861 research outputs found
Suicide Among Aboriginal People in Canada
This report looks at the complex issues that surround Aboriginal suicide in Canad
Invasion by P. falciparum Merozoites Suggests a Hierarchy of Molecular Interactions
Central to the pathology of malaria disease are the repeated cycles of parasite invasion and destruction of human erythrocytes. In Plasmodium falciparum, the most virulent species causing malaria, erythrocyte invasion involves several specific receptor–ligand interactions that direct the pathway used to invade the host cell, with parasites varying in their dependency on these different pathways. Gene disruption of a key invasion ligand in the 3D7 parasite strain, the P. falciparum reticulocyte binding-like homolog 2b (PfRh2b), resulted in the parasite invading via a novel pathway. Here, we show results that suggest the molecular basis for this novel pathway is not due to a molecular switch but is instead mediated by the redeployment of machinery already present in the parent parasite but masked by the dominant role of PfRh2b. This would suggest that interactions directing invasion are organized hierarchically, where silencing of dominant invasion ligands reveal underlying alternative pathways. This provides wild parasites with the ability to adapt to immune-mediated selection or polymorphism in erythrocyte receptors and has implications for the use of invasion-related molecules in candidate vaccines
Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites
BACKGROUND: The apicomplexan parasite Plasmodium falciparum causes the most severe form of malaria in humans. After invasion into erythrocytes, asexual parasite stages drastically alter their host cell and export remodeling and virulence proteins. Previously, we have reported identification and functional analysis of a short motif necessary for export of proteins out of the parasite and into the red blood cell. RESULTS: We have developed software for the prediction of exported proteins in the genus Plasmodium, and identified exported proteins conserved between malaria parasites infecting rodents and the two major causes of human malaria, P. falciparum and P. vivax. This conserved 'exportome' is confined to a few subtelomeric chromosomal regions in P. falciparum and the synteny of these and surrounding regions is conserved in P. vivax. We have identified a novel gene family PHIST (for Plasmodium helical interspersed subtelomeric family) that shares a unique domain with 72 paralogs in P. falciparum and 39 in P. vivax; however, there is only one member in each of the three species studied from the P. berghei lineage. CONCLUSION: These data suggest radiation of genes encoding remodeling and virulence factors from a small number of loci in a common Plasmodium ancestor, and imply a closer phylogenetic relationship between the P. vivax and P. falciparum lineages than previously believed. The presence of a conserved 'exportome' in the genus Plasmodium has important implications for our understanding of both common mechanisms and species-specific differences in host-parasite interactions, and may be crucial in developing novel antimalarial drugs to this infectious disease
Efficacy and safety of oral methazolamide in patients with type 2 diabetes: A 24-week, placebo-controlled, double-blind study
OBJECTIVE To evaluate the safety and efficacy of methazolamide as a potential therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS This double-blind, placebo-controlled study randomized 76 patients to oral methazolamide (40 mg b.i.d.) or placebo for 24 weeks. The primary efficacy end point for methazolamide treatment was a placebo-corrected reduction in HbA1c from baseline after 24 weeks (ΔHbA1c). RESULTS Mean ± SD baseline HbA1c was 7.1 ± 0.7% (54 ± 5 mmol/mol; n = 37) and 7.4 ± 0.6% (57 ± 5 mmol/mol; n = 39) in the methazolamide and placebo groups, respectively. Methazolamide treatment was associated with a ΔHbA1c of –0.39% (95% CI –0.82, 0.04; P < 0.05) (–4.3 mmol/mol [–9.0, 0.4]), an increase in the proportion of patients achieving HbA1c ≤6.5% (48 mmol/mol) from 8 to 33%, a rapid reduction in alanine aminotransferase (∼10 units/L), and weight loss (2%) in metformin-cotreated patients. CONCLUSIONS Methazolamide is the archetype for a new intervention in type 2 diabetes with clinical benefits beyond glucose control
The K2-HERMES Survey: Age and Metallicity of the Thick Disc
Asteroseismology is a promising tool to study Galactic structure and
evolution because it can probe the ages of stars. Earlier attempts comparing
seismic data from the {\it Kepler} satellite with predictions from Galaxy
models found that the models predicted more low-mass stars compared to the
observed distribution of masses. It was unclear if the mismatch was due to
inaccuracies in the Galactic models, or the unknown aspects of the selection
function of the stars. Using new data from the K2 mission, which has a
well-defined selection function, we find that an old metal-poor thick disc, as
used in previous Galactic models, is incompatible with the asteroseismic
information. We show that spectroscopic measurements of [Fe/H] and
[/Fe] elemental abundances from the GALAH survey indicate a mean
metallicity of for the thick disc. Here is the
effective solar-scaled metallicity, which is a function of [Fe/H] and
[/Fe]. With the revised disc metallicities, for the first time, the
theoretically predicted distribution of seismic masses show excellent agreement
with the observed distribution of masses. This provides an indirect
verification of the asteroseismic mass scaling relation is good to within five
percent. Using an importance-sampling framework that takes the selection
function into account, we fit a population synthesis model of the Galaxy to the
observed seismic and spectroscopic data. Assuming the asteroseismic scaling
relations are correct, we estimate the mean age of the thick disc to be about
10 Gyr, in agreement with the traditional idea of an old -enhanced
thick disc.Comment: 21 pages, submitted to MNRA
Integrative analysis of RUNX1 downstream pathways and target genes
Background: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for
a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and
bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia.
Results: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from
FPD-AML patients, 2) over-expression of RUNX1 and CBF[Beta], and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBF[Beta]. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions
of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes.
Conclusion: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic
implications
The GALAH survey: Milky Way disc metallicity and alpha-abundance trends in combined APOGEE-GALAH catalogues
GALAH and APOGEE are two high resolution multi object spectroscopic surveys
that provide fundamental stellar parameters and multiple elemental abundance
estimates for 400,000 stars in the Milky Way. They are complimentary in
both sky coverage and wavelength regime. Thus combining the two surveys will
provide us a large sample to investigate the disc metallicity and alpha
abundance trends. We use the Cannon data-driven approach selecting training
sets from among 20,000 stars in common for the two surveys to predict the
GALAH scaled stellar parameters from APOGEE spectra as well as APOGEE scaled
stellar parameters from GALAH spectra. We provide two combined catalogues with
GALAH scaled and APOGEE scaled stellar parameters each having 500,000
stars after quality cuts. With 470,000 stars that are common in both
these catalogues, we compare the GALAH scaled and APOGEE scaled metallicity
distribution functions (MDF), radial and vertical metallicity gradients as well
as the variation of [/Fe] vs [Fe/H] trends along and away from the
Galactic mid plane. We find mean metallicities of APOGEE scaled sample to be
higher compared to that for the GALAH scaled sample. We find similar
[/Fe] vs [Fe/H] trends using both samples consistent with previous
observational as well as simulation based studies. Radial and vertical
metallicity gradients derived using the two survey scaled samples are
consistent except in the inner and outer Galactocentric radius bins. Our
gradient estimates in the solar neighborhood are also consistent with previous
studies and are backed by larger sample size compared to previous works.Comment: 21 pages, 19 figures, submitted to MNRA
The GALAH survey: Co-orbiting stars and chemical tagging
We present a study using the second data release of the GALAH survey of
stellar parameters and elemental abundances of 15 pairs of stars identified by
Oh et al 2017. They identified these pairs as potentially co-moving pairs using
proper motions and parallaxes from Gaia DR1. We find that 11 very wide (>1.7
pc) pairs of stars do in fact have similar Galactic orbits, while a further
four claimed co-moving pairs are not truly co-orbiting. Eight of the 11
co-orbiting pairs have reliable stellar parameters and abundances, and we find
that three of those are quite similar in their abundance patterns, while five
have significant [Fe/H] differences. For the latter, this indicates that they
could be co-orbiting because of the general dynamical coldness of the thin
disc, or perhaps resonances induced by the Galaxy, rather than a shared
formation site. Stars such as these, wide binaries, debris of past star
formation episodes, and coincidental co-orbiters, are crucial for exploring the
limits of chemical tagging in the Milky Way.Comment: 14 pages, 9 figures, submitted to MNRAS. Updated for Gaia DR2 value
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