Towards Onboard Orbital Tracking of Seasonal Polar Volatiles on Mars

Current conditions on Mars support both a residual polar cap, composed mainly of water ice, and a seasonal cap, composed of CO2, which appears and disappears each winter. Kieffer and Titus characterized the recession of the seasonal south polar cap using an arctangent curve fit based on data from the Thermal Emission Spectrometer on Mars Global Surveyor [1]. They also found significant interannual deviations, at the regional scale, in the recession rate [2]. Further observations will enable the refinement of our models of polar cap evolution in both hemispheres. We have developed the Bimodal Image Temperature (BIT) Histogram Analysis method for the automated detection and tracking of the seasonal polar ice caps on Mars. It is specifically tailored for possible use onboard a spacecraft. We have evaluated BIT on uncalibrated data collected by the Thermal Emission Imaging System (THEMIS) instrument [3] on the Mars Odyssey spacecraft. In this paper, we focus on the northern seasonal cap, but our approach is directly applicable to the future analysis of the southern seasonal ice cap as well

Comparison on Functional Assays for Gq-Coupled GPCRs by Measuring Inositol Monophospate-1 and Intracellular Calcium in 1536-Well Plate Format

Cell-based functional assays used for compound screening and lead optimization play an important role in drug discovery for G-protein coupled receptors (GPCRs). Cell-based assays can define the role of a compound as an agonist, antagonist or inverse agonist and can provide detailed information about the potency and efficacy of a compound. In addition, cell-based screens can be used to identify allosteric modulators that interact with sites other than the binding site of the endogenous ligand. Intracellular calcium assays which use a fluorescent calcium binding dye (such as Fluo-3, Fluo-4 or Fura-2) have been used in compound screening campaigns to measure the activity of Gq-coupled GPCRs. However, such screening methodologies require a special instrumentation to record the rapid change in intracellular free calcium concentration over time. The radioactive inositol 1,4,5- triphosphate (IP3) assay measures 3H-inositol incorporation and is another traditional assay for the assessment of Gq-coupled GPCR activity, but it is not suitable for screening of large size compound collections because it requires a cell wash step and generates radioactive waste. To avoid these limitations, we have optimized and miniaturized a TR-FRET based IP-One assay that measures inositol monophosphate in a 1536-well plate format. This assay is homogenous, non-radioactive and does not require a kinetic readout. It has been tested with the cell lines expressing M1 acetylcholine, FFAR1, vasopressin V1b, or Neuropeptide S receptors. The activities of antagonists determined in the IP-One assay correlated well with these measured in the intracellular calcium assay while the correlation of agonist activities might vary from cell line to cell line. This IP-One assay offers an alternative method for high throughput screening of Gq-coupled GPCRs without using costly kinetic plate readers

Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial)

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Efficacy and Safety of High-Dose Ivermectin for Reducing Malaria Transmission (IVERMAL): Protocol for a Double-Blind, Randomized, Placebo-Controlled, Dose-Finding Trial in Western Kenya

Background: Innovative approaches are needed to complement existing tools for malaria elimination. Ivermectin is a broad spectrum antiparasitic endectocide clinically used for onchocerciasis and lymphatic filariasis control at single doses of 150‐200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150‐200 mcg/kg oral dose is short‐lived (6‐11 days). Modelling suggests higher doses, that prolong the mosquitocidal effects, are needed to make a significant contribution to malaria elimination. Ivermectin has a wide therapeutic index and previous studies have shown doses up to 2,000 mcg/kg, i.e. 10x the US Food and Drug Administration approved dose, are well tolerated and safe; the highest dose used for onchocerciasis is single‐dose 800 mcg/kg. Objective: To determine the safety, tolerability, and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3‐day course of the antimalarial dihydroartemisinin‐piperaquine, on mosquito survival. Methods: This is a double‐blind, randomised, placebo‐controlled, parallel‐group, 3‐arm, dose‐finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modelling were performed to determine the optimum dosing regimens to be tested. Modelling showed that a 3‐day regimen of 600 mcg/kg/day achieves similar median (5‐95 percentiles) Cmax concentrations of ivermectin to single‐dose of 800 mcg/kg, while increasing the median time above the LC50 (16 ng/mL) from 1.9 days (1.0‐5.7) to 6.8 (3.8‐13.4) days. The 300 mcg/kg/day dose was chosen at 50% of the higher dose to allow evaluation of the dose response. Mosquito survival will be assessed daily up to 28 days in laboratory‐reared Anopheles gambiae s.s. populations fed on patients’ blood taken at days 0, 2 (Cmax), 7 (primary outcome), 10, 14, 21, and 28 after the start of treatment. Safety outcomes include QT‐prolongation and mydriasis. The trial will be conducted in 6 health facilities in western Kenya and requires a sample size of 141 participants (47 per arm). Sub‐studies include: (1) rich pharmacokinetics and (2) direct skin vs membrane feeding assays. Results: Recruitment started July 20th, 2015. Data collection was completed on July 2nd, 2016. Unblinding and analysis will commence once the database has been completed, cleaned and locked. Discussion: High‐dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination. Trial registration: ClinicalTrials.gov: NCT02511353 (July 15, 2015)

Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, Copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.jmedchem.2c00204.The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure–activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial

“Kuteteza”: A community-engaged COVID-19 Prevention and Protection Initiative in Southern Malawi

Background: The COVID-19 epidemic in Malawi involved almost 90,000 recorded cases and 2,638 deaths. Data suggest that the Malawi epidemic developed largely in urban settings, but the extent of rural spread – exposing older adults in particular – is unclear. This concern led us, to develop the ‘Kuteteza’ partnership project: a community-based Public Health intervention involving the shielding of older adults and additional strategies to mitigate COVID-19 impacts in rural Malawi. We now present the results of a realist project evaluation. Methods Clinicians, Public Health professionals, and researchers collaborated with government and district level staff in two Malawi districts. After engagement with local structures, willing older adults (>60 years) and their communities made arrangements for supported 'shielding'. Masks, handwashing stations, and soap were also provided, and government partnerships allowed additional support for vulnerable groups. Finally, context-responsive community engagement reinforced COVID-19 prevention during peak risk periods. Our realist evaluation included collation of anonymised descriptive data and qualitative structured observations and focus groups – involving community members and volunteers – in each setting. Results The project involved 25 villages. Multi-level stakeholder engagement was pivotal in developing and establishing the work, and strong District Health Office support was integral to implementation. Team members contributed to national meetings, aligning the project with national guidance and stakeholder actions. Established partnerships with relevant ministries resulted in the incorporation of shielding in the Malawi COVID-19 response plan. In Kuteteza villages, handwashing stations and soap were used, and there was awareness of COVID-19 prevention measures. Further experiences and evaluation results are presented, including learning points for future outbreak responses. Conclusions Through effective stakeholder engagement and contribution to national response strategy, the Kuteteza project raised awareness and supported populations at a critical time in the pandemic. These approaches can be incorporated in future epidemic and emergency responses

The Role of Tourism and Recreation in the Spread of Non-Native Species: A Systematic Review and Meta-Analysis

Managing the pathways by which non-native species are introduced and spread is considered the most effective way of preventing species invasions. Tourism and outdoor recreation involve the frequent congregation of people, vehicles and vessels from geographically diverse areas. They are therefore perceived to be major pathways for the movement of non-native species, and ones that will become increasingly important with the continued growth of these sectors. However, a global assessment of the relationship between tourism activities and the introduction of non-native species–particularly in freshwater and marine environments–is lacking. We conducted a systematic review and meta-analysis to determine the impact of tourism and outdoor recreation on non-native species in terrestrial, marine and freshwater environments. Our results provide quantitative evidence that the abundance and richness of non-native species are significantly higher in sites where tourist activities take place than in control sites. The pattern was consistent across terrestrial, freshwater and marine environments; across a variety of vectors (e.g. horses, hikers, yachts); and across a range of taxonomic groups. These results highlight the need for widespread biosecurity interventions to prevent the inadvertent introduction of invasive non-native species (INNS) as the tourism and outdoor recreation sectors grow

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

UW Dawgstar: One Third of ION-F - An element of the Ionospheric Observation Nanosatellite Formation (ION-F)

The preliminary design for the UW Dawgstar nanosatellite is presented. The Dawgstar is a 13 kg satellite designed as a part of the University Nanosatellite Program funded by AFOSR, DARPA, AFRL, and NASA. The goal of this two-year program is to design, build, and fly nanosatellites. The mission overview is detailed, including the coupling with the University partners Utah State and Virginia Tech in the Ionospheric Observation Nanosatellite Formation (ION-F). The mission includes several formations and formation keeping experiments, and distributed ionospheric measurements. Each of the subsystems is also detailed, including the design and integration of eight miniature pulsed plasma thrusters for attitude control and formation flying

[Avian cytogenetics goes functional] Third report on chicken genes and chromosomes 2015

High-density gridded libraries of large-insert clones using bacterial artificial chromosome (BAC) and other vectors are essential tools for genetic and genomic research in chicken and other avian species... Taken together, these studies demonstrate that applications of large-insert clones and BAC libraries derived from birds are, and will continue to be, effective tools to aid high-throughput and state-of-the-art genomic efforts and the important biological insight that arises from them