N1 peak and change in LVC time after subacute treatment ( r = 0.750, p = 0.003). Conclusions: After 2 weeks of treatment, oropharyngeal sensory stimulation with capsaicinoids induced cortical changes that were correlated with improvements in swallowing biomechanics in older patients with OD. These results further show that sensory stimulation by TRPV1 agonists can become a useful pharmacological treatment for older patients with OD