1,315 research outputs found
Protease-activated alpha-2-macroglobulin can inhibit amyloid formation via two distinct mechanisms.
α(2)-Macroglobulin (α(2)M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α(2)M with proteases results in an 'activated' conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α(2)M. This study investigates, the effect of activation on the ability of α(2)M to inhibit amyloid formation by Aβ(1-42) and I59T human lysozyme and shows that protease-activated α(2)M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway
The Carnegie Supernova Project: Analysis of the First Sample of Low-Redshift Type-Ia Supernovae
We present the analysis of the first set of low-redshift Type Ia supernovae
(SNe Ia) by the Carnegie Supernova Project. Well-sampled, high-precision
optical (ugriBV) and near-infrared (NIR; YJHKs) light curves obtained in a
well-understood photometric system are used to provide light-curve parameters,
and ugriBVYJH template light curves. The intrinsic colors at maximum light are
calibrated to compute optical--NIR color excesses for the full sample, thus
allowing the properties of the reddening law in the host galaxies to be
studied. A low value of Rv~1.7, is derived when using the entire sample of SNe.
However, when the two highly reddened SNe in the sample are excluded, a value
Galactic standard of Rv~3.2 is obtained. The colors of these two events are
well matched by a reddening model due to circumstellar dust. The peak
luminosities are calibrated using a two-parameter linear fit to the decline
rates and the colors, or alternatively, the color excesses. In both cases,
dispersions in absolute magnitude of 0.12--0.16 mag are obtained, depending on
the filter-color combination. In contrast to the results obtained from color
excesses, these fits give Rv~1--2, even when the two highly reddened SNe are
excluded. This discrepancy suggests that, beyond the "normal" interstellar
reddening produced in the host galaxies, there is an intrinsic dispersion in
the colors of SNe Ia which is correlated with luminosity but independent of the
decline rate. Finally, a Hubble diagram is produced by combining the results of
the fits for each filter. The resulting scatter of 0.12 mag appears to be
limited by peculiar velocities as evidenced by the strong correlation between
the distance-modulus residuals among the different filters. The implication is
that the actual precision of SN Ia distances is 3--4%.Comment: 76 pages, 20 figures, accepted for publication in A
CfAIR2: Near Infrared Light Curves of 94 Type Ia Supernovae
CfAIR2 is a large homogeneously reduced set of near-infrared (NIR) light
curves for Type Ia supernovae (SN Ia) obtained with the 1.3m Peters Automated
InfraRed Imaging TELescope (PAIRITEL). This data set includes 4607 measurements
of 94 SN Ia and 4 additional SN Iax observed from 2005-2011 at the Fred
Lawrence Whipple Observatory on Mount Hopkins, Arizona. CfAIR2 includes JHKs
photometric measurements for 88 normal and 6 spectroscopically peculiar SN Ia
in the nearby universe, with a median redshift of z~0.021 for the normal SN Ia.
CfAIR2 data span the range from -13 days to +127 days from B-band maximum. More
than half of the light curves begin before the time of maximum and the coverage
typically contains ~13-18 epochs of observation, depending on the filter. We
present extensive tests that verify the fidelity of the CfAIR2 data pipeline,
including comparison to the excellent data of the Carnegie Supernova Project.
CfAIR2 contributes to a firm local anchor for supernova cosmology studies in
the NIR. Because SN Ia are more nearly standard candles in the NIR and are less
vulnerable to the vexing problems of extinction by dust, CfAIR2 will help the
supernova cosmology community develop more precise and accurate extragalactic
distance probes to improve our knowledge of cosmological parameters, including
dark energy and its potential time variation.Comment: 31 pages, 15 figures, 10 tables. Accepted to ApJS. v2 modified to
more closely match journal versio
Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates
Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans
Sequential and Batch Processing Methods of the EBP Learning Algorithm
Placental abnormalities can cause Pregnancy-Associated Disorders, including preeclampsia, intrauterine growth restriction, and placental insufficiency, resulting in complications for both the mother and fetus. Trophoblast cells within the labyrinthine layer of the placenta facilitate the exchange of nutrients, gases, and waste between mother and fetus; therefore, the development of this cell layer is critical for fetal development. As trophoblast cells differentiate, it is assumed their metabolism changes with their energy requirements. We hypothesize that proper regulation of trophoblast metabolism is a key component of normal placental development; therefore, we examined the role of AMP-activated kinase (AMPK, PRKAA1/2), a sensor of cellular energy status. Our previous studies have shown that AMPK knockdown alters both trophoblast differentiation and nutrient transport. In this study, AMPKα1/2 shRNA was used to investigate the metabolic effects of AMPK knockdown on SM10 placental labyrinthine progenitor cells before and after differentiation. Extracellular flux analysis confirmed that AMPK knockdown was sufficient to reduce trophoblast glycolysis, mitochondrial respiration, and ATP coupling efficiency. A reduction in AMPK in differentiated trophoblasts also resulted in increased mitochondrial volume. These data indicate that a reduction in AMPK disrupts cellular metabolism in both progenitors and differentiated placental trophoblasts. This disruption correlates to abortive trophoblast differentiation that may contribute to the development of Pregnancy-Associated Disorders
Drug discovery for male subfertility using high-throughput screening:a new approach to an unsolved problem
STUDY QUESTIONCan pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility?SUMMARY ANSWERHigh-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility.WHAT IS KNOWN ALREADYThere is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform.STUDY DESIGN, SIZE, DURATIONSpermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSA HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping.MAIN RESULTS AND THE ROLE OF CHANCEOf the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase in fluorescence in the primary screen were rescreened and evaluated further, resulting in 48 hit compounds that produced a concentration-dependent increase in [Ca2+]i. Sperm penetration studies confirmed in vitro exposure to two hit compounds (A and B) resulted in significant improvement in functional motility in spermatozoa from healthy volunteer donors (A: 1 cm penetration index 2.54, 2 cm penetration index 2.49; P < 0.005 and B: 1 cm penetration index 2.1, 2 cm penetration index 2.6; P < 0.005), but crucially, also in patient samples from those undergoing fertility treatment (A: 1 cm penetration index 2.4; P = 0.009, 2 cm penetration index 3.6; P = 0.02 and B: 1 cm penetration index 2.2; P = 0.0004, 2 cm penetration index 3.6; P = 0.002). This was primarily as a result of direct or indirect CatSper channel action, supported by evidence from electrophysiology studies of individual sperm.LIMITATIONS, REASONS FOR CAUTIONIncrease and fluxes in [Ca2+]i are fundamental to the regulation of sperm motility and function, including acrosome reaction. The use of calcium signalling as a surrogate for sperm motility is acknowledged as a potential limitation in this study.WIDER IMPLICATIONS OF THE FINDINGSWe conclude that HTS can robustly, efficiently, identify novel compounds that increase [Ca2+]i in human spermatozoa and functionally modify motility, and propose its use as a cornerstone to build and transform much-needed drug discovery for male infertility.</p
The Carnegie Supernova Project: First Photometry Data Release of Low-Redshift Type Ia Supernovae
The Carnegie Supernova Project (CSP) is a five-year survey being carried out
at the Las Campanas Observatory to obtain high-quality light curves of ~100
low-redshift Type Ia supernovae in a well-defined photometric system. Here we
present the first release of photometric data that contains the optical light
curves of 35 Type Ia supernovae, and near-infrared light curves for a subset of
25 events. The data comprise 5559 optical (ugriBV) and 1043 near-infrared
(YJHKs) data points in the natural system of the Swope telescope. Twenty-eight
supernovae have pre-maximum data, and for 15 of these, the observations begin
at least 5 days before B maximum. This is one of the most accurate datasets of
low-redshift Type Ia supernovae published to date. When completed, the CSP
dataset will constitute a fundamental reference for precise determinations of
cosmological parameters, and serve as a rich resource for comparison with
models of Type Ia supernovae.Comment: 93 pages, 8 figures, accepted for publication in A
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Human pregnancy zone protein stabilizes misfolded proteins including preeclampsia- and Alzheimer's-associated amyloid beta peptide.
Protein misfolding underlies the pathology of a large number of human disorders, many of which are age-related. An exception to this is preeclampsia, a leading cause of pregnancy-associated morbidity and mortality in which misfolded proteins accumulate in body fluids and the placenta. We demonstrate that pregnancy zone protein (PZP), which is dramatically elevated in maternal plasma during pregnancy, efficiently inhibits in vitro the aggregation of misfolded proteins, including the amyloid beta peptide (Aβ) that is implicated in preeclampsia as well as with Alzheimer's disease. The mechanism by which this inhibition occurs involves the formation of stable complexes between PZP and monomeric Aβ or small soluble Aβ oligomers formed early in the aggregation pathway. The chaperone activity of PZP is more efficient than that of the closely related protein alpha-2-macroglobulin (α2M), although the chaperone activity of α2M is enhanced by inducing its dissociation into PZP-like dimers. By immunohistochemistry analysis, PZP is found primarily in extravillous trophoblasts in the placenta. In severe preeclampsia, PZP-positive extravillous trophoblasts are adjacent to extracellular plaques containing Aβ, but PZP is not abundant within extracellular plaques. Our data support the conclusion that the up-regulation of PZP during pregnancy represents a major maternal adaptation that helps to maintain extracellular proteostasis during gestation in humans. We propose that overwhelming or disrupting the chaperone function of PZP could underlie the accumulation of misfolded proteins in vivo. Attempts to characterize extracellular proteostasis in pregnancy will potentially have broad-reaching significance for understanding disease-related protein misfolding.Wellcome Trust Programme Grant 094425/Z/10/
Transiting Disintegrating Planetary Debris around WD 1145+017
More than a decade after astronomers realized that disrupted planetary
material likely pollutes the surfaces of many white dwarf stars, the discovery
of transiting debris orbiting the white dwarf WD 1145+017 has opened the door
to new explorations of this process. We describe the observational evidence for
transiting planetary material and the current theoretical understanding (and in
some cases lack thereof) of the phenomenon.Comment: Invited review chapter. Accepted March 23, 2017 and published October
7, 2017 in the Handbook of Exoplanets. 15 pages, 10 figure
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