Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Objectives: The resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care. Methods: We studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1). Results: At T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts. Conclusions: Viraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission

Interspecies serum and complement-dependent mechanisms influencing the cellular uptake of nanoparticles.

Nanoparticles are utilized in a wide variety of biomedical fields and theranostic nanomedicine from imaging and sensing to drug delivery. Multifunctional nanoparticles encapsulated with imaging probes/diagnostic agents or therapeutic agents can be delivered in vivo via passive or active targeting, making them effective and efficient therapeutic agents. However, in order to optimize their efficacy, nanoparticle platforms must be designed in a way which limits cytotoxicity and optimizes biocompatibility for safe medical use. The human immune system is a complex system of networks and cascade reactions which are intricate and tightly regulated. It is mainly comprised of two important reaction systems, the complement and coagulation cascade. In order to prolong the nanoparticles circulating in the bloodstream as well as enhancing sustained release of drugs to targeted tissues, surface functionalization ultimately reduces coagulation or complement activation by inhibiting the adsorption of blood proteins (stealthing) on the nanoparticles surface, called opsonization. The most widely used surface functionalization is polyethylene glycol (PEG). The chemical conjugation of attaching this organic moiety to the nanoparticle is known as PEGylation. PEGylated particles undergo changes in physicochemical properties contributing to the overall stability and stealth ability PEG provides to nanoparticles. However, there are many drawbacks limiting the usefulness of PEGylation including complement activation or degradation. Therefore, we have proposed and fully characterized alternative polymers, poly(2-methyl-2-oxazoline) (PMOXA) and poly(2-ethyl-2-oxazoline) (PEtOXA) which are more biocompatible, can escape the mononuclear phagocyte system (MPS), and are easier to synthesize than PEG. Furthermore, we proposed two nanoparticle systems in order to characterize how biophysicochemical properties like surface functionalization and charge alter the way in which particles’ interact with biological systems. We used two nanoparticle systems: 1) Inorganic solid silica (SiO2-NPs) as they have become of increasing interest in controlled drug release due to their accessibility, versatility, high capacity of processing, and physical-chemical properties adapted through synthesis; 2) Gold nanoparticles (Au-NPs) due to their vast and unique optical and physical features. Au-NPs are inert, have extreme resistance to oxidation, and they are easily able to be functionalized by thiol compounds. In the second part of my dissertation, I use two alternative animal models in order to probe and characterize the interactions nanoparticles have in non-human systems. Prior to human clinical trials, drugs were often tested in vitro and in vivo in a murine model, yet failed to be approved when proceeding with human trials. In many cases, mice responded quite differently than humans to drugs, contributing to the high failure rate of drug development. In fact, the majority of drugs never reach the marketplace following clinical trials. Therefore, it is imperative to understand the attributes which contribute to this phenomena so as to increase therapeutic applications of nanoparticles

Mudanças e/ou permanências : relações étnico-raciais no livro didático de língua inglesa

Dissertação (mestrado)—Universidade de Brasília, Programa de Pós-Graduação em Linguística Aplicada, 2013.O objetivo deste trabalho é debater sobre a educação das relações étnico-raciais nos livros didáticos de língua inglesa com referência às Diretrizes Curriculares Nacionais para a Educação das Relações Étnico-raciais e para o Ensino de História e Cultura Afro-brasileira e Africana. Algumas obras de ensino de língua inglesa anteriores e posteriores à publicação das Diretrizes foram selecionadas para comparação. Esta investigação trata, portanto, de uma análise documental cuja teoria está embasada nas práticas interpretativas do pesquisador. Neste estudo, observa-se que inúmeras modificações foram realizadas nos livros didáticos de língua inglesa, com o passar do tempo, embora essas mudanças não contemplem, corretamente, os princípios das Diretrizes. Por essa razão, esta investigação sugere o uso e a adequação do proposto pelas Diretrizes nas obras, considerando-se necessária a apropriação, principalmente, da cultura e história afro-brasileira que não estão presentes na maior parte dos livros didáticos. ______________________________________________________________________________ ABSTRACTThe goal of this research is to discuss the education of ethnic-racial relations in English textbooks regarding the “National Curricular Guidelines to the Education of Ethnic-racial Relations and to the Teaching of Afro-Brazilian and African History and Culture.” Some English textbooks published before and after the establishment of the Guidelines, were selected to be compared. This study deals with the theory of documentary analysis which is based on the interpretative practices of the researcher. In this study, it is observed that many modifications in English textbooks took place with the passing of time, although these changes do not follow, correctly, the principles of the Guidelines. For this reason, this research proposes the use and the adequacy of these Guidelines in the textbooks, considering necessary the appropriation, mainly, of Afro-Brazilian culture and history, which are not shown in major part of the textbooks

Assessing citizen science in the marine environment

Citizen science, where the general public is engaged with and participates in a scientific project, is increasingly being recognised as an effective tool for science education, developing knowledge and science skills, promoting guardianship, democratising science and reducing the costs of long-term data collection compared to normal scientific research. However, there is reluctance by environmental managers to use it as a scientific method for monitoring due to concern regarding the quality of data collected by volunteers. The robustness of data collected by citizen scientists, in this case students (aged between five and fifteen), was assessed during a facilitated citizen science project that monitored the impacts of a dredging programme on the rocky intertidal shore of Otago Harbour in Dunedin, New Zealand. Students assessed biodiversity and percentage cover of substrate at two shore heights across six locations over three years (2016-2018) using transect/quadrat methods. In one year, trained scientists (minimum three years of tertiary education in marine science and experienced with the local marine environment) collected data in the same manner as students and the two datasets were compared to assess the quality of the student-collected data. Comparisons indicated that students and scientists showed similar ability to quantify species presence and abundance in a specific area. Multivariate analysis showed there were dissimilarities between the two datasets which was attributed to estimated densities of Austrominius modestus (beaked barnacle). Scientists and students estimated substrate cover using three different techniques (printed out photographs, volumetric measurements of sediment and visual percentage cover estimates) were assessed for their practicality for a citizen science project and agreeability of estimations between the two surveyors. It was found that using a combination of photographs and visual surveys was the most appropriate method for monitoring sediment on the rocky intertidal. Mind maps and identification tests were used to assess the development of science skills and knowledge during the project. Pre- and post-tests showed that students’ identification skills improved after participating in the project. There was also an increase in the number of students achieving 100% correct identification. Mind maps showed a shift in thinking from planning out their own scientific investigation (asking additional questions, gathering background information and predicting outcomes) to thinking about the methods and equipment required to carry out an investigation in the marine environment and future implications of the dredging. This research validated the data collected by citizen scientists as part of a facilitated marine monitoring project. It also provided valuable insight into Otago Harbour ecosystems and demonstrated an opportunity to engage students in collecting useful environmental data on a relevant issue. Long-term monitoring of coastal areas is greatly needed and the collaboration between scientists and the general public could be utilised to fill in the gaps in current monitoring schemes. Citizen science has the ability to improve environmental management by providing useful data sets that can be used to inform managers when making management decisions whilst increasing public environmental awareness. However, citizen science is not applicable for all forms of monitoring and should be only considered where appropriate levels of support are available, when science outcomes align with the goals of the community involved (which should be clarified prior to commencement of projects) and information gathered can be relayed on to the community. In order for citizen science to make a valuable contribution to scientific research, funding is essential for engaging scientists, volunteers and managers who each provide important roles ensuring citizen science projects collect quality data in an efficient manner

A density functional study of open-shell cyclopentadienyl-molybdenum(II) complexes. A comparison of stabilizing factors: Spin-pairing, Mo-X π bonding, and release of steric pressure

The dissociation of PH3 from the 18-electron system CpMoX(PH3)3 to afford the corresponding 16-electron CpMoX(PH3)2 fragment has been investigated theoretically by density functional theory for X = H, CH3, F, Cl, Br, I, OH, and PH2. The product is found to prefer a triplet spin state for all X ligands except PH2, the singlet-triplet gap varying between 1.7 kcal/mol for OH to 8.7 kcal/mol for F. The Mo-PH3 bond dissociation energy to the 16-electron ground state varies dramatically across the series, from 4.5 kcal/mol for OH to 23.5 kcal/mol for H, and correlates with experimental observations on trisubstituted phosphine derivatives. Geometry-optimized spin doublet CpMo(PH3)3, on the other hand, has a Mo-PH3 bond dissociation energy of 24.3 kcal/mol. The modulation of the Mo-PH3 bond dissociation energy by the introduction of X is analyzed in terms of three effects that stabilize the 16-electron product relative to the 18-electron starting complex: (i) adoption of the higher (triplet) spin state by release of pairing energy; (ii) Mo-X π interactions; (iii) release of steric pressure. A computational model for the approximate separation and evaluation of these three stabilizing effects is presented. According to the results of these calculations, the relative importance of the three effects depends on various factors related to the nature of X. For double-sided π-donor X ligands, the larger triplet-singlet gap is provided by the more electronegative atoms (F \u3e CL \u3e Br \u3e I), whereas single-sided π donors favor the singlet state. The π-stabilization ability goes in the order PH2 \u3e OH \u3e F \u3e other halogens \u3e H. Finally, the major steric interaction appears to be associated with the presence of inactive lone pairs and by their orientation/proximity to the PH3 ligands (Cl, Br \u3e I, OH \u3e F, PH2, H, CH3). The 16-electron methyl system establishes a marked α-agostic interaction in the singlet state, which nevertheless remains unfavored relative to an undistorted triplet configuration

Demonstrating high-precision photometry with a CubeSat: ASTERIA observations of 55 Cancri e

ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) is a 6U CubeSat space telescope (10 cm x 20 cm x 30 cm, 10 kg). ASTERIA's primary mission objective was demonstrating two key technologies for reducing systematic noise in photometric observations: high-precision pointing control and high-stabilty thermal control. ASTERIA demonstrated 0.5 arcsecond RMS pointing stability and $\pm$10 milliKelvin thermal control of its camera payload during its primary mission, a significant improvement in pointing and thermal performance compared to other spacecraft in ASTERIA's size and mass class. ASTERIA launched in August 2017 and deployed from the International Space Station (ISS) November 2017. During the prime mission (November 2017 -- February 2018) and the first extended mission that followed (March 2018 - May 2018), ASTERIA conducted opportunistic science observations which included collection of photometric data on 55 Cancri, a nearby exoplanetary system with a super-Earth transiting planet. The 55 Cancri data were reduced using a custom pipeline to correct CMOS detector column-dependent gain variations. A Markov Chain Monte Carlo (MCMC) approach was used to simultaneously detrend the photometry using a simple baseline model and fit a transit model. ASTERIA made a marginal detection of the known transiting exoplanet 55 Cancri e ($\sim2$~\Rearth), measuring a transit depth of $374\pm170$ ppm. This is the first detection of an exoplanet transit by a CubeSat. The successful detection of super-Earth 55 Cancri e demonstrates that small, inexpensive spacecraft can deliver high-precision photometric measurements.Comment: 23 pages, 9 figures. Accepted in A

Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape

Peer reviewedPublisher PD

Muon Simulations for Super-Kamiokande, KamLAND and CHOOZ

Muon backgrounds at Super-Kamiokande, KamLAND and CHOOZ are calculated using MUSIC. A modified version of the Gaisser sea level muon distribution and a well-tested Monte Carlo integration method are introduced. Average muon energy, flux and rate are tabulated. Plots of average energy and angular distributions are given. Implications on muon tracker design for future experiments are discussed.Comment: Revtex4 33 pages, 16 figures and 4 table

Star Formation Histories of the LEGUS dwarf galaxies. II. Spatially resolved star formation history of the Magellanic irregular NGC 4449

We present a detailed study of the Magellanic irregular galaxy NGC 4449 based on both archival and new photometric data from the Legacy Extragalactic UV Survey, obtained with the Hubble Space Telescope Advanced Camera for Surveys and Wide Field Camera 3. Thanks to its proximity ($D=3.82\pm 0.27$ Mpc) we reach stars 3 magnitudes fainter than the tip of the red giant branch in the F814W filter. The recovered star formation history spans the whole Hubble time, but due to the age-metallicity degeneracy of the red giant branch stars, it is robust only over the lookback time reached by our photometry, i.e. $\sim 3$ Gyr. The most recent peak of star formation is around 10 Myr ago. The average surface density star formation rate over the whole galaxy lifetime is $0.01$ M$_{\odot}$ yr$^{-1}$ kpc$^{-2}$. From our study it emerges that NGC 4449 has experienced a fairly continuous star formation regime in the last 1 Gyr with peaks and dips whose star formation rates differ only by a factor of a few. The very complex and disturbed morphology of NGC 4449 makes it an interesting galaxy for studies of the relationship between interactions and starbursts, and our detailed and spatially resolved analysis of its star formation history does indeed provide some hints on the connection between these two phenomena in this peculiar dwarf galaxy.Comment: 16 pages, 25 figures. Accepted for publication in the Astrophysical Journa