Molecular biology of amitraz resistance in cattle ticks of the genus Rhipicephalus

Amitraz is an important product for the control of cattle ticks around the world. In comparison with other products for the control of ticks, it is quite affordable and it has a rapid knock-down effect. It binds with and activates adrenergic neuro-receptors of animals and it inhibits the action of monoamine oxidases (MAO). Resistance to amitraz has been documented in Rhipicephalus microplus, R. decoloratus and R. appendiculatus. Four mechanisms of resistance have been proposed, each of which is supported by evidence but none of which has been definitively confirmed as the cause of resistance in the field. The proposed mechanisms include genetic target site insensitivity in two G protein-coupled receptors, the beta-adrenergic octopamine receptor (BAOR) and the octopamine/tyramine receptor (OCT/Tyr), increased expression or activity of monoamine oxidases and increased expression or activity of the ATP binding cassette transporter

Alkaline phosphatase in nasal secretion of cattle: biochemical and molecular characterisation

BACKGROUND: Nasal secretion (NS) was investigated as a source of information regarding the mucosal and systemic immune status of cattle challenged by respiratory disease. A method for the collection of substantial volumes (~12 ml) of NS from cattle was developed to establish a reference range of analytes that are present in the NS of healthy cattle. Biochemical profiles of NS from a group of 38 healthy Holstein-Friesian cows revealed high alkaline phosphatase (AP) activity of up to 2392 IU/L. The character and source of the high activity of AP in bovine NS was investigated. RESULTS: Histochemical analysis confirmed the localization of the AP enzyme activity to epithelial cells and serous glands of the nasal respiratory mucosa. Analysis of mRNA levels from nasal mucosa by end point RT-PCR and PCR product sequencing confirmed that the AP was locally produced and is identical at the nucleotide level to the non-specific AP splice variant found in bovine liver, bone and kidney. Analysis by isoelectric focussing confirmed that AP was produced locally at a high level in nasal epithelium demonstrating that AP from nasal secretion and nasal mucosa had similar pI bands, though differing from those of the liver, kidney, bone and intestine, suggesting different post-translational modification (PTM) of AP in these tissues. CONCLUSIONS: A nasal isozyme of AP has been identified that is present at a high activity in NS, resulting from local production and showing distinctive PTM and may be active in NS as an anti-endotoxin mediator

Heterogeneidad de facies en una rampa carbonatada del Kimmeridgiense (Jabaloyas, Este de España): análisis de campo y geomodelización tridimensional

The Upper Kimmeridgian outcrops exposed around the village of Jabaloyas (NE Spain) have been analyzed to document the facies heterogeneity across the shallow portion of a low angle carbonate ramp. The studied area covers a total surface of 12 square kilometres. Seventeen stratigraphic profiles have provided basic information to carry out the detailed facies analyses presented in this work. The studied unit corresponds to a high-frequency sequence, bounded by discontinuities that can be traced at regional scale. This sequence shows the widespread development of coral-microbial reef buildups with conical to cylindrical shape (up to 19 m thick). The characterization and interpretation of the different sort of inter-reef and post-reef facies resulted in the reconstruction of the sedimentary domains of the studied carbonate ramp, from burrowed mud-dominated skeletal facies (distal middle ramp), to grainy (skeletal, peloidal, oolitic) shoal and backshoal facies (inner ramp). The studied sequence is divided into four sedimentary episodes bounded by sharp facies changes. The lower two episodes include the vertical reef growth during rapid accommodation gain; the upper two episodes are marked by the rapid progradation of the inner ramp facies. The depositional facies and their stacking patterns in the Jabaloyas outcrops are similar to those described in the subsurface Arab D reservoirs. This Late Jurassic carbonate unit forms major hydrocarbon fields in the Middle East. For improving the geological distribution of reservoir heterogeneity in this kind of low angle carbonate ramp system, two 3D models have been created. A Fullfield Model of the overall geometry of the facies belts has allowed the quantification of vertical and lateral extension of the inter-reef and post-reef facies. A Sector Model, which includes individual reef bodies has been used to better simulate reservoir heterogeneity resulting from different diagenetic overprint.Los afloramientos del Kimmeridgiense Superior en las cercanías de Jabaloyas (NE de España) han sido estudiados para documentar la heterogeneidad de facies en las zonas más someras de una rampa carbonatada de bajo ángulo. El área de estudio cubre una superficie de 12 kilómetros cuadrados en la que se han levantado diecisiete columnas estratigráficas y se ha realizado un análisis detallado de facies. La unidad estratigráfica estudiada corresponde a una secuencia de alta frecuencia limitada por discontinuidades que pueden ser cartografiadas a escala regional. Dicha secuencia presenta bioconstrucciones arrecifales coralinas y microbianas con morfologías cónicas o cilíndricas de hasta 19 m de potencia. La caracterización e interpretación de las diferentes facies inter- y post-arrecifales ha permitido la reconstrucción de los diferentes dominios de la rampa carbonatada, desde facies no granosostenidas bioturbadas (rampa media distal), hasta facies granosostenidas (bioclásticas, peloidales, oolíticas) desarrolladas en bajíos activos y en zonas someras protegidas. La existencia de superficies bien cementadas y de cambios abruptos de facies asociados ha permitido la división de la secuencia en cuatro episodios de sedimentación. Los dos primeros incluyen el crecimiento de los arrecifes durante los periodos de ganancia de acomodación, mientras que los dos últimos vienen marcados por una rápida progradación de las facies de rampa interna. El patrón de apilamiento de esta unidad en los afloramientos de Jabaloyas muestra similitudes con aquellos descritos en los reservorios desarrollados en el Arab D, el cual genera campos de hidrocarburos de gran tamaño en Medio Oriente. Con el fin de precisar la heterogeneidad de facies a escala de reservorio en este tipo de rampas carbonatadas de bajo ángulo, se han elaborado dos modelos tridimensionales. Un modelo de campo completo ha permitido precisar la extensión y la geometría de los diferentes cinturones de facies; y un modelo sector, que incluye los cuerpos arrecifales, posteriormente utilizado para simular la heterogeneidad del reservorio con ayuda de estudios diagenéticos previos

The STOP COVID 2 study: Fluvoxamine vs placebo for outpatients with symptomatic COVID-19, a fully remote randomized controlled trial

BACKGROUND: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) RESULTS: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank CONCLUSIONS: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT04668950

LocoMMotion:a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0–1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1–20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2–36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9–5.6) and 12.4 months (95% CI: 10.3–NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action

14-3-3 Mediates Histone Cross-Talk during Transcription Elongation in Drosophila

Post-translational modifications of histone proteins modulate the binding of transcription regulators to chromatin. Studies in Drosophila have shown that the phosphorylation of histone H3 at Ser10 (H3S10ph) by JIL-1 is required specifically during early transcription elongation. 14-3-3 proteins bind H3 only when phosphorylated, providing mechanistic insights into the role of H3S10ph in transcription. Findings presented here show that 14-3-3 functions downstream of H3S10ph during transcription elongation. 14-3-3 proteins localize to active genes in a JIL-1–dependent manner. In the absence of 14-3-3, levels of actively elongating RNA polymerase II are severely diminished. 14-3-3 proteins interact with Elongator protein 3 (Elp3), an acetyltransferase that functions during transcription elongation. JIL-1 and 14-3-3 are required for Elp3 binding to chromatin, and in the absence of either protein, levels of H3K9 acetylation are significantly reduced. These results suggest that 14-3-3 proteins mediate cross-talk between histone phosphorylation and acetylation at a critical step in transcription elongation

Solving the multiple level warehouse layout problem using ant colony optimization

This paper addresses the multiple level warehouse layout problem, which involves assigning items to cells and levels with the objective of minimizing transportation costs. A monthly demand and an inventory requirement are associated with every item type along with vertical and horizontal unit transportation costs. The warehouse has one port to transport items vertically from ground floor to the other levels, where each item must be assigned to exactly one cell on the assigned level. An ant colony optimization (ACO) algorithm is adapted to this NP-complete problem and its performance is evaluated by comparing its solutions to the ones obtained using genetic algorithms (GA) as well as the optimal solutions for small problems. The computational results reflected the superiority of ACO in large-size problem instances, with a marginally better performance than GA in smaller ones, while solving the tested instances within a reasonable computational time. Furthermore, ACO was able to attain most of the known optimal solutions for small-size problem instances.Publisher's Versio