Zirconium Metal−Organic Polyhedra with Dual Behavior for Organophosphate Poisoning Treatment

Organophosphate nerve agents and pesticides are extremely toxic compounds because they result in acetylcholinesterase (AChE) inhibition and concomitant nerve system damage. Herein, we report the synthesis, structural characterization, and proof-of-concept utility of zirconium metal−organic polyhedra (Zr-MOPs) for organophosphate poisoning treatment. The results show the formation of robust tetrahedral cages [((n-butylCpZr)3(OH)3O)4L6]Cl6 (Zr-MOP-1; L = benzene-1,4- dicarboxylate, n-butylCp = n-butylcyclopentadienyl, Zr-MOP-10, and L = 4,4′-biphenyldicarboxylate) decorated with lipophilic alkyl residues and possessing accessible cavities of ∼9.8 and ∼10.7 Å inner diameters, respectively. These systems are able to both capture the organophosphate model compound diisopropylfluorophosphate (DIFP) and host and release the AChE reactivator drug pralidoxime (2-PAM). The resulting 2-PAM@ Zr-MOP-1(0) host−guest assemblies feature a sustained delivery of 2-PAM under simulated biological conditions, with a concomitant reactivation of DIFP-inhibited AChE. Finally, 2-PAM@Zr-MOP systems have been incorporated into biocompatible phosphatidylcholine liposomes with the resulting assemblies being non-neurotoxic, as proven using neuroblastoma cell viability assays.Spanish MCIN/AEI PID2020-113608RB-I00FEDER/Junta de Andalucia-Conserjeria de Economia y Conocimiento B-FQM-364-UGR18 B-FQM-006-UGR18FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades P18-RT-612 P20_00672Fondazione CRUIprograma Juan de la Cierva FormacionSpanish Government PID2020-118117RB-I00Center for Forestry Research & Experimentation (CIEF)European Commission SEJIGENT/2021/059 PROMETEU/2021/054La Caixa Foundation 100010434 LCF/BQ/PR20/11770014"Maria de Maeztu" Program for Centers of Excellence in RD CEX2019-000919-MH2020-MSCA-IF2019-888972-PSust-MO

A phase I trial of oncolytic adenovirus ICOVIR-5 administered intravenously to cutaneous and uveal melanoma patients

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 1013 viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer

Assessment of stress and nutritional biomarkers in cultured Octopus vulgaris paralarvae: Effects of geographical origin and dietary regime

The common octopus (Octopus vulgaris) is a promising species for aquaculture diversification, but massive mortality during the first life-cycle stages (paralarvae) is the main bottleneck for its commercial production in captivity. The aim of this study was to assess stress and nutritional condition biomarkers (HSP70, ROS enzymes and lipid peroxidation) (RNA/DNA, RNA/protein, protein/DNA and protein) inO.vulgarisparalarvae from different geographical origins and fed withArtemiaenriched with marine phospholipids or microalgae (control group). To this end paralarvae were cultured for 30days, in three different centres in Spain (Tarragona-Mediterranean area, Tenerife-Central Atlantic area and Vigo-North Atlantic area), under the same protocol, and fed onArtemiaenriched with marine phospholipids (LC60) (Marine Lecithin LC 60®, PhosphoTech Laboratoires) or microalgae (control group). Dry weight and most biomarkers analysed in hatchlings showed significant differences related to their origin (centre). Fifteen day old paralarvae presented significant differences in specific growth rate (SGR) associated with their dietary regime, and also showed differences in biomarkers associated both with their geographical origin and dietary regime. The results suggest that the SGR of paralarvae were positively influenced by LC60, promoting growth and in agreement with the results of nutritional condition biomarkers (nucleic acids ratios). The antioxidant defences against oxidative damage were also boosted in the LC60 paralarvae group, possibly as a result of the elevated content in highly polyunsaturated fatty acids. In addition, the partial correlations found between biomarkers varied according to diet. However, no positive effect of LC60 on survival was observed. The high variability found among geographical origins, despite the use of the same rearing protocol, highlights the need to clarify the sources of such variability

A view of the Brazil-Malvinas confluence, March 2015

The encountering of the subtropical Brazil Current (BC) and the subantarctic Malvinas Current (MC) along the western margin of the Argentine Basin forms the Brazil-Malvinas Confluence (BMC), one of the most intense open-ocean fronts in the world ocean and a site for the formation of intermediate water masses. Here, we provide a comprehensive description of the BMC based on physical and biogeochemical data – hydrographic stations, profiling floats and subsurface drifters – gathered in March 2015. We use these data in order to characterize the impinging and outflowing currents and to describe the cross- and along-frontal thermohaline structure. In addition, we compare the in-situ measurements with both climatological data and the Mercator Ocean eddy-resolving reanalysis. The hydrographic sections illustrate the contrasting properties between the two western boundary currents: warm, salty, nutrient- and oxygen-poor oligotrophic subtropical waters carried southward by the BC and the cold, fresh, oxygen- and nutrient-rich subantarctic waters carried northward by the MC. The frontal system is also characterized by the presence of thermohaline intrusions, with the cross-frontal gradients and along-front velocities sharpening as the colliding currents shape the frontal system. We also observe brackish waters spreading on top of the frontal jet as a result of both the confluence dynamics and off-shelf advection favored by north-easterly winds. These low-salinity waters are positively correlated with surface ageostrophic speeds over the frontal jet. The cruise data illustrates the high regional and mesoscale variability as compared with climatological conditions, and further document the submesoscale subsurface complexity, which is not properly captured by available operational models.Fil: Orúe Echevarría, Dorleta. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Pelegrí, Josep L.. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Alonso González, Iván J.. Oceomic, Marine Bio And Technology S.L; EspañaFil: Benítez Barrios, Verónica M.. Oceomic, Marine Bio And Technology S.L; EspañaFil: Emelianov, Mikhail. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: García Olivares, Antonio. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Gasser i Rubinat, Marc. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: De La Fuente, Patricia. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Herrero, Carmen. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Isern Fontanet, Jordi. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Masdeu Navarro, Marta. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Peña Izquierdo, Jesús. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Piola, Alberto Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; ArgentinaFil: Ramírez Garrido, Sergio. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Rosell Fieschi, Miquel. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Salvador, Joaquín. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Saraceno, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; Argentina. Universidad de Barcelona; EspañaFil: Valla, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ciencias de la Atmósfera y los Océanos; ArgentinaFil: Vallès Casanova, Ignasi. Consejo Superior de Investigaciones Científicas. Instituto de Ciencias del Mar; EspañaFil: Vidal, Montserrat. Universidad de Barcelona; Españ

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects

Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence

Marijuana consumption during adolescence has been proposed to be a stepping stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self administration (1 mg/kg), food reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F] fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP treated rats showed a higher rate of cocaine self administration as compared to vehicle treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food reinforced operant task, pointing to the cocaine specific nature of the effect seen in self administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP treated females when compared to their vehicle treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self administration, in a sex specific fashion. This increased susceptibility could be related to thechanges in brain metabolic activity induced by cannabinoids during adolescenceThis work was supported by Grants FIS G03/05 (Red de Trastornos Adictivos), BSO2001-1099, FIS 01-05-01, Plan Nacional sobre Drogas (PNSD) 2001–2003, PNSD 2004–2007, GR-SAL/0260/2004 to EA and Grants INT/2012/ 2002, CB06/01/0079, and CENIT (2006–2009) to MDPublicad

Measurement of σ(Λb)/σ(B0)×BR(Λb→Λcπ−)/BR(B0→D+π−)\sigma(\Lambda_b)/\sigma(B^0) \times BR(\Lambda_b\to\Lambda_c\pi^-) / BR(B^0\to D^+\pi^-) in ppˉp\bar{p} Collisions at s=1.96\sqrt{s}=1.96 TeV

We present the first observation of the baryon decay $\Lambda_b\to\Lambda_c\pi^-$ followed by $\Lambda_c\to p K^-\pi^+$ in 106 pb-1 of $p\bar{p}$ collisions at $\sqrt{s} = 1.96$ TeV in the CDF experiment. In order to reduce systematic error, the measured rate for $\Lambda_b$ decay is normalized to the kinematically similar meson decay $B^0\to D^+\pi^-$ followed by $D^+\to\pi^+K^-\pi^+$. We report the ratio of production cross sections ($\sigma$) times the ratio of branching fractions (BR) for the momentum region integrated above $p_T > 6$ GeV/c and pseudorapidity range $|\eta| < 1.3$: $\sigma(p\bar{p}\to \Lambda_b X) / \sigma (p\bar{p}\to B^0 X) \times BR(\Lambda_b\to\Lambda_c\pi^-) / BR(B^0\to D^+\pi^-) = 0.82 \pm 0.08(stat) \pm 0.11(syst) \pm 0.22 (BR(\Lambda_c\to p K^-\pi^+))$.Comment: Submitted to Phys.Rev.Let

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

Background: Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90-90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods: A scoping review was done following Arksey & O'Malley's methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results: Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions: This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied

Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma

<p>Abstract</p> <p>Background</p> <p>Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene <it>PON1</it>, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous <it>PON1 </it>polymorphisms and the risk of developing astrocytoma and meningioma.</p> <p>Methods</p> <p>Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous <it>PON1 </it>genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain.</p> <p>Results</p> <p>The frequencies of the <it>PON1 </it>genotypes and allelic variants of the polymorphisms <it>PON1 </it>L55M and <it>PON1 </it>Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: <it>PON1 </it>55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; <it>PON1 </it>192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the <it>p </it>values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma.</p> <p>Conclusions</p> <p>Common nonsynonymous <it>PON1 </it>polymorphisms are not related with the risk of developing astrocytoma and meningioma.</p