Signaling through the leukocyte integrin LFA-1 in T cells induces a transient activation of Rac-1 that is regulated by Vav and PI3K/Akt-1

12 p.-8 fig.Integrin LFA-1 is a receptor that is able to transmit multiple intracellular signals in leukocytes. Herein we show that LFA-1 induces a potent and transient increase in the activity of the small GTPase Rac-1 in T cells. Maximal Rac-1 activity peaked 10-15 min after LFA-1 stimulation and rapidly declined to basal levels at longer times. We have identified Vav, a guanine nucleotide exchange factor for Rac-1, and PI3K/Akt, as regulators of the activation and inactivation phases of the activity of Rac-1, respectively, in the context of LFA-1 signaling based on the following experimental evidence: (i) LFA-1 induced activation of Vav and PI3K/Akt with kinetics consistent with a regulatory role for these molecules on Rac-1, (ii) overexpression of a constitutively active Vav mutant induces activation of Rac independently of LFA-1 stimulation whereas overexpression of a dominant-negative Vav mutant blocks LFA-1-mediated Rac activation, (iii) pharmacological inhibition of PI3K/Akt prevented the fall in the activity of Rac-1 after its initial activation but had no effect on Vav activity, and (iv) overexpression of a dominant-negative or a constitutively active Akt-1 induced or inhibited, respectively, Rac-1 activity. Finally, we show that T cells with a sustained Rac activity have impaired capacity to elongate onto ICAM-1. These results demonstrate that down-regulation of the activity of this GTPase is a requirement for the regulation of T cell morphology and motility and highlight the importance of temporal regulation of the signaling triggered from this integrin.This work was supported in part by Grants CICYT SAF 2001–2807 from Ministerio de Ciencia y Tecnología and FIS-01/1367 from Ministerio de Sanidad y Consumo (to C. C.), a fellowship from Comunidad de Madrid (to L. S.-M.), a Formación de Profesorado Universitario predoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to N. S.-S.), and a postdoctoral fellowship from Ministerio de Educación, Cultura y Deporte (to M. D. G.-L.).Peer reviewe

Combinations of First Responder and Drone Delivery to Achieve 5-Minute AED Deployment in OHCA.

BACKGROUND: Defibrillation in the critical first minutes of out-of-hospital cardiac arrest (OHCA) can significantly improve survival. However, timely access to automated external defibrillators (AEDs) remains a barrier. OBJECTIVES: The authors estimated the impact of a statewide program for drone-delivered AEDs in North Carolina integrated into emergency medical service and first responder (FR) response for OHCA. METHODS: Using Cardiac Arrest Registry to Enhance Survival registry data, we included 28,292 OHCA patients ≥18 years of age between 1 January 2013 and 31 December 2019 in 48 North Carolina counties. We estimated the improvement in response times (time from 9-1-1 call to AED arrival) achieved by 2 sequential interventions: 1) AEDs for all FRs; and 2) optimized placement of drones to maximize 5-minute AED arrival within each county. Interventions were evaluated with logistic regression models to estimate changes in initial shockable rhythm and survival. RESULTS: Historical county-level median response times were 8.0 minutes (IQR: 7.0-9.0 minutes) with 16.5% of OHCAs having AED arrival times of <5 minutes (IQR: 11.2%-24.3%). Providing all FRs with AEDs improved median response to 7.0 minutes (IQR: 6.2-7.8 minutes) and increased OHCAs with <5-minute AED arrival to 22.3% (IQR: 16.4%-30.9%). Further incorporating optimized drone networks (326 drones across all 48 counties) improved median response to 4.8 minutes (IQR: 4.3-5.2 minutes) and OHCAs with <5-minute AED arrival to 56.3% (IQR: 46.9%-64.2%). Survival rates were estimated to increase by 34% for witnessed OHCAs with estimated drone arrival <5 minutes and ahead of FR and emergency medical service. CONCLUSIONS: Deployment of AEDs by FRs and optimized drone delivery can improve AED arrival times which may lead to improved clinical outcomes. Implementation studies are needed

Solubility of the metal precursor Ni(NO3)2⋅6H2O in high-pressure CO2 + ethanol mixtures

The solubility of Ni(NO3)2⋅6H2O in high-pressure CO2 + ethanol mixtures was measured using a high-pressure variable-volume view cell from (308.2 to 353.2 K) and up to 25.0 MPa. This compound has been used previously as a Ni precursor in metal deposition experiments using supercritical CO2. Ni(NO3)2•6H2O was not soluble in pure CO2 but the addition of ethanol into the system allowed the solubilisation of the hydrated salt in the mixture. Mole fraction of Ni(NO3)2•6H2O varied from 1.67 10-4 to 1.97 10-3. At these salt concentrations, the phase diagram of the CO2 + EtOH + Ni(NO3)2⋅6H2O system resembled that of the CO2 + EtOH binary system and, at the studied conditions, a vapourliquid equilibrium was observed. For the higher ethanol concentrations, the bubble points closely matched those of the CO2 + EtOH system. For the lower EtOH concentrations, however, much higher solubilisation pressures were required, due to the release of water molecules from the salt into the solution. Ni(NO3)2⋅6H2O solutions were stable in highpressure CO2 + EtOH mixtures at the studied conditions

No. 8 - The Cuban Embargo: Policy Outlook after 50 Years

Organized and sponsored by the Dean Rusk Center for International Law and Policy, The Cuban Embargo: Policy Outlook after 50 Years was a daylong conference exploring issues related to the impact of trade sanctions imposed by the United States on Cuba, pathways to lifting the embargo and potential U.S.-Cuba trade opportunities. Ambassador José R, Cabañas, the chief of mission at the Cuban Interests Section in Washinton, D.C., served as the keynote speaker for the event. The transcript of the conference proceedings has been edited for publication with the consent of the speakers

Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis

Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 94), MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N = 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: ≥ 2.9;P ≤ .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFC-based automated risk classification ready for implementation in clinical practice

Lo glocal y el turismo. Nuevos paradigmas de interpretación.

El estudio del turismo se realiza desde múltiples escalas y enfoques, este libro aborda muchos temas que es necesario discutir desde diversas perspectivas; es el caso de la reflexión sobre la propia disciplina y sus conceptos, así como los asuntos específicos referidos al impacto territorial, los tipos de turismo, las cuestiones ambientales, el tema de la pobreza, la competitividad, las políticas públicas, el papel de las universidades, las áreas naturales protegidas, la sustentabilidad, la cultura, el desarrollo, la seguridad, todos temas centrales documentados y expuestos con originalidad y dominio del asunto. Lo multiescalar es básico para la comprensión del sistema turístico, sistema formado de procesos globales, regionales y locales. El eje de discusión del libro es lo glocal, esa interacción entre lo nacional y local con lo global

Keynote Address

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Keynote Address

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Pharmaceutical co-crystals of the anti-inflammatory drug diflunisal and nicotinamide obtained using supercritical CO2 as an antisolvent

A method based on using supercritical CO2 as an antisolvent (SAS method) is explored as a co-crystallization technique. Co-crystallization is an emerging and powerful technique to improve the physicochemical properties of an active pharmaceutical ingredient. The solid-state and solution co-crystallization methods usually employed present several disadvantages. The one-step SAS method has a low environmental impact and overcomes some of the difficulties associated to conventional methods. The 2:1 co-crystals of the anti-inflammatory drug diflunisal (DIF) and nicotinamide (NIC) are prepared for the first time by SAS. Drug concentrations corresponding to the co-crystal stoichiometric composition are used. The influence of the SAS parameters temperature (35 and 40 °C), pressure (10.0 and 12.0 MPa), drug concentration (two levels) and solvent (acetone and ethanol) in the co-crystal formation is studied. A crystalline material in the form of needles of uniform width and more variable length is obtained. For comparison purposes, pure DIF and NIC are also processed by SAS. Co-crystals are characterized in terms of crystallinity, thermal behavior, coformer interactions and drug release; their dissolution rate improves with respect to that of pure DIF. SAS co-crystals exhibit the same crystal structure, melting point and FTIR spectrum as those previously obtained by liquid assisted ball mill grinding and solution crystallization