- Formic Acid Mediated Direct Z-Selective Reductive Coupling of Dienes and Aldehydes. [Journal Article]
- ACAngew Chem Int Ed Engl 2019 Jun 18
- Methods for the addition of unsaturated nucleophiles to carbonyls to generate Z-olefin products remain rare and often require alkyl borane or zinc reductants, limiting their utility. We demonstrate t…
Methods for the addition of unsaturated nucleophiles to carbonyls to generate Z-olefin products remain rare and often require alkyl borane or zinc reductants, limiting their utility. We demonstrate that formic acid mediates the Rh-catalyzed, Z-selective coupling of dienes and aldehydes. The process is distinguished by broad tolerance towards reducible or electrophilic groups. Kinetic analysis suggests that generation of the catalytically active Rh-intermediate by ligand dissociation is the rate determining step. The rapid generation and trapping of Rh-allyl intermediates is key to preventing chain-walking isomerization events that plague related protocols. Insights gained through this study may have wider implications in selective metal-catalyzed hydrofunctionalization reactions.
- Pyrimidine biosynthesis in pathogens - Structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae. [Journal Article]
- IJInt J Biol Macromol 2019 Jun 14
- The de novo pyrimidine biosynthesis pathway is essential for the proliferation of many pathogens. One of the pathway enzymes, dihydroorotase (DHO), catalyzes the reversible interconversion of N-carba…
The de novo pyrimidine biosynthesis pathway is essential for the proliferation of many pathogens. One of the pathway enzymes, dihydroorotase (DHO), catalyzes the reversible interconversion of N-carbamoyl-l-aspartate to 4,5-dihydroorotate. The substantial difference between bacterial and mammalian DHOs makes it a promising drug target for disrupting bacterial growth and thus an important candidate to evaluate as a response to antimicrobial resistance on a molecular level. Here, we present two novel three-dimensional structures of DHOs from Yersinia pestis (YpDHO), the plague-causing pathogen, and Vibrio cholerae (VcDHO), the causative agent of cholera. The evaluations of these two structures led to an analysis of all available DHO structures and their classification into known DHO types. Comparison of all the DHO active sites containing ligands that are listed in DrugBank was facilitated by a new interactive, structure-comparison and presentation platform. In addition, we examined the genetic context of characterized DHOs, which revealed characteristic patterns for different types of DHOs. We also generated a homology model for DHO from Plasmodium falciparum.
- Human response to live plague vaccine EV, Almaty region, Kazakhstan, 2014-2015. [Journal Article]
- PlosPLoS One 2019; 14(6):e0218366
- CONCLUSIONS: Based on the results of this study, we recommend initiating vaccination campaigns for the medical and veterinary staff, as well as the general population four months prior to the springtime epizootics of plague among wild rodents.
- Towards harmonisation of entomological surveillance in the Mediterranean area. [Review]
- PNPLoS Negl Trop Dis 2019; 13(6):e0007314
- The Mediterranean Basin is historically a hotspot for trade, transport, and migration. As a result, countries surrounding the Mediterranean Sea share common public health threats. Among them are vect…
The Mediterranean Basin is historically a hotspot for trade, transport, and migration. As a result, countries surrounding the Mediterranean Sea share common public health threats. Among them are vector-borne diseases, and in particular, mosquito-borne viral diseases are prime candidates as (re)emerging diseases and are likely to spread across the area. Improving preparedness and response capacities to these threats at the regional level is therefore a major issue. The implementation of entomological surveillance is, in particular, of utmost importance. Guidance in designing entomological surveillance systems is critical, and these systems may pursue different specific objectives depending on the disease. The purpose of the proposed review is to draw up guidelines for designing effective and sustainable entomological surveillance systems in order to improve preparedness and response. However, we make it clear that there is no universal surveillance system, so the thinking behind harmonisation is to define evidence-based standards in order to promote best practises, identify the most appropriate surveillance activities, and optimise the use of resources. Such guidance is aimed at policymakers and diverse stakeholders and is intended to be used as a framework for the implementation of entomological surveillance programmes. It will also be useful to collaborate and share information with health professionals involved in other areas of disease surveillance. Medical entomologists and vector control professionals will be able to refer to this report to advocate for tailored entomological surveillance strategies. The main threats targeted in this review are the vectors of dengue virus, chikungunya virus, Zika virus, West Nile virus, and Rift Valley fever virus. The vectors of all these arboviruses are mosquitoes.
- Host biology and environmental variables differentially predict flea abundances for two rodent hosts in a plague-relevant system. [Journal Article]
- IJInt J Parasitol Parasites Wildl 2019; 9:174-183
- While rodents frequently host ectoparasites that can vector zoonotic diseases, often little is known about their ectoparasite communities, even in places where hosts frequently interact with humans. …
While rodents frequently host ectoparasites that can vector zoonotic diseases, often little is known about their ectoparasite communities, even in places where hosts frequently interact with humans. Yosemite National Park is an area of high human-wildlife interaction and high potential zoonotic disease transfer. Nonetheless, relatively few studies have surveyed the flea communities on mammalian hosts in this area, and even fewer have characterized the environmental and host factors that predict infestation. We focused on two species, the alpine chipmunk (Tamias alpinus) and the lodgepole chipmunk (T. speciosus), which inhabit Yosemite and surrounding areas and can host fleas that vector plague. Because these hosts are exhibiting differential responses to environmental change, it is valuable to establish baselines for their flea communities before further changes occur. We surveyed fleas on these chipmunk hosts during three years (2013-2015), including in the year of a plague epizootic (2015), and documented significant inter-host differences in flea communities and changes across years. Flea abundance was associated with host traits including sex and fecal glucocorticoid metabolite levels. The average number of fleas per individual and the proportion of individuals carrying fleas increased across years for T. speciosus but not for T. alpinus. To better understand these patterns, we constructed models to identify environmental predictors of flea abundance for the two most common flea species, Ceratophyllus ciliatus mononis and Eumolpianus eumolpi. Results showed host-dependent differences in environmental predictors of flea abundance for E. eumolpi and C. ciliatus mononis, with notable ties to ambient temperature variation and elevation. These results provide insight into factors affecting flea abundance on two chipmunk species, which may be linked to changing climate and possible future plague epizootics.
- Late-onset Vibrio vulnificus septicemia without cirrhosis. [Case Reports]
- PProc (Bayl Univ Med Cent) 2019; 32(2):286-288
- Recent surveillance from the Centers for Disease Control and Prevention indicates rising annual incidence rates of Vibrio vulnificus infection. Unfortunately, this infection is often excluded from th…
Recent surveillance from the Centers for Disease Control and Prevention indicates rising annual incidence rates of Vibrio vulnificus infection. Unfortunately, this infection is often excluded from the differential diagnosis in lesser known at-risk populations. Transmission occurs via wound exposure or ingestion, with V. vulnificus foodborne illness having the highest mortality rate of all Vibrio species. Fatality rates of V. vulnificus rival those of Ebola and bubonic plague, so timely treatment is imperative. Current literature favors surgical debridement with a third-generation cephalosporin plus intravenous doxycycline or fluoroquinolone. Cephalosporin monotherapy is discouraged due to rising resistance. This case features V. vulnificus septicemia with prolonged incubation time in a noncirrhotic patient.
- Static spatial growth restriction micropatterning of endothelial colony forming cells influences their morphology and gene expression. [Journal Article]
- PlosPLoS One 2019; 14(6):e0218197
- CONCLUSIONS: Endothelial colony forming cells can be durably micropatterned using spatial growth restriction. Micropatterning has a significant effect on the gross and subcellular morphologies of both cell types. Further study is required to fully understand the effect of micropatterning on endothelial colony forming cell gene expression.
- Social capital predicts corruption risk in towns. [Journal Article]
- RSR Soc Open Sci 2019; 6(4):182103
- Corruption is a social plague: gains accrue to small groups, while its costs are borne by everyone. Significant variation in its level between and within countries suggests a relationship between soc…
Corruption is a social plague: gains accrue to small groups, while its costs are borne by everyone. Significant variation in its level between and within countries suggests a relationship between social structure and the prevalence of corruption, yet, large-scale empirical studies thereof have been missing due to lack of data. In this paper, we relate the structural characteristics of social capital of settlements with corruption in their local governments. Using datasets from Hungary, we quantify corruption risk by suppressed competition and lack of transparency in the settlement's awarded public contracts. We characterize social capital using social network data from a popular online platform. Controlling for social, economic and political factors, we find that settlements with fragmented social networks, indicating an excess of bonding social capital has higher corruption risk, and settlements with more diverse external connectivity, suggesting a surplus of bridging social capital is less exposed to corruption. We interpret fragmentation as fostering in-group favouritism and conformity, which increase corruption, while diversity facilitates impartiality in public life and stifles corruption.
- Human Neutrophil Isolation and Degranulation Responses to Yersinia pestis Infection. [Journal Article]
- MMMethods Mol Biol 2019; 2010:197-209
- Neutrophils are the primary immune cell recruited to the site of bacterial infection, where they can rapidly deploy vesicles filled with various pro-inflammatory and anti-microbial proteins. This deg…
Neutrophils are the primary immune cell recruited to the site of bacterial infection, where they can rapidly deploy vesicles filled with various pro-inflammatory and anti-microbial proteins. This degranulation process, combined with oxidative and nitrosative mechanisms, is a major part of the initial host response to kill microorganisms. Neutrophils are one of the main cell types that interact with Yersinia pestis during infection, which is often lethal in the absence of prompt antibiotic treatment. Intradermal inoculation of Y. pestis results in bubonic plague, and inhalation of aerosolized droplets containing Y. pestis results in pneumonic plague. Although neutrophils are recruited to the site of inoculation during both bubonic and pneumonic plague, the neutrophils fail to clear Y. pestis, and, during pneumonic plague, contribute to the development of severe pneumonia. Subverting neutrophil responses is critical to the development of fulminant disease, yet the mechanisms by which Y. pestis impairs neutrophils are poorly understood. Cell culture models are important tools for studying Y. pestis interactions with immune cells. We describe a cell culture model for the infection of human neutrophils with Y. pestis. Neutrophils are isolated from human peripheral blood at high purity and subsequently infected with Y. pestis. We specifically focus on the application of this in vitro infection assay to the analysis of neutrophil degranulation responses.
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- Intracellular Assays to Monitor Survival and Growth of Yersinia pestis Within Macrophages. [Journal Article]
- MMMethods Mol Biol 2019; 2010:181-196
- Yersinia pestis is able to survive and replicate within macrophages, while also being able to live in the extracellular milieu of the host. Assays that facilitate better understanding of how Y. pesti…
Yersinia pestis is able to survive and replicate within macrophages, while also being able to live in the extracellular milieu of the host. Assays that facilitate better understanding of how Y. pestis survives intracellularly and subverts normal host antimicrobial defenses require the ability to monitor intracellular Y. pestis survival and replication. In this chapter three different assays for monitoring intracellular survival and replication will be described, along with the formulas and methods to quantify and present the acquired data. These assays are fundamental to answering a multitude of questions pertaining to which bacterial factors are important for intracellular survival. Additionally, these assays can be used, with modifications, for other intracellular pathogens of interest. The first assay discussed will be the conventional bacterial enumeration assay, which quantifies bacterial numbers directly through a classic colony forming units (CFU) assay. Quantifying bacterial burden through CFU determination allows for differentiation between intracellular/cell-associated bacteria and extracellular bacteria. However, CFU determination is laborious, does not allow for direct kinetic monitoring of bacterial growth, and is difficult to adapt to high throughput assays. Bioluminescence bioreporters that use luciferase to monitor bacterial numbers allow for simple, plate reader-based, real-time kinetic monitoring of bacterial growth that is amendable to high throughput techniques. Finally, we will describe live cell microscopy using fluorescent bioreporters, which allows for monitoring of bacterial replication in individual cells and the possibility to visualize interactions between bacterial and host proteins during intracellular infection.