Accumulation and Intracellular Distribution of Aromatic Diamidines in African Trypanosomes

Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a devastating disease that affects millions of people in the poor nations of sub-Saharan Africa. There is a great need for new treatments of this disease, as only four drugs are currently available, and all are associated with toxicity and other problems. The diamidine, pentamidine, has long been used for the treatment of trypanosomiasis, despite its toxicity and lack of knowledge of its mechanism of action. Drug development efforts have recently focused on creating less toxic, more potent diamidine derivatives of pentamidine with an orally bioavailable formulation. DB289, the prodrug of DB75, is in Phase III clinical trials as an oral treatment of HAT. Almost 2000 diamidines and related compounds have been synthesized, many with potent anti-trypanosomal activity. Although DB75 and other diamidines are potent DNA binders, the overall mechanism of action of this series of compounds is unknown. The focus of this research is to investigate diamidine accumulation and distribution in trypanosomes in vitro and in vivo. Diamidines such as DB75 accumulate to high concentrations in vitro and in vivo in trypanosomes, and localize to the kinetoplast and nucleus, which contain DNA, as well as the acidocalcisomes. The increase in treatment failures of anti-trypanosomal compounds has been a major concern in recent years, especially with melarsoprol. Several trypanosome lines have been developed which are resistant to DB75 in the laboratory, and methods developed to investigate intracellular accumulation and distribution were extended to these lines. These lines lack the P2 transporter, thought to be the main uptake transporter for DB75. DB75 accumulation was lower in the resistant lines, with intracellular distribution also altered. Total accumulation, however, was substantial in these lines, despite lack of the major uptake transporter described for this compound. Benzofuran and benzimidazole diamidines were also investigated. The benzofuran series was found to accumulate in non-DNA containing organelles, which may represent a new mechanism of action for these diamidines. Together, the studies in this dissertation have proven that diamidines selectively accumulate in trypanosomes and that there is likely more than one mechanism of action for diamidines

Mass Media in Society

Panel Chair: Lisa Vazzi Student Presenters: Sarah Mathis, Camila Garcia, Douglas Laman, Amanda Crotzer, and Veronica Nicole Liang Sarah Mathis “The Effects of Media on Women’s Body Image” Camila Garcia “Positive Advantages of Mass Communication” Douglas Laman “Autism, Actually: A Look at Representation of Autism in Pop Culture” Amanda Crotzer “Thruth in Advertising: Targeting Children in and Age of Privatized Media Consumption

Concepts of Fitness and Wellness (GHC)

This Grants Collection for Concepts of Fitness and Wellness was created under a Round Seven ALG Textbook Transformation Grant. Affordable Learning Georgia Grants Collections are intended to provide faculty with the frameworks to quickly implement or revise the same materials as a Textbook Transformation Grants team, along with the aims and lessons learned from project teams during the implementation process. Documents are in .pdf format, with a separate .docx (Word) version available for download. Each collection contains the following materials: Linked Syllabus Initial Proposal Final Reporthttps://oer.galileo.usg.edu/health-collections/1005/thumbnail.jp

Inflammatory arthritis can be reined in by CpG-induced DC–NK cell cross talk

Unmethylated CpG-oligodeoxynucleotides (ODNs) are generally thought of as potent adjuvants with considerable therapeutic potential to enhance immune responses against microbes and tumors. Surprisingly, certain so-called stimulatory CpG-ODNs strongly inhibited the effector phase of inflammatory arthritis in the K/BxN serum transfer system, either preventively or therapeutically. Also unexpected was that the inhibitory influence did not depend on the adaptive immune system cells mobilized in an immunostimulatory context. Instead, they relied on cells of the innate immune system, specifically on cross talk between CD8α+ dendritic cells and natural killer cells, resulting in suppression of neutrophil recruitment to the joint, orchestrated through interleukin-12 and interferon-γ. These findings highlight potential applications of CpG-ODNs and downstream molecules as antiinflammatory agents

Determining the extragalactic extinction law with SALT. II. Additional sample

We present new results from an on-going programme to study the dust extragalactic extinction law in E/S0 galaxies with dust lanes with the Southern African Large Telescope (SALT) during its performance-verification phase. The wavelength dependence of the dust extinction for seven galaxies is derived in six spectral bands ranging from the near-ultraviolet atmospheric cutoff to the near-infrared. The derivation of an extinction law is performed by fitting model galaxies to the unextinguished parts of the image in each spectral band, and subtracting from these the actual images. We compare our results with the derived extinction law in the Galaxy and find them to run parallel to the Galactic extinction curve with a mean total-to-selective extinction value of 2.71+-0.43. We use total optical extinction values to estimate the dust mass for each galaxy, compare these with dust masses derived from IRAS measurements, and find them to range from 10^4 to 10^7 Solar masses. We study the case of the well-known dust-lane galaxy NGC2685 for which HST/WFPC2 data is available to test the dust distribution on different scales. Our results imply a scale-free dust distribution across the dust lanes, at least within ~1 arcsec (~60 pc) regions.Comment: 11 pages, 7 figures, 3 tables. Accepted for publication in MNRAS. R-band contour maps and B-R colour-index maps are low-resolution versions of those used in the MNRAS versio

The Spatially Resolved Star Formation Law from Integral Field Spectroscopy: VIRUS-P Observations of NGC 5194

We investigate the relation between the star formation rate surface density (Sigma_SFR) and the mass surface density of gas (Sigma_gas) in NGC 5194. VIRUS-P integral field spectroscopy is used to measure H-alpha, H-beta [NII]6548,6584, and [SII]6717,6731 emission line fluxes for 735 regions ~170 pc in diameter, and derive extinction corrected Sigma_SFRs. HI 21cm and CO maps are used to measure the HI and H_2 gas surface density for each region. We present a new method for fitting the Star Formation Law (SFL), which includes the intrinsic scatter in the relation as a free parameter, allows the inclusion of non-detections, and is free of the systematics involved in performing linear correlations over incomplete data in logarithmic space. We use the [SII]/H-alpha ratio to separate the H-alpha flux contribution from the diffuse ionized gas (DIG). After removing the DIG, we measure a slope N=0.82+/-0.05, and an intrinsic scatter epsilon=0.43+/-0.02 dex for the molecular gas SFL. We also measure a typical depletion timescale tau~2 Gyr, in good agreement with Bigiel et al. (2008). The HI density shows no correlation with the SFR, and the total gas SFL closely follows the molecular gas SFL. We assess the validity of corrections applied in narrow-band H-alpha measurements to overcome issues related to continuum subtraction, underlying photospheric absorption, and contamination by the [NII] doublet. The disagreement with the super-linear molecular SFL measured by Kennicutt et al. (2007) is due to differences in the fitting method. Our results support a low and close to constant star formation efficiency (SFE = 1/tau) in the molecular ISM. The data shows excellent agreement with the model of Krumholz et al (2009). The large intrinsic scatter may imply the existence of other important parameters setting the SFR.Comment: 23 pages, 19 figures, 14 pages of tables. Accepted for publication in ApJ. (Figure 16 has been corrected from the first submitted version.

Antiparasitic compounds that target DNA

Designed, synthetic heterocyclic diamidines have excellent activity against eukaryotic parasites that cause diseases such as sleeping sickness and leishmania and adversely affect millions of people each year. The most active compounds bind specifically and strongly in the DNA minor groove at AT sequences. The compounds enter parasite cells rapidly and appear first in the kinetoplast that contains the mitochondrial DNA of the parasite. With time the compounds are also generally seen in the cell nucleus but are not significantly observed in the cytoplasm. The kinetoplast decays over time and disappears from the mitochondria of treated cells. At this point the compounds begin to be observed in other regions of the cell, such as the acidocalcisomes. The cells typically die in 24–48 hours after treatment. Active compounds appear to selectively target extended AT sequences and induce changes in kinetoplast DNA minicircles that cause a synergistic destruction of the catenated kinetoplast DNA network and cell death

The Case for a Low Extragalactic Gamma-ray Background

Measurements of the diffuse extragalactic gamma-ray background (EGRB) are complicated by a strong Galactic foreground. Estimates of the EGRB flux and spectrum, obtained by modeling the Galactic emission, have produced a variety of (sometimes conflicting) results. The latest analysis of the EGRET data found an isotropic flux I_x=1.45+-0.05 above 100 MeV, in units of 10^-5 s^-1 cm^-2 sr^-1. We analyze the EGRET data in search for robust constraints on the EGRB flux, finding the gamma-ray sky strongly dominated by Galactic foreground even at high latitudes, with no conclusive evidence for an additional isotropic component. The gamma-ray intensity measured towards the Galactic poles is similar to or lower than previous estimates of I_x. The high latitude profile of the gamma-ray data is disk-like for 40<|b[deg]|<70, and even steeper for |b|>70; overall it exhibits strong Galactic features and is well fit by a simple Galactic model. Based on the |b|>40 data we find that I_x<0.5 at a 99% confidence level, with evidence for a much lower flux. We show that correlations with Galactic tracers, previously used to identify the Galactic foreground and estimate I_x, are not satisfactory; the results depend on the tracers used and on the part of the sky examined, because the Galactic emission is not linear in the Galactic tracers and exhibits spectral variations across the sky. The low EGRB flux favored by our analysis places stringent limits on extragalactic scenarios involving gamma-ray emission, such as radiation from blazars, intergalactic shocks and production of ultra-high energy cosmic rays and neutrinos. We suggest methods by which future gamma-ray missions such as GLAST and AGILE could indirectly identify the EGRB.Comment: Accepted for publication in JCAP. Increased sizes of polar regions examined, and added discussion of spectral data. Results unchange

Desenhando as novas fronteiras para a compreensão do transtorno obsessivo-compulsivo: uma revisão de sua relação com o medo e a ansiedade

Anxiety is an important component of the psychopathology of the obsessive-compulsive disorder (OCD). So far, most interventions that have proven to be effective for treating OCD are similar to those developed for other anxiety disorders. However, neurobiological studies of OCD came to conclusions that are not always compatible with those previously associated with other anxiety disorders. OBJECTIVES: The aim of this study is to review the degree of overlap between OCD and other anxiety disorders phenomenology and pathophysiology to support the rationale that guides research in this field. RESULTS: Clues about the neurocircuits involved in the manifestation of anxiety disorders have been obtained through the study of animal anxiety models, and structural and functional neuroimaging in humans. These investigations suggest that in OCD, in addition to dysfunction in cortico-striatal pathways, the functioning of an alternative neurocircuitry, which involves amygdalo-cortical interactions and participates in fear conditioning and extinction processes, may be impaired. CONCLUSION: It is likely that anxiety is a relevant dimension of OCD that impacts on other features of this disorder. Therefore, future studies may benefit from the investigation of the expression of fear and anxiety by OCD patients according to their type of obsessions and compulsions, age of OCD onset, comorbidities, and patterns of treatment response