SD 1313-0019 -- Another second-generation star with [Fe/H] = -5.0, observed with the Magellan Telescope

We present a Magellan/MIKE high-resolution (R ~ 35,000) spectrum of the ancient star SD 1313-0019 which has an iron abundance of [Fe/H] = -5.0, paired with a carbon enhancement of [C/Fe] ~ 3.0. The star was initially identified by Allende Prieto et al. in the BOSS survey. Its medium-resolution spectrum suggested a higher metallicity of [Fe/H] = -4.3 due to the CaII K line blending with a CH feature which is a common issue related to the search for the most iron-poor stars. This star joins several other, similar stars with [Fe/H] < -5.0 that all display a combination of low iron and high carbon abundances. Other elemental abundances of SD 1313-0019 follow that of more metal-rich halo stars. From fitting the abundance pattern with yields of Population III supernova, we conclude that SD 1313-0019 had only one massive progenitor star with 20 - 30 M_sun that must have undergone a mixing and fallback episode. Overall, there are now five stars known with [Fe/H] < -5.0 (1D LTE abundances). This population of second-generation stars strongly suggests massive first stars that almost exclusively produced large amounts of carbon through stellar winds and/or their mixing and fallback supernova explosions. As a consequence, their natal clouds -- presumably some early minihalo structures -- contained ample amounts of carbon and oxygen that likely facilitated the formation of these first low-mass stars.Comment: 7 pages and 3 figures, accepted by ApJ

Low redshift constraints on energy-momentum-powered gravity models

There has been recent interest in the cosmological consequences of energy-momentum-powered gravity models, in which the matter side of Einstein's equations is modified by the addition of a term proportional to some power, $n$, of the energy-momentum tensor, in addition to the canonical linear term. In this work we treat these models as phenomenological extensions of the standard $\Lambda$CDM, containing both matter and a cosmological constant. We also quantitatively constrain the additional model parameters using low redshift background cosmology data that are specifically from Type Ia supernovas and Hubble parameter measurements. We start by studying specific cases of these models with fixed values of $n,$ which lead to an analytic expression for the Friedmann equation; we discuss both their current constraints and how the models may be further constrained by future observations of Type Ia supernovas for WFIRST complemented by measurements of the redshift drift by the ELT. We then consider and constrain a more extended parameter space, allowing $n$ to be a free parameter and considering scenarios with and without a cosmological constant. These models do not solve the cosmological constant problem per se. Nonetheless these models can phenomenologically lead to a recent accelerating universe without a cosmological constant at the cost of having a preferred matter density of around $\Omega_M\sim0.4$ instead of the usual $\Omega_M\sim0.3$. Finally we also briefly constrain scenarios without a cosmological constant, where the single component has a constant equation of state which needs not be that of matter; we provide an illustrative comparison of this model with a more standard dynamical dark energy model with a constant equation of state.Comment: 13+2 pages, 12+1 figures; A&A (in press

Investigating the Effects of Mutations on Protein Aggregation in the Cell

The conversion of peptides and proteins into highly ordered and intractable aggregates is associated with a range of debilitating human diseases and represents a widespread problem in biotechnology. Protein engineering studies carried out in vitro have shown that mutations promote aggregation when they either destabilize the native state of a globular protein or accelerate the conversion of unfolded or partially folded conformations into oligomeric structures. We have extended such studies to investigate protein aggregation in vivo where a number of additional factors able to modify dramatically the aggregation behavior of proteins are present. We have expressed, in Escherichia coli cells, an E. coli protein domain, HypF-N. The results for a range of mutational variants indicate that although mutants with a conformational stability similar to that of the wild-type protein are soluble in the E. coli cytosol, variants with single point mutations predicted to destabilize the protein invariably aggregate after expression. We show, however, that aggregation of destabilized variants can be prevented by incorporating multiple mutations designed to reduce the intrinsic propensity of the polypeptide chain to aggregate; in the cases discussed here, this is achieved by an increase in the net charge of the protein. These results suggest that the principles being established to rationalize aggregation behavior in vitro have general validity for situations in vivo where aggregation has both biotechnological and medical relevance

Characterization of pairs of toxic and nontoxic misfolded protein oligomers elucidates the structural determinants of oligomer toxicity in protein misfolding diseases

Conspectus: The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer’s and Parkinson’s diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies. These oligomers are small, diffusible species that can form as intermediates in the amyloid fibril formation process or be released by mature fibrils after they are formed. They have been closely associated with the induction of neuronal dysfunction and cell death. It has proven rather challenging to study these oligomeric species because of their short lifetimes, low concentrations, extensive structural heterogeneity, and challenges associated with producing stable, homogeneous, and reproducible populations. Despite these difficulties, investigators have developed protocols to produce kinetically, chemically, or structurally stabilized homogeneous populations of protein misfolded oligomers from several amyloidogenic peptides and proteins at experimentally ameneable concentrations. Furthermore, procedures have been established to produce morphologically similar but structurally distinct oligomers from the same protein sequence that are either toxic or nontoxic to cells. These tools offer unique opportunities to identify and investigate the structural determinants of oligomer toxicity by a close comparative inspection of their structures and the mechanisms of action through which they cause cell dysfunction. This Account reviews multidisciplinary results, including from our own groups, obtained by combining chemistry, physics, biochemistry, cell biology, and animal models for pairs of toxic and nontoxic oligomers. We describe oligomers comprised of the amyloid-β peptide, which underlie Alzheimer’s disease, and α-synuclein, which are associated with Parkinson’s disease and other related neurodegenerative pathologies, collectively known as synucleinopathies. Furthermore, we also discuss oligomers formed by the 91-residue N-terminal domain of [NiFe]-hydrogenase maturation factor from E. coli, which we use as a model non-disease-related protein, and by an amyloid stretch of Sup35 prion protein from yeast. These oligomeric pairs have become highly useful experimental tools for studying the molecular determinants of toxicity characteristic of protein misfolding diseases. Key properties have been identified that differentiate toxic from nontoxic oligomers in their ability to induce cellular dysfunction. These characteristics include solvent-exposed hydrophobic regions, interactions with membranes, insertion into lipid bilayers, and disruption of plasma membrane integrity. By using these properties, it has been possible to rationalize in model systems the responses to pairs of toxic and nontoxic oligomers. Collectively, these studies provide guidance for the development of efficacious therapeutic strategies to target rationally the cytotoxicity of misfolded protein oligomers in neurodegenerative conditions

"The difference that makes a difference": highlighting the role of variable contexts within an HIV Prevention Community Randomised Trial (HPTN 071/PopART) in 21 study communities in Zambia and South Africa.

This paper explores contextual heterogeneity within a community randomised trial HPTN 071 (Population Effects of Antiretroviral Treatment to Reduce HIV Transmission) carried out in 21 study communities (12 Zambian, 9 South African). The trial evaluates the impact of a combination HIV prevention package (including household-based HIV counselling and testing and anti-retroviral treatment (ART) eligibility regardless of CD4-count) on HIV incidence. The selection, matching and randomisation of study communities relied on key epidemiological and demographic variables and community and stakeholder support. In 2013, following the selection of study communities, a "Broad Brush Survey" (BBS) approach was used to rapidly gather qualitative data on each study community, prior to the implementation of the trial intervention. First-year process indicator intervention data (2014-2015) were collected during the household-based intervention by community lay workers. Using an open/closed typology of urban communities (indicating more or less heterogeneity), this qualitative inquiry presents key features of 12 Zambian communities using a list of four meta-indicators (physical features, social organisation, networks and community narratives). These indicators are then compared with four intervention process indicators in a smaller set of four study communities. The process indicators selected for this analysis indicate response to the intervention (uptake) amongst adults. The BBS qualitative data are used to interpret patterns of similarity and variability in the process indicators across four communities. We found that meta-indicators of local context helped to interpret patterns of similarity and variability emerging across and within the four communities. Features especially significant for influencing heterogeneity in process indicators include proportion of middle-class residents, proximity to neighbouring communities and town centre, the scale of the informal economy, livelihood-linked mobility, presence of HIV stakeholders over time and commitment to community action. Future interdisciplinary analysis is needed to explore if these patterns of difference continue to hold up over the full intervention period and all intervention communities

Folding and Aggregation Are Selectively Influenced by the Conformational Preferences of the α-Helices of Muscle Acylphosphatase

The native state of human muscle acylphosphatase (AcP) presents two alpha-helices. In this study we have investigated folding and aggregation of a number of protein variants having mutations aimed at changing the propensity of these helical regions. Equilibrium and kinetic measurements of folding indicate that only helix-2, spanning residues 55-67, is largely stabilized in the transition state for folding therefore playing a relevant role in this process. On the contrary, the aggregation rate appears to vary only for the variants in which the propensity of the region corresponding to helix-1, spanning residues 22-32, is changed. Mutations that stabilize the first helix slow down the aggregation process while those that destabilize it increase the aggregation rate. AcP variants with the first helix destabilized aggregate with rates increased to different extents depending on whether the introduced mutations also alter the propensity to form beta-sheet structure. The fact that the first alpha-helix is important for aggregation and the second helix is important for folding indicates that these processes are highly specific. This partitioning does not reflect the difference in intrinsic alpha-helical propensities of the two helices, because helix-1 is the one presenting the highest propensity. Both processes of folding and aggregation do not therefore initiate from regions that have simply secondary structure propensities favorable for such processes. The identification of the regions involved in aggregation and the understanding of the factors that promote such a process are of fundamental importance to elucidate the principles by which proteins have evolved and for successful protein design

Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity

Protein aggregation into amyloid fibrils and protofibrillar aggregates is associated with a number of the most common neurodegenerative diseases. We have established, using a computational approach, that knowledge of the primary sequences of proteins is sufficient to predict their in vitro aggregation propensities. Here we demonstrate, using rational mutagenesis of the Aβ42 peptide based on such computational predictions of aggregation propensity, the existence of a strong correlation between the propensity of Aβ42 to form protofibrils and its effect on neuronal dysfunction and degeneration in a Drosophila model of Alzheimer disease. Our findings provide a quantitative description of the molecular basis for the pathogenicity of Aβ and link directly and systematically the intrinsic properties of biomolecules, predicted in silico and confirmed in vitro, to pathogenic events taking place in a living organism

Two isoperimetric inequalities for the Sobolev constant

In this note we prove two isoperimetric inequalities for the sharp constant in the Sobolev embedding and its associated extremal function. The first such inequality is a variation on the classical Schwarz Lemma from complex analysis, similar to recent inequalities of Burckel, Marshall, Minda, Poggi-Corradini, and Ransford, while the second generalises an isoperimetric inequality for the first eigenfunction of the Laplacian due to Payne and Rayner.Comment: 11 page

Prefibrillar amyloid protein aggregates share common features of cytotoxicity.

The intracellular free Ca(2+) concentration and redox status of murine fibroblasts exposed to prefibrillar aggregates of the HypF N-terminal domain have been investigated in vitro and in vivo using a range of fluorescent probes. Aggregate entrance into the cytoplasm is followed by an early rise of reactive oxygen species and free Ca(2+) levels and eventually by cell death. Such changes correlate directly with the viability of the cells and are not observed when cell are cultured in the presence of reducing agents or in Ca(2+)-free media. In addition, moderate cell stress following exposure to the aggregates was found to be fully reversible. The results show that the cytotoxicity of prefibrillar aggregates of HypF-N, a protein not associated with clinical disease, has the same fundamental origin as that produced by similar types of aggregates of proteins linked with specific amyloidoses. These findings suggest that misfolded proteinaceous aggregates stimulate generic cellular responses as a result of the exposure of regions of the structure (such as hydrophobic residues and the polypeptide main chain) that are buried in the normally folded proteins. They also support the idea that a higher number of degenerative pathologies than previously known might be considered as protein deposition diseases

Conversion of the Native N-Terminal Domain of TDP-43 into a Monomeric Alternative Fold with Lower Aggregation Propensity

TAR DNA-binding protein 43 (TDP-43) forms intraneuronal cytoplasmic inclusions associated with amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. Its N-terminal domain (NTD) can dimerise/oligomerise with the head-to-tail arrangement, which is essential for function but also favours liquid-liquid phase separation and inclusion formation of full-length TDP-43. Using various biophysical approaches, we identified an alternative conforma-tional state of NTD in the presence of Sulfobetaine 3-10 (SB3-10), with higher content of α-helical structure and tryptophan solvent exposure. NMR shows a highly mobile structure, with partially folded regions and β-sheet content decrease, with a concomitant increase of α-helical structure. It is monomeric and reverts to native oligomeric NTD upon SB3-10 dilution. The equilibrium GdnHCl-induced denaturation shows a cooperative folding and a somewhat lower conformational stability. When the aggregation processes were compared with and without pre-incubation with SB3-10, but at the identical final SB3-10 concentration, a slower aggregation was found in the former case, despite the reversible attainment of the native conformation in both cases. This was attributed to protein monomerization and oligomeric seeds disruption by the conditions promoting the alternative con-formation. Overall, the results show a high plasticity of TDP-43 NTD and identify strategies to monomerise TDP-43 NTD for methodological and biomedical applications