Genetic diversity of the E Protein of Dengue Type 3 Virus

<p>Abstract</p> <p>Background</p> <p>Dengue is the most important arbovirus disease in tropical and subtropical countries. The viral envelope (E) protein is responsible for cell receptor binding and is the main target of neutralizing antibodies. The aim of this study was to analyze the diversity of the E protein gene of DENV-3. E protein gene sequences of 20 new viruses isolated in Ribeirao Preto, Brazil, and 427 sequences retrieved from GenBank were aligned for diversity and phylogenetic analysis.</p> <p>Results</p> <p>Comparison of the E protein gene sequences revealed the presence of 47 variable sites distributed in the protein; most of those amino acids changes are located on the viral surface. The phylogenetic analysis showed the distribution of DENV-3 in four genotypes. Genotypes I, II and III revealed internal groups that we have called lineages and sub-lineages. All amino acids that characterize a group (genotype, lineage, or sub-lineage) are located in the 47 variable sites of the E protein.</p> <p>Conclusion</p> <p>Our results provide information about the most frequent amino acid changes and diversity of the E protein of DENV-3.</p

Ribosomal oxygenases are structurally conserved from prokaryotes to humans

2-Oxoglutarate (2OG)-dependent oxygenases have important roles in the regulation of gene expression via demethylation of N-methylated chromatin components1,2 and in the hydroxylation of transcription factors3 and splicing factor proteins4. Recently, 2OG-dependent oxygenases that catalyse hydroxylation of transfer RNA5,6,7 and ribosomal proteins8 have been shown to be important in translation relating to cellular growth, TH17-cell differentiation and translational accuracy9,10,11,12. The finding that ribosomal oxygenases (ROXs) occur in organisms ranging from prokaryotes to humans8 raises questions as to their structural and evolutionary relationships. In Escherichia coli, YcfD catalyses arginine hydroxylation in the ribosomal protein L16; in humans, MYC-induced nuclear antigen (MINA53; also known as MINA) and nucleolar protein 66 (NO66) catalyse histidine hydroxylation in the ribosomal proteins RPL27A and RPL8, respectively. The functional assignments of ROXs open therapeutic possibilities via either ROX inhibition or targeting of differentially modified ribosomes. Despite differences in the residue and protein selectivities of prokaryotic and eukaryotic ROXs, comparison of the crystal structures of E. coli YcfD and Rhodothermus marinus YcfD with those of human MINA53 and NO66 reveals highly conserved folds and novel dimerization modes defining a new structural subfamily of 2OG-dependent oxygenases. ROX structures with and without their substrates support their functional assignments as hydroxylases but not demethylases, and reveal how the subfamily has evolved to catalyse the hydroxylation of different residue side chains of ribosomal proteins. Comparison of ROX crystal structures with those of other JmjC-domain-containing hydroxylases, including the hypoxia-inducible factor asparaginyl hydroxylase FIH and histone Nε-methyl lysine demethylases, identifies branch points in 2OG-dependent oxygenase evolution and distinguishes between JmjC-containing hydroxylases and demethylases catalysing modifications of translational and transcriptional machinery. The structures reveal that new protein hydroxylation activities can evolve by changing the coordination position from which the iron-bound substrate-oxidizing species reacts. This coordination flexibility has probably contributed to the evolution of the wide range of reactions catalysed by oxygenases

Influence of probenecid on the pharmacokinetics and pharmacodynamics of sorafenib

Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200–800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2–15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC0–12 h) as primary endpoint. During concomitant probenecid, s

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

Coastal shoreline change assessments at global scales

During the present era of rapid climate change and sea-level rise, coastal change science is needed at global, regional, and local scales. Essential elements of this science, regardless of scale, include that the methods are defendable and that the results are independently verifiable. The recent contribution by Almar et al.1 does not achieve either of these measures as shown by: (i) the use of an error-prone proxy for coastal shoreline and (ii) analyses that are circular and explain little of the data variance

ZTF Early Observations of Type Ia Supernovae. I. Properties of the 2018 Sample

Early-time observations of Type Ia supernovae (SNe Ia) are essential to constrain the properties of their progenitors. In this paper, we present high-quality light curves of 127 SNe Ia discovered by the Zwicky Transient Facility (ZTF) in 2018. We describe our method to perform forced point-spread function photometry, which can be applied to other types of extragalactic transients. With a planned cadence of six observations per night (three g + three r), all of the 127 SNe Ia are detected in both g and r bands more than 10 days (in the rest frame) prior to the epoch of g-band maximum light. The redshifts of these objects range from z = 0.0181 to 0.165; the median redshift is 0.074. Among the 127 SNe, 50 are detected at least 14 days prior to maximum light (in the rest frame), with a subset of nine objects being detected more than 17 days before g-band peak. This is the largest sample of young SNe Ia collected to date; it can be used to study the shape and color evolution of the rising light curves in unprecedented detail. We discuss six peculiar events in this sample: one 02cx-like event ZTF18abclfee (SN 2018crl), one Ia-CSM SN ZTF18aaykjei (SN 2018cxk), and four objects with possible super-Chandrasekhar mass progenitors: ZTF18abhpgje (SN 2018eul), ZTF18abdpvnd (SN 2018dvf), ZTF18aawpcel (SN 2018cir), and ZTF18abddmrf (SN 2018dsx). © 2019. The American Astronomical Society

ZTF 18aaqeasu (SN 2018byg): A Massive Helium-shell Double Detonation on a Sub-Chandrasekhar Mass White Dwarf

The detonation of a helium shell on a white dwarf has been proposed as a possible explosion triggering mechanism for Type Ia supernovae. Here, we report ZTF 18aaqeasu (SN 2018byg/ATLAS 18pqq), a peculiar Type I supernova, consistent with being a helium-shell double-detonation. With a rise time of $\approx 18$ days from explosion, the transient reached a peak absolute magnitude of $M_R \approx -18.2$ mag, exhibiting a light curve akin to sub-luminous SN 1991bg-like Type Ia supernovae, albeit with an unusually steep increase in brightness within a week from explosion. Spectra taken near peak light exhibit prominent Si absorption features together with an unusually red color ($g-r \approx 2$ mag) arising from nearly complete line blanketing of flux blue-wards of 5000 \AA. This behavior is unlike any previously observed thermonuclear transient. Nebular phase spectra taken at and after $\approx 30$ days from peak light reveal evidence of a thermonuclear detonation event dominated by Fe-group nucleosynthesis. We show that the peculiar properties of ZTF 18aaqeasu are consistent with the detonation of a massive ($\approx 0.15$ M$_\odot$) helium shell on a sub-Chandrasekhar mass ($\approx 0.75$ M$_\odot$) white dwarf after including mixing of $\approx 0.2$ M$_\odot$ of material in the outer ejecta. These observations provide evidence of a likely rare class of thermonuclear supernovae arising from detonations of massive helium shells.Comment: 10 pages, 6 figures. Submitted to ApJ