61 research outputs found
McKean Complex| An analysis of six Middle Prehistoric period sites in the Northwestern Plains
A TPX2 Proteomimetic Has Enhanced Affinity for Aurora-A Due to Hydrocarbon Stapling of a Helix
Inhibition of protein kinases using ATP-competitive compounds is an important strategy in drug discovery. In contrast, the allosteric regulation of kinases through the disruption of protein-protein interactions has not been widely adopted, despite the potential for selective targeting. Aurora-A kinase regulates mitotic entry and mitotic spindle assembly and is a promising target for anticancer therapy. The microtubule-associated protein TPX2 activates Aurora-A through binding to two sites. Aurora-A recognition is mediated by two motifs within the first 43 residues of TPX2, connected by a flexible linker. To characterize the contributions of these three structural elements, we prepared a series of TPX2 proteomimetics and investigated their binding affinity for Aurora-A using isothermal titration calorimetry. A novel stapled TPX2 peptide was developed that has improved binding affinity for Aurora-A and mimics the function of TPX2 in activating Aurora-A's autophosphorylation. We conclude that the helical region of TPX2 folds upon binding Aurora-A, and that stabilization of this helix does not compromise Aurora-A activation. This study demonstrates that the preparation of these proteomimetics using modern synthesis methods is feasible and their biochemical evaluation demonstrates the power of proteomimetics as tool compounds for investigating PPIs involving intrinsically disordered regions of proteins
Increased use of malaria rapid diagnostic tests improves targeting of anti-malarial treatment in rural Tanzania: implications for nationwide rollout of malaria rapid diagnostic tests.
ABSTRACT: BACKGROUND: The World Health Organization recommends parasitological confirmation of all malaria cases. Tanzania is implementing a phased rollout of malaria rapid diagnostic tests (RDTs) for routine use in all levels of care as one strategy to increase parasitological confirmation of malaria diagnosis. This study was carried out to evaluated artemisinin combination therapy (ACT) prescribing patterns in febrile patients with and without uncomplicated malaria in one pre-RDT implementation and one post-RDT implementation area. METHODS: A cross-sectional health facility surveys was conducted during high and low malaria transmission seasons in 2010 in both areas. Clinical information and a reference blood film on all patients presenting for an initial illness consultation were collected. Malaria was defined as a history of fever in the past 48 hours and microscopically confirmed parasitaemia. Routine diagnostic testing was defined as RDT or microscopy ordered by the health worker and performed at the health facility as part of the health worker-patient consultation. Correct diagnostic testing was defined as febrile patient tested with RDT or microscopy. Over-testing was defined as a febrile patient tested with RDT or microscopy. Correct treatment was defined as patient with malaria prescribed ACT. Over-treatment was defined as patient without malaria prescribed ACT. RESULTS: A total of 1,247 febrile patients (627 from pre-implementation area and 620 from post-implementation area) were included in the analysis. In the post-RDT implementation area, 80.9% (95% CI, 68.2-89.3) of patients with malaria received recommended treatment with ACT compared to 70.3% (95% CI, 54.7-82.2) of patients in the pre-RDT implementation area. Correct treatment was significantly higher in the post-implementation area during high transmission season (85.9% (95%CI, 72.0-93.6) compared to 58.3% (95%CI, 39.4-75.1) in pre-implementation area (p=0.01). Over-treatment with ACT of patients without malaria was less common in the post-RDT implementation area (20.9%; 95% CI, 14.7-28.8) compared to the pre-RDT implementation area (45.8%; 95% CI, 37.2-54.6) (p<0.01) in high transmission. The odds of overtreatment was significantly lower in post- RDT area (adjusted Odds Ratio (OR: 95%CI) 0.57(0.36-0.89); and much higher with clinical diagnosis adjusted OR (95%CI) 2.24(1.37-3.67) CONCLUSION: Implementation of RDTs increased use of RDTs for parasitological confirmation and reduced over-treatment with ACT during high malaria transmission season in one area in Tanzania. Continued monitoring of the national RDT rollout will be needed to assess whether these changes in case management practices will be replicated in other areas and sustained over time. Additional measures (such as refresher trainings, closer supervisions, etc) may be needed to improve ACT targeting during low transmission seasons
Early and extensive CD55 loss from red blood cells supports a causal role in malarial anaemia
BACKGROUND\ud
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Levels of complement regulatory proteins (CrP) on the surface of red blood cells (RBC) decrease during severe malarial anaemia and as part of cell ageing process. It remains unclear whether CrP changes seen during malaria contribute to the development of anaemia, or result from an altered RBC age distribution due to suppressive effects of malaria on erythropoiesis.\ud
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METHODS\ud
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A cross sectional study was conducted in the north-east coast of Tanzania to investigate whether the changes in glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins (CD55 and CD59) contributes to malaria anaemia. Blood samples were collected from a cohort of children under intensive surveillance for Plasmodium falciparum parasitaemia and illness. Levels of CD55 and CD59 were measured by flow cytometer and compared between anaemic (8.08 g/dl) and non- anaemic children (11.42 g/dl).\ud
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RESULTS\ud
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Levels of CD55 and CD59 decreased with increased RBC age. CD55 levels were lower in anaemic children and the difference was seen in RBC of all ages. Levels of CD59 were lower in anaemic children, but these differences were not significant. CD55, but not CD59, levels correlated positively with the level of haemoglobin in anaemic children.\ud
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CONCLUSION\ud
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The extent of CD55 loss from RBC of all ages early in the course of malarial anaemia and the correlation of CD55 with haemoglobin levels support the hypothesis that CD55 may play a causal role in this disorder
COMAP Early Science: VII. Prospects for CO Intensity Mapping at Reionization
We introduce COMAP-EoR, the next generation of the Carbon Monoxide Mapping
Array Project aimed at extending CO intensity mapping to the Epoch of
Reionization. COMAP-EoR supplements the existing 30 GHz COMAP Pathfinder with
two additional 30 GHz instruments and a new 16 GHz receiver. This combination
of frequencies will be able to simultaneously map CO(1--0) and CO(2--1) at
reionization redshifts () in addition to providing a significant
boost to the sensitivity of the Pathfinder. We examine a set of
existing models of the EoR CO signal, and find power spectra spanning several
orders of magnitude, highlighting our extreme ignorance about this period of
cosmic history and the value of the COMAP-EoR measurement. We carry out the
most detailed forecast to date of an intensity mapping cross-correlation, and
find that five out of the six models we consider yield signal to noise ratios
(S/N) for COMAP-EoR, with the brightest reaching a S/N above 400.
We show that, for these models, COMAP-EoR can make a detailed measurement of
the cosmic molecular gas history from , as well as probe the
population of faint, star-forming galaxies predicted by these models to be
undetectable by traditional surveys. We show that, for the single model that
does not predict numerous faint emitters, a COMAP-EoR-type measurement is
required to rule out their existence. We briefly explore prospects for a
third-generation Expanded Reionization Array (COMAP-ERA) capable of detecting
the faintest models and characterizing the brightest signals in extreme detail.Comment: Paper 7 of 7 in series. 19 pages, 10 figures, to be submitted to Ap
COMAP Early Science: VI. A First Look at the COMAP Galactic Plane Survey
We present early results from the COMAP Galactic Plane Survey conducted
between June 2019 and April 2021, spanning in Galactic
longitude and |b|<1.\!\!^{\circ}5 in Galactic latitude with an angular
resolution of . The full survey will span -
and will be the first large-scale radio continuum survey at
GHz with sub-degree resolution. We present initial results from the first part
of the survey, including diffuse emission and spectral energy distributions
(SEDs) of HII regions and supernova remnants. Using low and high frequency
surveys to constrain free-free and thermal dust emission contributions, we find
evidence of excess flux density at GHz in six regions that we interpret
as anomalous microwave emission. Furthermore we model UCHII contributions using
data from the GHz CORNISH catalogue and reject this as the cause of the
GHz excess. Six known supernova remnants (SNR) are detected at GHz,
and we measure spectral indices consistent with the literature or show evidence
of steepening. The flux density of the SNR W44 at GHz is consistent with
a power-law extrapolation from lower frequencies with no indication of spectral
steepening in contrast with recent results from the Sardinia Radio Telescope.
We also extract five hydrogen radio recombination lines to map the warm ionized
gas, which can be used to estimate electron temperatures or to constrain
continuum free-free emission. The full COMAP Galactic plane survey, to be
released in 2023/2024, will be an invaluable resource for Galactic
astrophysics.Comment: Paper 6 of 7 in series. 28 pages, 10 figures, submitted to Ap
COMAP Early Science: IV. Power Spectrum Methodology and Results
We present the power spectrum methodology used for the first-season COMAP
analysis, and assess the quality of the current data set. The main results are
derived through the Feed-feed Pseudo-Cross-Spectrum (FPXS) method, which is a
robust estimator with respect to both noise modeling errors and experimental
systematics. We use effective transfer functions to take into account the
effects of instrumental beam smoothing and various filter operations applied
during the low-level data processing. The power spectra estimated in this way
have allowed us to identify a systematic error associated with one of our two
scanning strategies, believed to be due to residual ground or atmospheric
contamination. We omit these data from our analysis and no longer use this
scanning technique for observations. We present the power spectra from our
first season of observing and demonstrate that the uncertainties are
integrating as expected for uncorrelated noise, with any residual systematics
suppressed to a level below the noise. Using the FPXS method, and combining
data on scales we estimate , the first direct 3D
constraint on the clustering component of the CO(1-0) power spectrum in the
literature.Comment: Paper 4 of 7 in series. 18 pages, 11 figures, as accepted in Ap
COMAP Early Science: III. CO Data Processing
We describe the first season COMAP analysis pipeline that converts raw
detector readouts to calibrated sky maps. This pipeline implements four main
steps: gain calibration, filtering, data selection, and map-making. Absolute
gain calibration relies on a combination of instrumental and astrophysical
sources, while relative gain calibration exploits real-time total-power
variations. High efficiency filtering is achieved through spectroscopic
common-mode rejection within and across receivers, resulting in nearly
uncorrelated white noise within single-frequency channels. Consequently,
near-optimal but biased maps are produced by binning the filtered time stream
into pixelized maps; the corresponding signal bias transfer function is
estimated through simulations. Data selection is performed automatically
through a series of goodness-of-fit statistics, including and
multi-scale correlation tests. Applying this pipeline to the first-season COMAP
data, we produce a dataset with very low levels of correlated noise. We find
that one of our two scanning strategies (the Lissajous type) is sensitive to
residual instrumental systematics. As a result, we no longer use this type of
scan and exclude data taken this way from our Season 1 power spectrum
estimates. We perform a careful analysis of our data processing and observing
efficiencies and take account of planned improvements to estimate our future
performance. Power spectrum results derived from the first-season COMAP maps
are presented and discussed in companion papers.Comment: Paper 3 of 7 in series. 26 pages, 23 figures, submitted to Ap
COMAP Early Science: V. Constraints and Forecasts at
We present the current state of models for the carbon monoxide (CO)
line-intensity signal targeted by the CO Mapping Array Project (COMAP)
Pathfinder in the context of its early science results. Our fiducial model,
relating dark matter halo properties to CO luminosities, informs parameter
priors with empirical models of the galaxy-halo connection and previous CO(1-0)
observations. The Pathfinder early science data spanning wavenumbers
-Mpc represent the first direct 3D constraint on the
clustering component of the CO(1-0) power spectrum. Our 95% upper limit on the
redshift-space clustering amplitude K greatly
improves on the indirect upper limit of K reported from the CO
Power Spectrum Survey (COPSS) measurement at Mpc. The COMAP
limit excludes a subset of models from previous literature, and constrains
interpretation of the COPSS results, demonstrating the complementary nature of
COMAP and interferometric CO surveys. Using line bias expectations from our
priors, we also constrain the squared mean line intensity-bias product,
K, and the cosmic molecular gas
density, Mpc (95% upper
limits). Based on early instrument performance and our current CO signal
estimates, we forecast that the five-year Pathfinder campaign will detect the
CO power spectrum with overall signal-to-noise of 9-17. Between then and now,
we also expect to detect the CO-galaxy cross-spectrum using overlapping galaxy
survey data, enabling enhanced inferences of cosmic star-formation and
galaxy-evolution history.Comment: Paper 5 of 7 in series. 17 pages + appendix and bibliography (30
pages total); 15 figures, 6 tables; accepted for publication in ApJ; v3
reflects the accepted version with minor changes and additions to tex
COMAP Early Science: II. Pathfinder Instrument
Line intensity mapping (LIM) is a new technique for tracing the global
properties of galaxies over cosmic time. Detection of the very faint signals
from redshifted carbon monoxide (CO), a tracer of star formation, pushes the
limits of what is feasible with a total-power instrument. The CO Mapping
Project (COMAP) Pathfinder is a first-generation instrument aiming to prove the
concept and develop the technology for future experiments, as well as
delivering early science products. With 19 receiver channels in a hexagonal
focal plane arrangement on a 10.4 m antenna, and an instantaneous 26-34 GHz
frequency range with 2 MHz resolution, it is ideally suited to measuring
CO(=1-0) from . In this paper we discuss strategies for designing
and building the Pathfinder and the challenges that were encountered. The
design of the instrument prioritized LIM requirements over those of ancillary
science. After a couple of years of operation, the instrument is well
understood, and the first year of data is already yielding useful science
results. Experience with this Pathfinder will drive the design of the next
generations of experiments.Comment: Paper 2 of 7 in series. 27 pages, 28 figures, submitted to Ap
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