The effect of cyanoacrylate fuming on subsequent protein stain enhancement of fingermarks in blood

This study investigates the effect of cyanoacrylate (CA) fuming, at atmospheric and vacuum conditions, on subsequent protein stain (acid violet 17) enhancement of fingermarks in blood. Fingermark depletions in blood were deposited on three nonporous surfaces (e.g., plastic bag) and aged for a set period of time (up to 28 days) before enhancement with the water-ethanol-acetic acid and methanol formulations of acid violet 17 (AV17). All trials were carried out in duplicate. One depletion was pre-treated with CA fuming followed by the enhancement technique and the other depletion was treated with only the enhancement technique (control).As expected, atmospheric CA fuming hindered the subsequent enhancement of blood with the AV17 water-ethanol-acetic acid formulation but not the methanol formulation. The same observations were also recorded under vacuum CA fuming conditions. Preliminary work with vacuum metal deposition did not hinder subsequent AV17 protein stain enhancement with either formulation

Data Quality from a Community-Based, Water-Quality Monitoring Project in the Yukon River Basin

This paper examines the quality of data collected by the Indigenous Observation Network, a community-based water-quality project in the Yukon River Basin of Alaska and Canada. The Indigenous Observation Network relies on community technicians to collect surface-water samples from as many as fifty locations to achieve their goals of monitoring the quality of the Yukon River and major tributaries in the basin and maintaining a long-term record of baseline data against which future changes can be measured. This paper addresses concerns about the accuracy, precision, and reliability of data collected by non-professionals. The Indigenous Observation Network data are examined in the context of a standard data life cycle: plan, collect, assure, and describe; as compared to professional scientific activities. Field and laboratory protocols and procedures of the Indigenous Observation Network are compared to those utilized by professional scientists. The data of the Indigenous Observation Network are statistically compared to those collected by professional scientists through a retrospective analysis of a set of water-quality parameters reported by all three projects over a number of years. No statistical differences were found among the three projects for pH, Calcium, Magnesium, or Alkalinity, although statistically significant differences were found for Sodium, Chloride, Sulfate, and Potassium concentrations. The statistical differences found were small and likely not significant in terms of interpreting the data for a variety of uses. Our results suggest that Indigenous Observation Network data are of high quality, and with consistent protocols and participant training, community based monitoring projects can collect data that are accurate, precise, and reliable

Vulnerability of Subsistence Systems Due to Social and Environmental Change: A Case Study in the Yukon-Kuskokwim Delta, Alaska

Arctic Indigenous communities have been classified as highly vulnerable to climate change impacts. The remoteness of Arctic communities, their dependence upon local species and habitats, and the historical marginalization of Indigenous peoples enhances this characterization of vulnerability. However, vulnerability is a result of diverse historical, social, economic, political, cultural, institutional, natural resource, and environmental conditions and processes and is not easily reduced to a single metric. Furthermore, despite the widespread characterization of vulnerability, Arctic Indigenous communities are extremely resilient as evidenced by subsistence institutions that have been developed over thousands of years. We explored the vulnerability of subsistence systems in the Cup’ik village of Chevak and Yup’ik village of Kotlik through the lens of the strong seasonal dimensions of resource availability. In the context of subsistence harvesting in Alaska Native villages, vulnerability may be determined by analyzing the exposure of subsistence resources to climate change impacts, the sensitivity of a community to those impacts, and the capacity of subsistence institutions to absorb these impacts. Subsistence resources, their seasonality, and perceived impacts to these resources were investigated via semi-structured interviews and participatory mapping-calendar workshops. Results suggest that while these communities are experiencing disproportionate impacts of climate change, Indigenous ingenuity and adaptability provide an avenue for culturally appropriate adaptation strategies. However, despite this capacity for resiliency, rapid socio-cultural changes have the potential to be a barrier to community adaptation and the recent, ongoing shifts in seasonal weather patterns may make seasonally specific subsistence adaptations to landscape particularly vulnerable.Les collectivités autochtones de l’Arctique sont classées comme étant fortement vulnérables aux incidences du changement climatique. L’éloignement des collectivités de l’Arctique, leur dépendance des espèces et des habitats locaux de même que la marginalisation historique des peuples autochtones intensifient cette vulnérabilité. Toutefois, la vulnérabilité est le résultat de conditions et de processus divers sur le plan historique, social, économique, politique, culturel, institutionnel, environnemental et des ressources naturelles. Il est difficile d’attribuer la vulnérabilité à un seul aspect. Malgré cette vaste caractérisation de la vulnérabilité, les collectivités autochtones de l’Arctique sont extrêmement résilientes, comme en attestent les modes de subsistance qui se sont développés au fil de milliers d’années. Nous avons exploré la vulnérabilité des systèmes de subsistance du village cup’ik de Chevak et du village yup’ik de Kotlik du point de vue des dimensions saisonnières fortes de la disponibilité des ressources. Dans le contexte des récoltes de subsistance des villages autochtones de l’Alaska, la vulnérabilité peut être déterminée au moyen de l’exposition des ressources de subsistance aux incidences du changement climatique, de la sensibilité d’une collectivité à ces incidences et de la capacité des institutions de subsistance à absorber ces incidences. Les ressources de subsistance, leur saisonnalité et les incidences perçues de ces ressources ont été étudiées au moyen d’entrevues semi-structurées et d’ateliers participatifs d’établissement de calendrier. Selon les résultats, bien que ces collectivités soient aux prises avec des incidences disproportionnées de changement climatique, l’ingéniosité et l’adaptabilité des Autochtones pavent le chemin à des stratégies d’adaptation convenant à leur culture. Cependant, malgré cette capacité de résilience, les changements socioculturels accélérés ont la possibilité de faire obstacle à l’adaptation collective, sans compter que la variation continue des tendances climatiques saisonnières peut rendre les adaptations de subsistance saisonnières au paysage particulièrement vulnérables

Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism

A key step in drug discovery, common to many disease areas, is preclinical demonstration of efficacy in a mouse model of disease. However, this demonstration and its translation to the clinic can be impeded by mouse-specific pathways of drug metabolism. Here we show that a mouse line extensively humanized for the cytochrome P450 gene superfamily (“8HUM”) can circumvent these problems. The pharmacokinetics, metabolite profiles and magnitude of drug-drug interactions of a test set of approved medicines were in much closer alignment with clinical observations than in wild-type mice. Infection with Mycobacterium tuberculosis, Leishmania donovani and Trypanosoma cruzi was well tolerated in 8HUM, permitting efficacy assessment. During such assessments, mouse-specific metabolic liabilities were bypassed while the impact of clinically relevant active metabolites and DDI on efficacy were well-captured. Removal of species differences in metabolism by replacement of wild-type mice with 8HUM therefore reduces compound attrition while improving clinical translation, accelerating drug discovery

Structure Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.</p

Collagen fleeces do not improve colonic anastomotic strength but increase bowel obstructions in an experimental rat model

To investigate whether a collagen fleece kept in place by fibrin glue might seal off a colorectal anastomosis, provide reinforcement, and subsequently improve anastomotic healing. Wistar rats underwent a 1-cm left-sided colonic resection followed by a 4-suture end-to-end anastomosis. They were then randomly assigned to one of three treatment groups: no additional intervention (control, n = 20), the anastomosis covered with fibrin glue (fibrin glue, n = 20), the anastomosis covered with a collagen fleece, kept in place with fibrin glue (collagen fleece, n = 21). At either 3 or 7 days follow-up, anastomotic bursting pressure was measured and tissue was obtained for histology and collagen content assessment after which animals were sacrificed. Three rats in the control (15%), three in the fibrin glue (15%), and one in the collagen group (4.8%) died due to anastomotic complications (P = 0.497). Anastomotic bursting pressures were not significantly different between groups at 3 and 7 days follow-up (P = 0.659 and P = 0.427, respectively). However, bowel obstructions occurred significantly more often in the collagen group compared to the control group (14/21 vs. 3/20, P = 0.003). Collagen contents were not different between groups, but histology showed a more severe inflammation in the collagen group compared to the other groups at both 3 and 7 days follow-up. A collagen fleece kept in place by fibrin glue does not improve healing of colonic anastomoses in rats. Moreover, this technique induces significantly more bowel obstructions in rats, warranting further study before being translated to a clinical settin

Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives

The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8–1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2–0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs

Changing times, changing stories: generational differences in climate change perspectives from four remote indigenous communities in Subarctic Alaska

Indigenous Arctic and Subarctic communities currently are facing a myriad of social and environmental changes. In response to these changes, studies concerning indigenous knowledge (IK) and climate change vulnerability, resiliency, and adaptation have increased dramatically in recent years. Risks to lives and livelihoods are often the focus of adaptation research; however, the cultural dimensions of climate change are equally important because cultural dimensions inform perceptions of risk. Furthermore, many Arctic and Subarctic IK climate change studies document observations of change and knowledge of the elders and older generations in a community, but few include the perspectives of the younger population. These observations by elders and older generations form a historical baseline record of weather and climate observations in these regions. However, many indigenous Arctic and Subarctic communities are composed of primarily younger residents. We focused on the differences in the cultural dimensions of climate change found between young adults and elders. We outlined the findings from interviews conducted in four indigenous communities in Subarctic Alaska. The findings revealed that (1) intergenerational observations of change were common among interview participants in all four communities, (2) older generations observed more overall change than younger generations interviewed by us, and (3) how change was perceived varied between generations. We defined "observations" as the specific examples of environmental and weather change that were described, whereas "perceptions" referred to the manner in which these observations of change were understood and contextualized by the interview participants. Understanding the differences in generational observations and perceptions of change are key issues in the development of climate change adaptation strategies