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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/
The Carnegie Supernova Project: First Near-Infrared Hubble Diagram to z~0.7
The Carnegie Supernova Project (CSP) is designed to measure the luminosity
distance for Type Ia supernovae (SNe Ia) as a function of redshift, and to set
observational constraints on the dark energy contribution to the total energy
content of the Universe. The CSP differs from other projects to date in its
goal of providing an I-band {rest-frame} Hubble diagram. Here we present the
first results from near-infrared (NIR) observations obtained using the Magellan
Baade telescope for SNe Ia with 0.1 < z < 0.7. We combine these results with
those from the low-redshift CSP at z <0.1 (Folatelli et al. 2009). We present
light curves and an I-band Hubble diagram for this first sample of 35 SNe Ia
and we compare these data to 21 new SNe Ia at low redshift. These data support
the conclusion that the expansion of the Universe is accelerating. When
combined with independent results from baryon acoustic oscillations (Eisenstein
et al. 2005), these data yield Omega_m = 0.27 +/- 0.0 (statistical), and
Omega_DE = 0.76 +/- 0.13 (statistical) +/- 0.09 (systematic), for the matter
and dark energy densities, respectively. If we parameterize the data in terms
of an equation of state, w, assume a flat geometry, and combine with baryon
acoustic oscillations, we find that w = -1.05 +/- 0.13 (statistical) +/- 0.09
(systematic). The largest source of systematic uncertainty on w arises from
uncertainties in the photometric calibration, signaling the importance of
securing more accurate photometric calibrations for future supernova cosmology
programs. Finally, we conclude that either the dust affecting the luminosities
of SNe Ia has a different extinction law (R_V = 1.8) than that in the Milky Way
(where R_V = 3.1), or that there is an additional intrinsic color term with
luminosity for SNe Ia independent of the decline rate.Comment: 44 pages, 23 figures, 9 tables; Accepted for publication in the
Astrophysical Journa
Deconstructing superorganisms and societies to address big questions in biology
Social insect societies are long-standing models for understanding social behaviour and evolution. Unlike other advanced biological societies (such as the multicellular body), the component parts of social insect societies can be easily deconstructed and manipulated. Recent methodological and theoretical innovations have exploited this trait to address an expanded range of biological questions. We illustrate the broadening range of biological insight coming from social insect biology with four examples. These new frontiers promote open-minded, interdisciplinary exploration of one of the richest and most complex of biological phenomena: sociality
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
Talking Less during Social Interactions Predicts Enjoyment: A Mobile Sensing Pilot Study
Can we predict which conversations are enjoyable without hearing the words that are spoken? A total of 36 participants used a mobile app, My Social Ties, which collected data about 473 conversations that the participants engaged in as they went about their daily lives. We tested whether conversational properties (conversation length, rate of turn taking, proportion of speaking time) and acoustical properties (volume, pitch) could predict enjoyment of a conversation. Surprisingly, people enjoyed their conversations more when they spoke a smaller proportion of the time. This pilot study demonstrates how conversational properties of social interactions can predict psychologically meaningful outcomes, such as how much a person enjoys the conversation. It also illustrates how mobile phones can provide a window into everyday social experiences and well-being
The Peculiar SN 2005hk: Do Some Type Ia Supernovae Explode as Deflagrations?
We present extensive u'g'r'i'BVRIYJHKs photometry and optical spectroscopy of
SN 2005hk. These data reveal that SN 2005hk was nearly identical in its
observed properties to SN 2002cx, which has been called ``the most peculiar
known type Ia supernova.'' Both supernovae exhibited high ionization SN
1991T-like pre-maximum spectra, yet low peak luminosities like SN 1991bg. The
spectra reveal that SN 2005hk, like SN 2002cx, exhibited expansion velocities
that were roughly half those of typical type Ia supernovae. The R and I light
curves of both supernovae were also peculiar in not displaying the secondary
maximum observed for normal type Ia supernovae. Our YJH photometry of SN 2005hk
reveals the same peculiarity in the near-infrared. By combining our optical and
near-infrared photometry of SN 2005hk with published ultraviolet light curves
obtained with the Swift satellite, we are able to construct a bolometric light
curve from ~10 days before to ~60 days after B maximum. The shape and unusually
low peak luminosity of this light curve, plus the low expansion velocities and
absence of a secondary maximum at red and near-infrared wavelengths, are all in
reasonable agreement with model calculations of a 3D deflagration which
produces ~0.25 M_sun of 56Ni.Comment: Accepted by PASP, to appear in April 2007 issue, 63 pages, 16
figures, 11 table
Alpha-2-Macroglobulin Is Acutely Sensitive to Freezing and Lyophilization: Implications for Structural and Functional Studies.
Alpha-2-macroglobulin is an abundant secreted protein that is of particular interest because of its diverse ligand binding profile and multifunctional nature, which includes roles as a protease inhibitor and as a molecular chaperone. The activities of alpha-2-macroglobulin are typically dependent on whether its conformation is native or transformed (i.e. adopts a more compact conformation after interactions with proteases or small nucleophiles), and are also influenced by dissociation of the native alpha-2-macroglobulin tetramer into stable dimers. Alpha-2-macroglobulin is predominately present as the native tetramer in vivo; once purified from human blood plasma, however, alpha-2-macroglobulin can undergo a number of conformational changes during storage, including transformation, aggregation or dissociation. We demonstrate that, particularly in the presence of sodium chloride or amine containing compounds, freezing and/or lyophilization of alpha-2-macroglobulin induces conformational changes with functional consequences. These conformational changes in alpha-2-macroglobulin are not always detected by standard native polyacrylamide gel electrophoresis, but can be measured using bisANS fluorescence assays. Increased surface hydrophobicity of alpha-2-macroglobulin, as assessed by bisANS fluorescence measurements, is accompanied by (i) reduced trypsin binding activity, (ii) increased chaperone activity, and (iii) increased binding to the surfaces of SH-SY5Y neurons, in part, via lipoprotein receptors. We show that sucrose (but not glycine) effectively protects native alpha-2-macroglobulin from denaturation during freezing and/or lyophilization, thereby providing a reproducible method for the handling and long-term storage of this protein.Early Career Fellowship from the National Health and Medical Research Council GNT1012521(A.R.W.); Wellcome Trust Programme Grant (J.R.K., C.M.D.) 094425/Z/10/Z; Samsung GRO Grant (M.R.W.)This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013003
Cardiovascular Disease in Blacks with HIV/AIDS in the United States: A Systematic Review of the Literature
Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.
OBJECTIVE: To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects. METHODS: Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends. RESULTS: Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020. CONCLUSIONS: Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently
The origin and evolution of the normal Type Ia SN 2018aoz with infant-phase reddening and excess emission
SN~2018aoz is a Type Ia SN with a -band plateau and excess emission in the
infant-phase light curves 1 day after first light, evidencing an
over-density of surface iron-peak elements as shown in our previous study.
Here, we advance the constraints on the nature and origin of SN~2018aoz based
on its evolution until the nebular phase. Near-peak spectroscopic features show
the SN is intermediate between two subtypes of normal Type Ia: Core-Normal and
Broad-Line. The excess emission could have contributions from the radioactive
decay of surface iron-peak elements as well as ejecta interaction with either
the binary companion or a small torus of circumstellar material. Nebular-phase
limits on H and He~I favour a white dwarf companion, consistent with
the small companion size constrained by the low early SN luminosity, while the
absence of [O~I] and He~I disfavours a violent merger of the progenitor. Of the
two main explosion mechanisms proposed to explain the distribution of surface
iron-peak elements in SN~2018aoz, the asymmetric Chandrasekhar-mass explosion
is less consistent with the progenitor constraints and the observed blueshifts
of nebular-phase [Fe~II] and [Ni~II]. The helium-shell double-detonation
explosion is compatible with the observed lack of C spectral features, but
current 1-D models are incompatible with the infant-phase excess emission,
color, and absence of nebular-phase [Ca~II]. Although
the explosion processes of SN~2018aoz still need to be more precisely
understood, the same processes could produce a significant fraction of Type Ia
SNe that appear normal after 1 day.Comment: Submitted for publication in ApJ. 35 pages, 16 figures, 7 table
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