Genetic and Epigenetic Determinants of Transcription in the Divergent Eukaryote Leishmania major

Leishmania spp. and other trypanosomatid protozoa use a highly unusual mechanism to generate functional messenger RNAs (mRNAs) in which protein-coding genes are transcribed polycistronically. Here, transcription initiates primarily in divergent strand switch regions (dSSRs), where two polycistronic gene clusters are oriented head-to-head. These regions lack all known eukaryotic cis-regulatory elements, and it is not known how genetic and epigenetic factors cooperate to define dSSRs as regions of productive initiation. To quantitatively identify regulatory elements and to study the contribution of epigenetic factors to dSSR function, we combined genome-wide studies of chromatin structure with a focused interrogation of a single dSSR using a novel integrated bidirectional, dual-luciferase reporter. Chromatin-based studies demonstrated that Leishmania lack well-positioned nuclease-hypersensitive sites associated with promoters in other eukaryotes. Rather, nuclease-hypersensitive sites are positioned heterogeneously across broad regions associated with epigenetic marks indicative of active transcription, suggesting that transcription initiation events occur promiscuously within regions associated with a transcriptionally-permissive epigenetic state. Our studies using the bidirectional reporter validate these observations and strongly suggest that Leishmania do not require cis-regulatory elements for efficient bidirectional transcription initiating in dSSRs, as a large region of the dSSR can be replaced with unrelated sequences without altering bidirectional reporter gene expression. In addition to these genetic studies we also focused on epigenetic determinants of transcriptional activity in Leishmania, with respect to both transcription initiation and transcription termination. We showed that the histone variants H2A.Z and H2B.V, which are associated with transcriptionally permissive regions in T. brucei, are essential in L. major, while the transcription termination-associated histone variant H3.V is not. Interestingly, unlike Leishmania lacking the DNA modification base J, H3.V-null L. major shows no defects in transcription termination. Although the study of essential genes in Leishmania is challenging at this time, we present preliminary data describing elements of inducible gene expression systems which may improve our ability to study essential genes. Together, the data in this thesis show that transcription of protein-coding genes is primarily determined epigenetically, and suggest that chromatin-related processes may be an attractive target for therapeutic intervention

MOVILIDAD FRONTERIZA EN THEIR DOGS CAME WITH THEM DE HELENA MARÍA VIRAMONTES

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The double disparity facing rural local health departments: A short report

Rural residents in the U.S. face significant health challenges, including higher rates of risky health behaviors and worse health outcomes than many other groups. Rural communities are also typically served by local health departments (LHDs) that have fewer human and financial resources than their suburban and urban peers. As a result of history and need, rural LHDs are more likely than urban LHDs to provide direct health services, which may result in limited resources for population-based activities. This review examines the double disparity facing rural LHDs and their constituents: pervasively poorer health behaviors and outcomes and a historical lack of investment by local, state, and federal public health entities

A Survey of OB / GYN Physicians' Training & Current Practice Patterns in Breast Care

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94493/1/tbj12028.pd

The Double Disparity Facing Rural Local Health Departments

Residents of rural jurisdictions face significant health challenges, including some of the highest rates of risky health behaviors and worst health outcomes of any group in the country. Rural communities are served by smaller local health departments (LHDs) that are more understaffed and underfunded than their suburban and urban peers. As a result of history and current need, rural LHDs are more likely than their urban peers to be providers of direct health services, leading to relatively lower levels of population-focused activities. This review examines the double disparity faced by rural LHDs and their constituents: pervasively poorer health behaviors and outcomes and a historical lack of investment by local, state, and federal public health entities

Pulmonary exposure to single-walled carbon nanotubes does not affect the early immune response against Toxoplasma gondii

Background Single-walled carbon nanotubes (SWCNT) trigger pronounced inflammation and fibrosis in the lungs of mice following administration via pharyngeal aspiration or inhalation. Human exposure to SWCNT in an occupational setting may occur in conjunction with infections and this could yield enhanced or suppressed responses to the offending agent. Here, we studied whether the sequential exposure to SWCNT via pharyngeal aspiration and infection of mice with the ubiquitous intracellular parasite Toxoplasma gondii would impact on the immune response of the host against the parasite. Methods C57BL/6 mice were pre-exposed by pharyngeal administration of SWCNT (80 + 80 μg/mouse) for two consecutive days followed by intravenous injection with either 1x103 or 1x104 green fluorescence protein and luciferase-expressing T. gondii tachyzoites. The dissemination of T. gondii was monitored by in vivobioluminescence imaging in real time for 7 days and by plaque formation. The inflammatory response was analysed in bronchoalveolar lavage (BAL) fluid, and by assessment of morphological changes and immune responses in lung and spleen. Results There were no differences in parasite distribution between mice only inoculated with T. gondii or those mice pre-exposed for 2 days to SWCNT before parasite inoculum. Lung and spleen histology and inflammation markers in BAL fluid reflected the effects of SWCNT exposure and T. gondii injection, respectively. We also noted that CD11c positive dendritic cells but not F4/80 positive macrophages retained SWCNT in the lungs 9 days after pharyngeal aspiration. However, co-localization of T. gondii with CD11c or F4/80 positive cells could not be observed in lungs or spleen. Pre-exposure to SWCNT did not affect the splenocyte response to T. gondii. Conclusions Taken together, our data indicate that pre-exposure to SWCNT does not enhance or suppress the early immune response to T. gondii in mice

Mathematical modeling of the metastatic process

Mathematical modeling in cancer has been growing in popularity and impact since its inception in 1932. The first theoretical mathematical modeling in cancer research was focused on understanding tumor growth laws and has grown to include the competition between healthy and normal tissue, carcinogenesis, therapy and metastasis. It is the latter topic, metastasis, on which we will focus this short review, specifically discussing various computational and mathematical models of different portions of the metastatic process, including: the emergence of the metastatic phenotype, the timing and size distribution of metastases, the factors that influence the dormancy of micrometastases and patterns of spread from a given primary tumor.Comment: 24 pages, 6 figures, Revie

High-Order Visual Processing, Visual Symptoms, and Visual Hallucinations: A Possible Symptomatic Progression of Parkinson's Disease

Objective: To determine whether Parkinson disease (PD) patients with (VH) have different clinical characteristics and gray-matter volume than those with visual misperceptions (VM) or other visual symptoms (OvS).Background: The spectrum of visual complaints in PD is broad and complex.Methods: We conducted a retrospective chart review of 525 PD patients to identify the frequency of visual symptoms and the association with clinical and radiological features. Brain volumetric MRI data was analyzed using multivariate logistic regression to differentiate cases with and without visual symptoms.Results: Among 525 PD cases, visual complaints were documented in 177 (33.7%). Among these, 83 (46.9%) had VH, 31 (17.5%) had VM, and 63 (35.6%) had OvS (diplopia, blurry vision, photophobia, dry eyes, and eye pain or soreness). When compared to OvS, patients with VH had significantly higher age, duration of disease, rate of REM sleep behavior disorder, and cognitive impairment. Visual hallucinations patients had decreased age-adjusted volumetric averages in 28/30 gray-matter regions when compared to PD without visual symptoms and 30/30 gray-matter regions when compared to VM patients.Conclusions: Visual symptoms in PD may represent a spectrum from OvS to VM to VH, with progression of the latter associated with older age, duration of disease, presence of REM sleep behavior disorder, cognitive impairment, and decreased gray-matter volume