Interannual variability of Mars South Polar cap

Telescopic data on the twentieth century regressions of Mars' south polar cap were reexamined for evidence of interannual variability. Several regressions, particularly that of 1956, are found to differ significantly from the mean. The possibility of correlations with major dust storms is explored

Modified Gravity and Dark Energy models Beyond w(z)w(z)CDM Testable by LSST

One of the main science goals of the Large Synoptic Survey Telescope (LSST) is to uncover the nature of cosmic acceleration. In the base analysis, possible deviations from the Lambda-Cold-Dark-Matter ($\Lambda$CDM) background evolution will be probed by fitting a $w(z)$CDM model, which allows for a redshift-dependent dark energy equation of state with $w(z)$, within general relativity (GR). A rich array of other phenomena can arise due to deviations from the standard $\Lambda$CDM+GR model though, including modifications to the growth rate of structure and lensing, and novel screening effects on non-linear scales. Concrete physical models are needed to provide consistent predictions for these (potentially small) effects, to give us the best chance of detecting them and separating them from astrophysical systematics. A complex plethora of possible models has been constructed over the past few decades, with none emerging as a particular favorite. This document prioritizes a subset of these models along with rationales for further study and inclusion into the LSST Dark Energy Science Collaboration (DESC) data analysis pipelines, based on their observational viability, theoretical plausibility, and level of theoretical development. We provide references and theoretical expressions to aid the integration of these models into DESC software and simulations, and give justifications for why other models were not prioritized. While DESC efforts are free to pursue other models, we provide here guidelines on which theories appear to have higher priority for collaboration efforts due to their perceived promise and greater instructional value.Comment: 61 pages. Some acknowledgments and references added. This is version-1.1 of an internal collaboration document of LSST-DESC that is being made public and is not planned for submission to a journa

Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies

Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p ≤ 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required

Genetic variation in hippocampal microRNA expression differences in C57BL/6 J X DBA/2 J (BXD) recombinant inbred mouse strains

Background miRNAs are short single-stranded non-coding RNAs involved in post-transcriptional gene regulation that play a major role in normal biological functions and diseases. Little is currently known about how expression of miRNAs is regulated. We surveyed variation in miRNA abundance in the hippocampus of mouse inbred strains, allowing us to take a genetic approach to the study of miRNA regulation, which is novel for miRNAs. The BXD recombinant inbred panel is a very well characterized genetic reference panel which allows quantitative trait locus (QTL) analysis of miRNA abundance and detection of correlates in a large store of brain and behavioural phenotypes. Results We found five suggestive trans QTLs for the regulation of miRNAs investigated. Further analysis of these QTLs revealed two genes, Tnik and Phf17, under the miR-212 regulatory QTLs, whose expression levels were significantly correlated with miR-212 expression. We found that miR-212 expression is correlated with cocaine-related behaviour, consistent with a reported role for this miRNA in the control of cocaine consumption. miR-31 is correlated with anxiety and alcohol related behaviours. KEGG pathway analysis of each miRNA’s expression correlates revealed enrichment of pathways including MAP kinase, cancer, long-term potentiation, axonal guidance and WNT signalling. Conclusions The BXD reference panel allowed us to establish genetic regulation and characterize biological function of specific miRNAs. QTL analysis enabled detection of genetic loci that regulate the expression of these miRNAs. eQTLs that regulate miRNA abundance are a new mechanism by which genetic variation influences brain and behaviour. Analysis of one of these QTLs revealed a gene, Tnik, which may regulate the expression of a miRNA, a molecular pathway and a behavioural phenotype. Evidence of genetic covariation of miR-212 abundance and cocaine related behaviours is strongly supported by previous functional studies, demonstrating the value of this approach for discovery of new functional roles and downstream processes regulated by miRNA

Impacts of Climate Change on indirect human exposure to pathogens and chemicals from agriculture

Objective: Climate change is likely to affect the nature of pathogens and chemicals in the environment and their fate and transport. Future risks of pathogens and chemicals could therefore be very different from those of today. In this review, we assess the implications of climate change for changes in human exposures to pathogens and chemicals in agricultural systems in the United Kingdom and discuss the subsequent effects on health impacts. Data sources: In this review, we used expert input and considered literature on climate change ; health effects resulting from exposure to pathogens and chemicals arising from agriculture ; inputs of chemicals and pathogens to agricultural systems ; and human exposure pathways for pathogens and chemicals in agricultural systems. Data synthesis: We established the current evidence base for health effects of chemicals and pathogens in the agricultural environment ; determined the potential implications of climate change on chemical and pathogen inputs in agricultural systems ; and explored the effects of climate change on environmental transport and fate of different contaminant types. We combined these data to assess the implications of climate change in terms of indirect human exposure to pathogens and chemicals in agricultural systems. We then developed recommendations on future research and policy changes to manage any adverse increases in risks. Conclusions: Overall, climate change is likely to increase human exposures to agricultural contaminants. The magnitude of the increases will be highly dependent on the contaminant type. Risks from many pathogens and particulate and particle-associated contaminants could increase significantly. These increases in exposure can, however, be managed for the most part through targeted research and policy changes

Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit-immunodeficient mice.

Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34(+) cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1(-/-)-IL2Rγc(-/-) (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdc(scid/scid)-IL2Rγc(-/-) (NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W(41)/W(41) derivatives showed superior chimerism in the W(41)-deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice. Exp Hematol 2017 Apr; 48:41-49

Archeological Testing and Data Recovery at 41ZV202, Zavala County, Texas

At the request of the Texas Department of Transportation, Environmental Affairs Division (TxDOT-ENV), the Center for Archaeological Research (CAR) of The University of Texas at San Antonio (UTSA) conducted archeological significance testing at 41ZV202, a prehistoric site located in northwestern Zavala County, in March of 2003. The work, conducted under Texas Antiquities Permit No. 3071 issued to Dr. Steven A. Tomka, was done in anticipation of the potential widening by TxDOT of FM 481. While materials dating to the Archaic were also present, the testing demonstrated the presence of significant Late Prehistoric (Austin Interval) deposits with good integrity within a portion of the TxDOT right-of-way (ROW). As TxDOT construction could not avoid these deposits, and as both the Texas Historical Commission (THC) and TxDOT concurred with CAR’s recommendations that the deposits were eligible for listing on the National Register of Historic Places (NRHP) under criterion d of 36CFR 60.4, data recovery investigations were initiated. CAR began that work in July and August of 2003. The testing permit was amended to include the data recovery efforts. Dr. Russell Greaves served as project archeologist for both the testing and data recovery effort at 41ZV202. The testing and data recovery work consisted of the excavation of a 53-m-long Gradall trench, exposing and profiling a 75-m-long road cut, and the hand excavation of 52 1 x 1 meter units that removed approximately 34.6 m3 of soil. Testing identified two large, dark stained areas designated Features 4 and 5, an associated hearth (Feature 7), and a small cluster of FCR (Feature 6). Just over 1,000 chipped stone items were recovered, including several Scallorn points, one reworked dart point, several bifaces, and two flake tools. Eleven AMS radiocarbon dates were submitted from deposits, with eight clustering around 1000 BP. Data recovery efforts defined FCR features 8 through 13. In addition, 24 arrow points, several dart points, a variety of unifacial and bifacial tools, a small number of cores, roughly 6,000 pieces of debitage, and a variety of burned sandstone, were recovered. We also collected small quantities of bone and mussel shell along with about 14,350 gastropod shells, and a variety of soil samples. Finally, all calcium carbonate nodules were retained from the screens. Following the completion of data recovery efforts, the CAR was directed by TxDOT to develop a research design for the analysis of the material from 41ZV202. TxDOT and THC accepted that research design in November of 2004, at which time the CAR began analysis and report production. Unfortunately, by 2005 project archeologist Russell Greaves had left the CAR. At that point, CAR assistant director Dr. Raymond Mauldin took over the project. The analysis of the 41ZV202 Late Prehistoric data outlined in this report is conducted in the context of a large-scale, theoretically driven model of adaptation for hunters and gatherers loosely based on aspects of Optimal Foraging Theory. In addition to 41ZV202, the approach relies on comparative data sets from Late Archaic and other Late Prehistoric sites from South and South-Central Texas to investigate shifts in subsistence, technology, and mobility across this broad region. At this time, discard decisions have not been made. However, all artifacts and associated samples collected and retained during this project, along with all project-associated documentation, are to be permanently curated at the CAR according to Texas Historical Commission guidelines

A comparative study of fragment screening methods on the p38α kinase: new methods, new insights

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(™) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(™)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-011-9454-9) contains supplementary material, which is available to authorized users