Underreporting of side effects of standard first-line ART in the routine setting in Blantyre, Malawi

Introduction: In the Malawi ART programme, 92% of 250,000 patients are using the standard first-line regime of stavudine-lamivudine-nevaripine. National ART reports indicate <4% experience ART side effects, much less than expected from literature.Methods: We interviewed adult patients on standard first-line ART for at least one year, after routine visits to an urban clinic in Blantyre, Malawi. We determined the prevalence of symptoms that are common side-effects, described discrepancies between symptoms that patients reported to us and those that had been recorded by attending staff as side-effects in the point-of-care electronic monitoring system, and studied factors associated with such discrepancies.Results: Of 170 participants, 75 (44%) reported at least one symptom, most common were symptoms suggesting peripheral neuropathy (n=57) and lipodystrophy (n=16). Forty-six (66%) symptomatic patients said they reported symptoms to attending ART staff. Side-effects were recorded in the clinic database for just 4 patients. Toxicity recording was too low for meaningful analysis of factors associated with discrepancies between reporting and recording of side-effects. The prevalence of symptoms indicating characteristic side-effects of the standard first-line regimen was 39% based on interviews, and 2% in the electronic monitoring system. Conclusion: There was gross under-recording of side-effects in this setting, mainly due to not recording by ART staff. Pressure of work and insufficient perceived benefit of side-effect recording are suspected causes. Local and national ART reports do not reflect the true toxicity of the standard firstline regimen

Can Clustal-style progressive pairwise alignment of multiple sequences be used in RNA secondary structure prediction?

<p>Abstract</p> <p>Background</p> <p>In ribonucleic acid (RNA) molecules whose function depends on their final, folded three-dimensional shape (such as those in ribosomes or spliceosome complexes), the secondary structure, defined by the set of internal basepair interactions, is more consistently conserved than the primary structure, defined by the sequence of nucleotides.</p> <p>Results</p> <p>The research presented here investigates the possibility of applying a progressive, pairwise approach to the alignment of multiple RNA sequences by simultaneously predicting an energy-optimized consensus secondary structure. We take an existing algorithm for finding the secondary structure common to two RNA sequences, Dynalign, and alter it to align profiles of multiple sequences. We then explore the relative successes of different approaches to designing the tree that will guide progressive alignments of sequence profiles to create a multiple alignment and prediction of conserved structure.</p> <p>Conclusion</p> <p>We have found that applying a progressive, pairwise approach to the alignment of multiple ribonucleic acid sequences produces highly reliable predictions of conserved basepairs, and we have shown how these predictions can be used as constraints to improve the results of a single-sequence structure prediction algorithm. However, we have also discovered that the amount of detail included in a consensus structure prediction is highly dependent on the order in which sequences are added to the alignment (the guide tree), and that if a consensus structure does not have sufficient detail, it is less likely to provide useful constraints for the single-sequence method.</p

Quantitative principles of cis-translational control by general mRNA sequence features in eukaryotes.

BackgroundGeneral translational cis-elements are present in the mRNAs of all genes and affect the recruitment, assembly, and progress of preinitiation complexes and the ribosome under many physiological states. These elements include mRNA folding, upstream open reading frames, specific nucleotides flanking the initiating AUG codon, protein coding sequence length, and codon usage. The quantitative contributions of these sequence features and how and why they coordinate to control translation rates are not well understood.ResultsHere, we show that these sequence features specify 42-81% of the variance in translation rates in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, Mus musculus, and Homo sapiens. We establish that control by RNA secondary structure is chiefly mediated by highly folded 25-60 nucleotide segments within mRNA 5' regions, that changes in tri-nucleotide frequencies between highly and poorly translated 5' regions are correlated between all species, and that control by distinct biochemical processes is extensively correlated as is regulation by a single process acting in different parts of the same mRNA.ConclusionsOur work shows that general features control a much larger fraction of the variance in translation rates than previously realized. We provide a more detailed and accurate understanding of the aspects of RNA structure that directs translation in diverse eukaryotes. In addition, we note that the strongly correlated regulation between and within cis-control features will cause more even densities of translational complexes along each mRNA and therefore more efficient use of the translation machinery by the cell

Telepresence and the Role of the Senses

The telepresence experience can be evoked in a number of ways. A well-known example is a player of videogames who reports about a telepresence experience, a subjective experience of being in one place or environment, even when physically situated in another place. In this paper we set the phenomenon of telepresence into a theoretical framework. As people react subjectively to stimuli from telepresence, empirical studies can give more evidence about the phenomenon. Thus, our contribution is to bridge the theoretical with the empirical. We discuss theories of perception with an emphasis on Heidegger, Merleau-Ponty and Gibson, the role of the senses and the Spinozian belief procedure. The aim is to contribute to our understanding of this phenomenon. A telepresence-study that included the affordance concept is used to empirically study how players report sense-reactions to virtual sightseeing in two cities. We investigate and explore the interplay of the philosophical and the empirical. The findings indicate that it is not only the visual sense that plays a role in this experience, but all senses

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved

FHY1 Mediates Nuclear Import of the Light-Activated Phytochrome A Photoreceptor

The phytochrome (phy) family of photoreceptors is of crucial importance throughout the life cycle of higher plants. Light-induced nuclear import is required for most phytochrome responses. Nuclear accumulation of phyA is dependent on two related proteins called FHY1 (Far-red elongated HYpocotyl 1) and FHL (FHY1 Like), with FHY1 playing the predominant function. The transcription of FHY1 and FHL are controlled by FHY3 (Far-red elongated HYpocotyl 3) and FAR1 (FAr-red impaired Response 1), a related pair of transcription factors, which thus indirectly control phyA nuclear accumulation. FHY1 and FHL preferentially interact with the light-activated form of phyA, but the mechanism by which they enable photoreceptor accumulation in the nucleus remains unsolved. Sequence comparison of numerous FHY1-related proteins indicates that only the NLS located at the N-terminus and the phyA-interaction domain located at the C-terminus are conserved. We demonstrate that these two parts of FHY1 are sufficient for FHY1 function. phyA nuclear accumulation is inhibited in the presence of high levels of FHY1 variants unable to enter the nucleus. Furthermore, nuclear accumulation of phyA becomes light- and FHY1-independent when an NLS sequence is fused to phyA, strongly suggesting that FHY1 mediates nuclear import of light-activated phyA. In accordance with this idea, FHY1 and FHY3 become functionally dispensable in seedlings expressing a constitutively nuclear version of phyA. Our data suggest that the mechanism uncovered in Arabidopsis is conserved in higher plants. Moreover, this mechanism allows us to propose a model explaining why phyA needs a specific nuclear import pathway

Analysis of the EIAV Rev-Responsive Element (RRE) Reveals a Conserved RNA Motif Required for High Affinity Rev Binding in Both HIV-1 and EIAV

A cis-acting RNA regulatory element, the Rev-responsive element (RRE), has essential roles in replication of lentiviruses, including human immunodeficiency virus (HIV-1) and equine infection anemia virus (EIAV). The RRE binds the viral trans-acting regulatory protein, Rev, to mediate nucleocytoplasmic transport of incompletely spliced mRNAs encoding viral structural genes and genomic RNA. Because of its potential as a clinical target, RRE-Rev interactions have been well studied in HIV-1; however, detailed molecular structures of Rev-RRE complexes in other lentiviruses are still lacking. In this study, we investigate the secondary structure of the EIAV RRE and interrogate regulatory protein-RNA interactions in EIAV Rev-RRE complexes. Computational prediction and detailed chemical probing and footprinting experiments were used to determine the RNA secondary structure of EIAV RRE-1, a 555 nt region that provides RRE function in vivo. Chemical probing experiments confirmed the presence of several predicted loop and stem-loop structures, which are conserved among 140 EIAV sequence variants. Footprinting experiments revealed that Rev binding induces significant structural rearrangement in two conserved domains characterized by stable stem-loop structures. Rev binding region-1 (RBR-1) corresponds to a genetically-defined Rev binding region that overlaps exon 1 of the EIAV rev gene and contains an exonic splicing enhancer (ESE). RBR-2, characterized for the first time in this study, is required for high affinity binding of EIAV Rev to the RRE. RBR-2 contains an RNA structural motif that is also found within the high affinity Rev binding site in HIV-1 (stem-loop IIB), and within or near mapped RRE regions of four additional lentiviruses. The powerful integration of computational and experimental approaches in this study has generated a validated RNA secondary structure for the EIAV RRE and provided provocative evidence that high affinity Rev binding sites of HIV-1 and EIAV share a conserved RNA structural motif. The presence of this motif in phylogenetically divergent lentiviruses suggests that it may play a role in highly conserved interactions that could be targeted in novel anti-lentiviral therapies

Computational Biology in Costa Rica: The Role of a Small Country in the Global Context of Bioinformatics

Introduction: The successful development of high throughput methods for DNA sequencing, transcriptomics, proteomics, and other –omics, has contributed to the emergence of novel possibilities for the examination of complex biological systems through computational analysis. These fields have witnessed unprecedented advances in high income countries. Nevertheless, the role of other nations needs to be examined in order to delineate their contribution within the global context of bioinformatics. Previous articles have focused on the expansion of Computational Biology in Brazil and Mexico [1],[2], two of the largest Latin American countries, and which have shown political commitment to foster their scientific development. Costa Rica is a small Central American country with a population of 4 million, with its territory 164 and 38 times smaller than Brazil and Mexico, respectively. Thus, it is interesting to visualize the possibilities and challenges of this low-income country in the context of the global bioinformatics endeavor.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Testing foundations of quantum mechanics with photons

The foundational ideas of quantum mechanics continue to give rise to counterintuitive theories and physical effects that are in conflict with a classical description of Nature. Experiments with light at the single photon level have historically been at the forefront of tests of fundamental quantum theory and new developments in photonics engineering continue to enable new experiments. Here we review recent photonic experiments to test two foundational themes in quantum mechanics: wave-particle duality, central to recent complementarity and delayed-choice experiments; and Bell nonlocality where recent theoretical and technological advances have allowed all controversial loopholes to be separately addressed in different photonics experiments.Comment: 10 pages, 5 figures, published as a Nature Physics Insight review articl