Ebastine in the light of CONGA recommendations for the development of third-generation antihistamines

In 2003 a consensus group on new-generation antihistamines (CONGA) defined the characteristics required for a third-generation H1 antihistamine as there had been much controversy about this issue since the early 1990s. One of the antihistamines that had been claimed to belong to such a group is the second-generation antihistamine, ebastine. The objective of this review is to analyze the pharmacology of ebastine, in light of the CONGA recommendations for the development of new-generation antihistamines: (1) anti-inflammatory properties, (2) potency, efficacy and effectiveness, (3) lack of cardiotoxicity, (4) lack of drug interactions, (5) lack of CNS effects, and (6) pharmacological approach. Ebastine seems to have anti-inflammatory properties that help to ameliorate nasal congestion, though this has not yet been conclusively demonstrated. Its pharmacological–therapeutic profile does not differ greatly from that of other second-generation antihistamines. Its cardiac safety has been widely assessed and no cardiac toxicity has been found at therapeutic doses despite initial concerns. The risk of potentially relevant drug interactions has been investigated and ruled out. Ebastine does not produce sedation at therapeutic doses and drug interaction studies with classical CNS depressants have not demonstrated a synergistic effect. Pharmacologically, ebastine is an H1 inverse agonist. Perhaps the answer to the quest for new-generation antihistamines lies not only in H1 but in a combined approach with other histamine receptors

On the benefits of tasking with OpenMP

Tasking promises a model to program parallel applications that provides intuitive semantics. In the case of tasks with dependences, it also promises better load balancing by removing global synchronizations (barriers), and potential for improved locality. Still, the adoption of tasking in production HPC codes has been slow. Despite OpenMP supporting tasks, most codes rely on worksharing-loop constructs alongside MPI primitives. This paper provides insights on the benefits of tasking over the worksharing-loop model by reporting on the experience of taskifying an adaptive mesh refinement proxy application: miniAMR. The performance evaluation shows the taskified implementation being 15–30% faster than the loop-parallel one for certain thread counts across four systems, three architectures and four compilers thanks to better load balancing and system utilization. Dynamic scheduling of loops narrows the gap but still falls short of tasking due to serial sections between loops. Locality improvements are incidental due to the lack of locality-aware scheduling. Overall, the introduction of asynchrony with tasking lives up to its promises, provided that programmers parallelize beyond individual loops and across application phases.Peer ReviewedPostprint (author's final draft

Extreme Floods in Small Mediterranean Catchments: Long-Term Response to Climate Variability and Change

Climate change implies changes in the frequency and magnitude of flood events. The influence of climate variability on flooding was evaluated by an analysis of sedimentary (palaeofloods) and documentary archives. A 500-year palaeoflood record at Montilea River (657 km(2) in catchment area), eastern Spain, revealed up to 31 palaeofloods with a range of discharges of 20-950 m(3) s(-1), and with at least five floods exceeding 740-950 m(3) s(-1). This information contrasts with the available gauged flood registers (since year 1971) with an annual maximum daily discharge of 129 m(3) s(-1). Our palaeoflood dataset indicates flood cluster episodes at (1) 1570-1620, (2) 1775-1795, (3) 1850-1890, and (4) 1920-1969. Flood rich periods 1 and 3 corresponded to cooler than usual (about 0.3 degrees C and 0.2 degrees C) climate oscillations, whereas 2 and 4 were characterised by higher inter-annual climatic variability (floods and droughts). This high inter-annual rainfall variability increased over the last 150 years, leading to a reduction of annual maximum flow. Flood quantiles (>50 years) calculated from palaeoflood+gauged data showed 30%-40% higher peak discharges than those using only instrumental records, whereas when increasing the catchment area (1500 km(2)) the discharge estimation variance decreased to-15%. The results reflect the higher sensitivity of small catchments to changes on flood magnitude and frequency due to climate variability whereas a larger catchment buffers the response due to the limited extent of convective storms. Our findings show that extended flood records provide robust knowledge about hazardous flooding that can assist in the prioritization of low-regret actions for flood-risk adaptation to climate change

Unexplored olive cultivars from the Valencian Community (Spain): some chemical characteristics as a valorization strategy

[EN] The olive processing industry has till date been dominated by a small group of cultivars, leading to the possibility of some olive cultivars becoming extinct in the near future. In this study, we determined the composition of some chemical components in the olive oils from 31 minor olive cultivars of the Valencian Community. Our main aim was to identify suitable cultivars, which could produce differentiated olive oils, thus aiming towards their valorization. The average oil content of minor olive cultivars was found to be good, with some of them reporting approximately 60% (dry basis). On average, the total phenolic content was 229mg kg(-1), with cv. Mas Blanc reporting the highest content (570mg kg(-1)). Among the various tocopherols found in olives, -tocopherol was the main constituent, with a maximum concentration of 290.6mg kg(-1). Linoleic acid was the main polyunsaturated fatty acid and varied between 3.4% (cv. Del Pomet) and 16.9% (cv. Blanqueta Enguera). Special attention needs to be paid to the composition of sterols, since some olive oils exceeded the limits established for some sterols by the current European legislation. Some of the cultivars studied were highly productive, and originated differentiated olive oils with a rich composition of antioxidants and essential fatty acids. In some cases, these beneficial compounds were higher than those of commercial oils obtained from the most common cultivars worldwide. These results could contribute to the commercial exploitation of some of the studied cultivars.Salazar-García, DC.; Malheiro, R.; Pereira, JA.; López- Cortés, I. (2019). Unexplored olive cultivars from the Valencian Community (Spain): some chemical characteristics as a valorization strategy. 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Host Alternation Is Necessary to Maintain the Genome Stability of Rift Valley Fever Virus

Arthropod-borne viruses are transmitted among vertebrate hosts by insect vectors. Unusually, Rift Valley fever virus (RVFV) can also be transmitted by direct contacts of animals/humans with infectious tissues. What are the molecular mechanisms and evolutionary events leading to adopt one mode of transmission rather than the other? Viral replication is implied to be different in a vertebrate host and an invertebrate host. The alternating host cycle tends to limit virus evolution by adopting a compromise fitness level for replication in both hosts. To test this hypothesis, we used a cell culture model system to study the evolution of RVFV. We found that freeing RVFV from alternating replication in mammalian and mosquito cells led to large deletions in the NSs gene carrying the virulence factor. Resulting NSs-truncated viruses were able to protect mice from a challenge with a virulent RVFV. Thus, in nature, virulence is likely maintained by continuous alternating passages between vertebrates and insects. Thereby, depending on the mode of transmission adopted, the evolution of RVFV will be of major importance to predict the outcome of outbreaks

Genetic and Anatomic Determinants of Enzootic Venezuelan Equine Encephalitis Virus Infection of Culex (Melanoconion) taeniopus

Venezuelan equine encephalitis (VEE) is a re-emerging, mosquito-borne viral disease with the potential to cause fatal encephalitis in both humans and equids. Recently, detection of endemic VEE caused by enzootic strains has escalated in Mexico, Peru, Bolivia, Colombia and Ecuador, emphasizing the importance of understanding the enzootic transmission cycle of the etiologic agent, VEE virus (VEEV). The majority of work examining the viral determinants of vector infection has been performed in the epizootic mosquito vector, Aedes (Ochlerotatus) taeniorhynchus. Based on the fundamental differences between the epizootic and enzootic cycles, we hypothesized that the virus-vector interaction of the enzootic cycle is fundamentally different from that of the epizootic model. We therefore examined the determinants for VEEV IE infection in the enzootic vector, Culex (Melanoconion) taeniopus, and determined the number and susceptibility of midgut epithelial cells initially infected and their distribution compared to the epizootic virus-vector interaction. Using chimeric viruses, we demonstrated that the determinants of infection for the enzootic vector are different than those observed for the epizootic vector. Similarly, we showed that, unlike A. taeniorhynchus infection with subtype IC VEEV, C. taeniopus does not have a limited subpopulation of midgut cells susceptible to subtype IE VEEV. These findings support the hypothesis that the enzootic VEEV relationship with C. taeniopus differs from the epizootic virus-vector interaction in that the determinants appear to be found in both the nonstructural and structural regions, and initial midgut infection is not limited to a small population of susceptible cells

Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection

Burden of pneumonia caused by Streptococcus pneumoniae remains high despite the availability of conjugate vaccines. Mucosal immunization targeting the lungs is an attractive alternative for the induction of local immune responses to improve protection against pneumonia. Our group had previously described the development of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) polymeric nanoparticles (NPs) adsorbed with Pneumococcal surface protein A from clade 4 (PspA4Pro) within L-leucine microcarriers (nanocomposite microparticles-NCMPs) for mucosal delivery targeting the lungs (NP/NCMP PspA4Pro). NP/NCMP PspA4Pro was now used for immunization of mice. Inoculation of this formulation induced anti-PspA4Pro IgG antibodies in serum and lungs. Analysis of binding of serum IgG to intact bacteria showed efficient binding to bacteria expressing PspA from clades 3, 4 and 5 (family 2), but no binding to bacteria expressing PspA from clades 1 and 2 (family 1) was observed. Both mucosal immunization with NP/NCMP PspA4Pro and subcutaneous injection of the protein elicited partial protection against intranasal lethal pneumococcal challenge with a serotype 3 strain expressing PspA from clade 5 (PspA5). Although similar survival levels were observed for mucosal immunization with NP/NCMP PspA4Pro and subcutaneous immunization with purified protein, NP/NCMP PspA4Pro induced earlier control of the infection. Conversely, neither immunization with NP/NCMP PspA4Pro nor subcutaneous immunization with purified protein reduced bacterial burden in the lungs after challenge with a serotype 19F strain expressing PspA from clade 1 (PspA1). Mucosal immunization with NP/NCMP PspA4Pro targeting the lungs is thus able to induce local and systemic antibodies, conferring protection only against a strain expressing PspA from the homologous family 2

Aconitase B Is Required for Optimal Growth of Xanthomonas campestris pv. vesicatoria in Pepper Plants

The aerobic plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria (Xcv) colonizes the intercellular spaces of pepper and tomato. One enzyme that might contribute to the successful proliferation of Xcv in the host is the iron-sulfur protein aconitase, which catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle and might also sense reactive oxygen species (ROS) and changes in cellular iron levels. Xcv contains three putative aconitases, two of which, acnA and acnB, are encoded by a single chromosomal locus. The focus of this study is aconitase B (AcnB). acnB is co-transcribed with two genes, XCV1925 and XCV1926, encoding putative nucleic acid-binding proteins. In vitro growth of acnB mutants was like wild type, whereas in planta growth and symptom formation in pepper plants were impaired. While acnA, XCV1925 or XCV1926 mutants showed a wild-type phenotype with respect to bacterial growth and in planta symptom formation, proliferation of the acnB mutant in susceptible pepper plants was significantly impaired. Furthermore, the deletion of acnB led to reduced HR induction in resistant pepper plants and an increased susceptibility to the superoxide-generating compound menadione. As AcnB complemented the growth deficiency of an Escherichia coli aconitase mutant, it is likely to be an active aconitase. We therefore propose that optimal growth and survival of Xcv in pepper plants depends on AcnB, which might be required for the utilization of citrate as carbon source and could also help protect the bacterium against oxidative stress

Lentiviral gene therapy for X-linked chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4–1.8 copies per neutrophil) and the persistence of 16–46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients