Mechanical transport and transmission of Cryptosporidium parvum oocysts by wild filth flies

Over the course of six months wild filth flies were collected from traps left for 7-10 days in a barn with or without a calf shedding Cryptosporidium parvum Genotype 2 oocysts in diarrheic feces. The oocysts of C. parvum transported on the flies' exoskeletons and eluted from their droplets left on visited surfaces were infectious for mice. The mean number of oocysts carried by a fly varied from 4 to 131, and the total oocyst number per collection varied from 56 to approximately 4.56 x 10(3). Fly abundance and intensity of mechanical transmission of infectious C. parvum oocysts were positively correlated, and both increased significantly when an infected calf was in the barn. Molecular data showed that the oocysts shed by infected calves were carried by flies for at least 3 weeks. Filth flies can acquire infectious C. parvum oocysts from unsanitary sites, deposit them on visited surfaces, and therefore may be involved in human or animal cryptosporidiosis.     

Genetic and environmental control of host-gut microbiota interactions

Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Toward this end, we profiled gut microbiota using 16s rRNA gene sequencing in a panel of 110 diverse inbred strains of mice. This panel has previously been studied for a wide range of metabolic traits and can be used for high-resolution association mapping. Using a SNP-based approach with a linear mixed model, we estimated the heritability of microbiota composition. We conclude that, in a controlled environment, the genetic background accounts for a substantial fraction of abundance of most common microbiota. The mice were previously studied for response to a high-fat, high-sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, A×B19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. Among these, we chose Akkermansia muciniphila, a common anaerobe previously associated with metabolic effects. When administered to strain A×B19 by gavage, the dietary response was significantly blunted for obesity, plasma lipids, and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publicly available data provide a resource for future studies.Studies carried out over the last decade have revealed that gut microbiota contribute to a variety of common disorders, including obesity and diabetes (Musso et al. 2011), colitis (Devkota et al. 2012), atherosclerosis (Wang et al. 2011), rheumatoid arthritis (Vaahtovuo et al. 2008), and cancer (Yoshimoto et al. 2013). The evidence for metabolic interactions is particularly strong, as a large body of data now supports the conclusion that gut microbiota influence the energy harvest from dietary components, particularly complex carbohydrates, and that metabolites such as the short-chain fatty acids produced by gut bacteria can perturb metabolic traits, including adiposity and insulin resistance (Turnbaugh et al. 2006, 2009; Backhed et al. 2007; Wen et al. 2008; Ridaura et al. 2013). Gut microbiota communities are assembled each generation, influenced by maternal seeding, environmental factors, host genetics, and age, resulting in substantial variations in composition among individuals in human populations (Eckburg et al. 2005; Costello et al. 2009; Human Microbiome Project Consortium 2012; Goodrich et al. 2014). Most experimental studies of host-gut microbiota interactions have employed large perturbations, such as comparisons of germ-free versus conventional mice, and the significance of common variations in gut microbiota composition for disease susceptibility is still poorly understood. Furthermore, while studies with germ-free mice have clearly implicated microbiota in clinically relevant traits, it has proven difficult to identify the responsible taxa of bacteria.We now report a population-based analysis of host-gut microbiota interactions in the mouse. One of the issues we explore is the role of host genetics. Although some evidence is consistent with significant heritability of gut microbiota composition, the extent to which the host controls microbiota composition under controlled environmental conditions is unclear. We also examined the role of common variations in gut microbiota in metabolic traits such as obesity and insulin resistance and mapped loci contributing to the abundance of certain microbiota. We performed our study using a resource termed the Hybrid Mouse Diversity Panel (HMDP), consisting of about 100 inbred strains of mice that have been either sequenced or subjected to high-density genotyping (Bennett et al. 2010). The resource has several advantages for genetic analysis as compared to traditional genetic crosses. First, it allows high-resolution mapping by association rather than linkage analysis, and it has now been used for the identification of a number of novel genes underlying complex traits (Farber et al. 2011; Lavinsky et al. 2015; Parks et al. 2015; Rau et al. 2015). Second, since the strains are permanent, the data from separate studies can be integrated, allowing the development of large, publicly available databases of physiological and molecular traits relevant to a variety of clinical disorders (systems.genetics.ucla.edu and phenome.jax.org). Third, the panel is ideal for examining gene-by-environment interactions, since it is possible to examine individuals of a particular genotype under a variety of conditions (Orozco et al. 2012; Parks et al. 2013).     

Objective Structured Clinical Examination From Virtually Anywhere!

The Objective Structured Clinical Examination (OSCE) is used in nurse practitioner (NP) education programs to evaluate students’ clinical competency. The OSCE was developed to be done with students on campus in a simulation laboratory, but for online NP programs, an on-campus environment is a barrier to the use of OSCEs. The virtual OSCE eliminates this barrier and provides an effective method of implementing OSCEs and evaluating student competencies in online NP education.     

Insights in Public Health Electronic Cigarettes: Marketing to Hawai‘i's Adolescents

Electronic cigarettes (e-cigarettes) are an emerging phenomenon that is becoming increasingly popular among adolescents. Current e-cigarette use among adolescents has more than doubled in the past few years nationally and more than tripled in Hawai‘i, despite the fact that safety in terms of health and injury from use is widely unknown. The use of e-cigarettes among adolescents is of particular concern because they may act as a gateway to smoking conventional tobacco cigarettes, substitute for cigarettes where smoking would normally not be allowed, and weaken the effect of clean air policies, and displace effective smoking cessation treatments. Additionally, the use of e-cigarettes may lead to the use of conventional cigarettes. There is special concern that e-cigarette companies are recruiting adolescents who would not have otherwise tried smoking by using tactics such as offering e-cigarettes in attractive flavorings and using the same successful strategies to market their product as tobacco companies have used for conventional cigarettes in past decades. It has been shown that exposure to cigarette marketing is related to initiation and progression in adolescent smoking. Yet, there remains no regulation on the marketing of e-cigarettes to adolescents. It can be extrapolated that expanded regulation that includes limits on the marketing of e-cigarettes may help decrease use among adolescents and prevent the possible increase of smoking rates.     

The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia

Venetoclax is a promising agent in the treatment of acute myeloid leukemia (AML), though its antileukemic activity is limited to combination therapies. Mcl-1 downregulation, Bim upregulation, and DNA damage have been identified as potential ways to enhance venetoclax activity. In this study, we combine venetoclax with the dual PI3K and histone deacetylase inhibitor CUDC-907, which can downregulate Mcl-1, upregulate Bim, and induce DNA damage, as well as downregulate c-Myc. We establish that CUDC-907 and venetoclax synergistically induce apoptosis in AML cell lines and primary AML patient samples ex vivo. CUDC-907 downregulates CHK1, Wee1, RRM1, and c-Myc, which were found to play a role in venetoclax-induced apoptosis. Interestingly, we find that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an AML cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of AML.     

Neutrophil extracellular traps and thrombosis in COVID-19

Journal of Thrombosis and Thrombolysis - Studies of patients with COVID-19 have demonstrated markedly dysregulated coagulation and a high risk of morbid arterial and venous thrombotic events....