Ligands of Therapeutic Utility for the Liver X Receptors.

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism. This review provides a summary of known endogenous, naturally occurring, and synthetic ligands. The review also offers considerations from a molecular modeling perspective with which to design more specific LXRβ ligands based on the interaction energies of ligands and the important amino acid residues in the LXRβ ligand binding domain

Maintaining surface-phase purity is key to efficient open air fabricated cuprous oxide solar cells

This is the final published version. It first appeared at http://scitation.aip.org/content/aip/journal/aplmater/3/2/10.1063/1.4913442.Electrochemically deposited Cu 2O solar cells are receiving growing attention owing to a recent doubling in efficiency. This was enabled by the controlled chemical environment used in depositing doped ZnO layers by atomic layer deposition, which is not well suited to large-scale industrial production. While open air fabrication with atmospheric pressure spatial atomic layer deposition overcomes this limitation, we find that this approach is limited by an inability to remove the detrimental CuO layer that forms on the Cu 2O surface. Herein, we propose strategies for achieving efficiencies in atmospherically processed cells that are equivalent to the high values achieved in vacuum processed cells.The authors acknowledge funding from the Cambridge Commonwealth, European and International Trusts (R.L.Z.H. and Y.I.), Rutherford Foundation of New Zealand (R.L.Z.H.), an NSF Graduate Research Fellowship (R.E.B.), EPSRC of the UK (S.H.), University of Cambridge EPSRC Centre for Doctoral Training in Nanoscience (S.H.), Girton College Cambridge (K.P.M.), an NSF CAREER Award ECCS-1150878 (T.B.), the National Research Foundation Singapore through the Singapore Massachusetts Institute of Technology Alliance for Research and Technology’s Low Energy Electronics Systems research program (T.B.), and an ERC Advanced Investigator Grant, Novox, ERC-2009-adG247276 (J.L.D.)

The GALEX View of "Boyajian's Star" (KIC 8462852)

The enigmatic star KIC 8462852, informally known as "Boyajian's Star", has exhibited unexplained variability from both short timescale (days) dimming events, and years-long fading in the Kepler mission. No single physical mechanism has successfully explained these observations to date. Here we investigate the ultraviolet variability of KIC 8462852 on a range of timescales using data from the GALEX mission that occurred contemporaneously with the Kepler mission. The wide wavelength baseline between the Kepler and GALEX data provides a unique constraint on the nature of the variability. Using 1600 seconds of photon-counting data from four GALEX visits spread over 70 days in 2011, we find no coherent NUV variability in the system on 10-100 second or months timescales. Comparing the integrated flux from these 2011 visits to the 2012 NUV flux published in the GALEX-CAUSE Kepler survey, we find a 3% decrease in brightness for KIC 8462852. We find this level of variability is significant, but not necessarily unusual for stars of similar spectral type in the GALEX data. This decrease coincides with the secular optical fading reported by Montet & Simon (2016). We find the multi-wavelength variability is somewhat inconsistent with typical interstellar dust absorption, but instead favors a R$_V$ = 5.0 $\pm$ 0.9 reddening law potentially from circumstellar dust.Comment: 8 pages, 4 figures, ApJ Accepte

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies

Objectives: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients. Methods: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry. Results: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study. Conclusions: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions

Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans

Dysregulation of the haem-haemopexin axis is associated with severe malaria in a case-control study of Ugandan children.

BACKGROUND: Malaria is associated with haemolysis and the release of plasma haem. Plasma haem can cause endothelial injury and organ dysfunction, and is normally scavenged by haemopexin to limit toxicity. It was hypothesized that dysregulation of the haem-haemopexin pathway contributes to severe and fatal malaria infections. METHODS: Plasma levels of haemin (oxidized haem), haemopexin, haptoglobin, and haemoglobin were quantified in a case-control study of Ugandan children with Plasmodium falciparum malaria. Levels at presentation were compared in children with uncomplicated malaria (UM; n = 29), severe malarial anaemia (SMA; n = 27) or cerebral malaria (CM; n = 31), and evaluated for utility in predicting fatal (n = 19) vs non-fatal (n = 39) outcomes in severe disease. A causal role for haemopexin was assessed in a pre-clinical model of experimental cerebral malaria (ECM), following disruption of mouse haemopexin gene (hpx). Analysis was done using Kruskall Wallis tests, Mann-Whitney tests, log-rank tests for survival, and repeated measures ANOVA. RESULTS: In Ugandan children presenting with P. falciparum malaria, haemin levels were higher and haemopexin levels were lower in SMA and CM compared to children with UM (haemin, p \u3c 0.01; haemopexin, p \u3c 0.0001). Among all cases of severe malaria, elevated levels of haemin and cell-free haemoglobin at presentation were associated with subsequent mortality (p \u3c 0.05). Compared to ECM-resistant BALB/c mice, susceptible C57BL/6 mice had lower circulating levels of haemopexin (p \u3c 0.01), and targeted deletion of the haemopexin gene, hpx, resulted in increased mortality compared to their wild type littermates (p \u3c 0.05). CONCLUSIONS: These data indicate that plasma levels of haemin and haemopexin measured at presentation correlate with malaria severity and levels of haemin and cell-free haemoglobin predict outcome in paediatric severe malaria. Mechanistic studies in the ECM model support a causal role for the haem-haemopexin axis in ECM pathobiology

Parasite-Derived Plasma Microparticles Contribute Significantly to Malaria Infection-Induced Inflammation through Potent Macrophage Stimulation

There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflammatory activity in other disease states. Here we demonstrate that MPs, derived from the plasma of malaria infected mice, but not naive mice, induce potent activation of macrophages in vitro as measured by CD40 up-regulation and TNF production. In vitro, these MPs induced significantly higher levels of macrophage activation than intact infected red blood cells. Immunofluorescence staining revealed that MPs contained significant amounts of parasite material indicating that they are derived primarily from infected red blood cells rather than platelets or endothelial cells. MP driven macrophage activation was completely abolished in the absence of MyD88 and TLR-4 signalling. Similar levels of immunogenic MPs were produced in WT and in TNF−/−, IFN-γ−/−, IL-12−/− and RAG-1−/− malaria-infected mice, but were not produced in mice injected with LPS, showing that inflammation is not required for the production of MPs during malaria infection. This study therefore establishes parasitized red blood cell-derived MPs as a major inducer of systemic inflammation during malaria infection, raising important questions about their role in severe disease and in the generation of adaptive immune responses

S66: A Well-balanced Database of Benchmark Interaction Energies Relevant to Biomolecular Structures

With numerous new quantum chemistry methods being developed in recent years and the promise of even more new methods to be developed in the near future, it is clearly critical that highly accurate, well-balanced, reference data for many different atomic and molecular properties be available for the parametrization and validation of these methods. One area of research that is of particular importance in many areas of chemistry, biology, and material science is the study of noncovalent interactions. Because these interactions are often strongly influenced by correlation effects, it is necessary to use computationally expensive high-order wave function methods to describe them accurately. Here, we present a large new database of interaction energies calculated using an accurate CCSD(T)/CBS scheme. Data are presented for 66 molecular complexes, at their reference equilibrium geometries and at 8 points systematically exploring their dissociation curves; in total, the database contains 594 points: 66 at equilibrium geometries, and 528 in dissociation curves. The data set is designed to cover the most common types of noncovalent interactions in biomolecules, while keeping a balanced representation of dispersion and electrostatic contributions. The data set is therefore well suited for testing and development of methods applicable to bioorganic systems. In addition to the benchmark CCSD(T) results, we also provide decompositions of the interaction energies by means of DFT-SAPT calculations. The data set was used to test several correlated QM methods, including those parametrized specifically for noncovalent interactions. Among these, the SCS-MI-CCSD method outperforms all other tested methods, with a root-mean-square error of 0.08 kcal/mol for the S66 data set

The Siren Site and the Long Transition from Archaic to Late Prehistoric Lifeways on the Eastern Edwards Plateau of Central Texas

On behalf of the Texas Department of Transportation (TxDOT), SWCA Environmental Consultants (SWCA) conducted testing and data recovery investigations at the Siren site (41WM1126), a prehistoric multi-component site in the Interstate Highway 35 right-of-way along the South Fork of the San Gabriel River in Williamson County, Texas. The work was done to fulfill TxDOT’s compliance obligations under the National Historic Preservation Act and the Antiquities Code of Texas. The testing investigations were conducted under Antiquities Permit 3834, and the subsequent data recovery was under Permit 3938. Kevin Miller served as Principal Investigator on both permits. Though the site extends far beyond the area of potential effects both horizontally and vertically, the investigations focused on Late Archaic and Late Prehistoric components within a relatively limited area that would be subject to project impacts. The investigations were conducted in February 2006. The investigations identified five isolable components that were intermittently laid down from approximately 2600 to 900 years ago. A substantial Late Prehistoric Austin phase occupation is represented by Scallorn projectile points, stone tools, burned rock, faunal materials, and radiocarbon dates from cooking features. The component feature assemblage includes a cluster of discrete, well-preserved burned rock features that range from small fire-cracked rock concentrations to a large, slab-lined feature that dominates the cluster. The underlying components include four cultural strata representing a series of phases in the final millennium or so of the long Archaic period. These components span approximately 2600 to 1500 b.p., though earlier, deeply buried components were also noted on the site. These deeper deposits were not the focus of the investigations, however, since they would not be affected by the project. The Archaic components revealed a suite of small side-notched dart points such as Ensor, Fairland, and Frio, as well as many earlier broad-bladed styles such as Castroville, Montell, Marshall, and Pedernales. These robust components contained numerous burned rock features of varying size and function, abundant tools, well-preserved faunal materials, macrobotanical remains including geophytes from several earth ovens, and a large suite of radiocarbon dates. The features include an incipient burned rock midden, burned rock clusters, a debitage reduction area, a biface cache, slab-lined hearths, basin-shaped hearths, and small circular hearths. The distributions of artifacts and features within the Archaic components across the excavation blocks showed significant variations. These differences reflect sequential components that provide a view of diachronic trends in technology, subsistence, economy, and a suite of other behaviors and activities during the long transition from Archaic to Late Prehistoric adaptations. As previously determined by the testing excavations and further substantiated by the data recovery investigations, the Siren site, most notably the Late Archaic and Late Prehistoric components, is eligible for the National Register of Historic Places under Criterion D, 36 CFR 60.4, and eligible for State Archeological Landmark designation under Criteria 1 and 2 of the Rules of Practice and Procedure for the Antiquities Code of Texas, 13 TAC 26.8. The excavations and subsequent analysis have mitigated the adverse effects of the bridge construction by recovering the vast majority of the affected components within the area of potential effect. No further archaeological work is recommended. Portions of the site outside the area of potential effects have not been fully evaluated, and any future impacts beyond the mitigated areas warrant further assessment

Three Pathogens in Sympatric Populations of Pumas, Bobcats, and Domestic Cats: Implications for Infectious Disease Transmission

Anthropogenic landscape change can lead to increased opportunities for pathogen transmission between domestic and non-domestic animals. Pumas, bobcats, and domestic cats are sympatric in many areas of North America and share many of the same pathogens, some of which are zoonotic. We analyzed bobcat, puma, and feral domestic cat samples collected from targeted geographic areas. We examined exposure to three pathogens that are taxonomically diverse (bacterial, protozoal, viral), that incorporate multiple transmission strategies (vector-borne, environmental exposure/ ingestion, and direct contact), and that vary in species-specificity. Bartonella spp., Feline Immunodeficiency Virus (FIV), and Toxoplasma gondii IgG were detected in all three species with mean respective prevalence as follows: puma 16%, 41% and 75%; bobcat 31%, 22% and 43%; domestic cat 45%, 10% and 1%. Bartonella spp. were highly prevalent among domestic cats in Southern California compared to other cohort groups. Feline Immunodeficiency Virus exposure was primarily associated with species and age, and was not influenced by geographic location. Pumas were more likely to be infected with FIV than bobcats, with domestic cats having the lowest infection rate. Toxoplasma gondii seroprevalence was high in both pumas and bobcats across all sites; in contrast, few domestic cats were seropositive, despite the fact that feral, free ranging domestic cats were targeted in this study. Interestingly, a directly transmitted species-specific disease (FIV) was not associated with geographic location, while exposure to indirectly transmitted diseases – vectorborne for Bartonella spp. and ingestion of oocysts via infected prey or environmental exposure for T. gondii – varied significantly by site. Pathogens transmitted by direct contact may be more dependent upon individual behaviors and intra-specific encounters. Future studies will integrate host density, as well as landscape features, to better understand the mechanisms driving disease exposure and to predict zones of cross-species pathogen transmission among wild and domestic felids