Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes.

BACKGROUND: Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging. RESULTS: A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity. CONCLUSION: The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

NuSTAR Hard X-ray Survey of the Galactic Center Region I: Hard X-ray Morphology and Spectroscopy of the Diffuse Emission

We present the first sub-arcminute images of the Galactic Center above 10 keV, obtained with NuSTAR. NuSTAR resolves the hard X-ray source IGR J17456-2901 into non-thermal X-ray filaments, molecular clouds, point sources and a previously unknown central component of hard X-ray emission (CHXE). NuSTAR detects four non-thermal X-ray filaments, extending the detection of their power-law spectra with $\Gamma\sim1.3$-$2.3$ up to ~50 keV. A morphological and spectral study of the filaments suggests that their origin may be heterogeneous, where previous studies suggested a common origin in young pulsar wind nebulae (PWNe). NuSTAR detects non-thermal X-ray continuum emission spatially correlated with the 6.4 keV Fe K$\alpha$ fluorescence line emission associated with two Sgr A molecular clouds: MC1 and the Bridge. Broad-band X-ray spectral analysis with a Monte-Carlo based X-ray reflection model self-consistently determined their intrinsic column density ($\sim10^{23}$ cm$^{-2}$), primary X-ray spectra (power-laws with $\Gamma\sim2$) and set a lower limit of the X-ray luminosity of Sgr A* flare illuminating the Sgr A clouds to $L_X \stackrel{>}{\sim} 10^{38}$ erg s$^{-1}$. Above ~20 keV, hard X-ray emission in the central 10 pc region around Sgr A* consists of the candidate PWN G359.95-0.04 and the CHXE, possibly resulting from an unresolved population of massive CVs with white dwarf masses $M_{\rm WD} \sim 0.9 M_{\odot}$. Spectral energy distribution analysis suggests that G359.95-0.04 is likely the hard X-ray counterpart of the ultra-high gamma-ray source HESS J1745-290, strongly favoring a leptonic origin of the GC TeV emission.Comment: 27 pages. Accepted for publication in the Astrophysical Journa

Species Used for Drug Testing Reveal Different Inhibition Susceptibility for 17beta-Hydroxysteroid Dehydrogenase Type 1

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution

NuSTAR Hard X-ray Survey of the Galactic Center Region I: Hard X-ray Morphology and Spectroscopy of the Diffuse Emission

We present the first sub-arcminute images of the Galactic Center above 10 keV, obtained with NuSTAR. NuSTAR resolves the hard X-ray source IGR J17456–2901 into non-thermal X-ray filaments, molecular clouds, point sources, and a previously unknown central component of hard X-ray emission (CHXE). NuSTAR detects four non-thermal X-ray filaments, extending the detection of their power-law spectra with Γ ~ 1.3–2.3 up to ~50 keV. A morphological and spectral study of the filaments suggests that their origin may be heterogeneous, where previous studies suggested a common origin in young pulsar wind nebulae (PWNe). NuSTAR detects non-thermal X-ray continuum emission spatially correlated with the 6.4 keV Fe Kα fluorescence line emission associated with two Sgr A molecular clouds: MC1 and the Bridge. Broadband X-ray spectral analysis with a Monte-Carlo based X-ray reflection model self-consistently determined their intrinsic column density (~1023 cm−2), primary X-ray spectra (power-laws with Γ ~ 2) and set a lower limit of the X-ray luminosity of Sgr A* flare illuminating the Sgr A clouds to LX gsim 1038 erg s−1. Above ~20 keV, hard X-ray emission in the central 10 pc region around Sgr A* consists of the candidate PWN G359.95–0.04 and the CHXE, possibly resulting from an unresolved population of massive CVs with white dwarf masses MWD ~ 0.9 M⊙. Spectral energy distribution analysis suggests that G359.95–0.04 is likely the hard X-ray counterpart of the ultra-high gamma-ray source HESS J1745–290, strongly favoring a leptonic origin of the GC TeV emission.Astronom

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Selective preservation of changes to standing balance control despite psychological and autonomic habituation to a postural threat

Abstract Humans exhibit changes in postural control when confronted with threats to stability. This study used a prolonged threat exposure protocol to manipulate emotional state within a threatening context to determine if any threat-induced standing behaviours are employed independent of emotional state. Retention of balance adaptations was also explored. Thirty-seven adults completed a series of 90-s standing trials at two surface heights (LOW: 0.8 m above ground, away from edge; HIGH: 3.2 m above ground, at edge) on two visits 2–4 weeks apart. Psychological and autonomic state was assessed using self-report and electrodermal measures. Balance control was assessed using centre of pressure (COP) and lower limb electromyographic recordings. Upon initial threat exposure, individuals leaned backward, reduced low-frequency centre of pressure (COP) power, and increased high-frequency COP power and plantar/dorsiflexor coactivation. Following repeated exposure, the psychological and autonomic response to threat was substantially reduced, yet only high-frequency COP power and plantar/dorsiflexor coactivation habituated. Upon re-exposure after 2–4 weeks, there was partial recovery of the emotional response to threat and few standing balance adaptations were retained. This study suggests that some threat-induced standing behaviours are coupled with the psychological and autonomic state changes induced by threat, while others may reflect context-appropriate adaptations resistant to habituation

Structural diversity of lanthanoid salicylate hydrates

From metathesis reactions between lanthanoid salts and sodium salicylate (Na(salH)) in water, four classes of lanthanoid salicylate hydrates have been identified. Single crystal X-ray studies established a new monomeric class [Ln(salH)3(H2O)3]·3H2O (6Ln). This new rhombohedral R3c, Z = 6 form '6Ln' has the nine coordinate metal atom on a crystallographic 3-axis, for Ln = Sm–Gd, Ho, Er, Yb, Lu, Y. We also have augmented or defined the previously known different forms, consolidating or extending their putative 'domains of existence'. The monohydrate, Ln = '1Ce', monoclinic, P21/n, has been re-examined at lowtemperature suggesting further elasticity in its formulation beyond the recently proposed '[Ln(H2sal) (Hsal)(sal)H2O)](∞|∞)' for the Ln = Gd complex, '1Gd', one of the protonic hydrogen atoms being associated with a very short phenoxyl–O···carboxylate–O distance (2.427(3) Å). With refinement and the insights from a previous Ln = Eu study, suggest the protonic disposition to be around the O···O median. The 'domain of existence' for this form embraces Ln = La (dependent on a powder diffraction study) – Gd. The tetrahydrate is manifested in two forms: triclinic, centrosymmetric binuclear Ln2(salH)6(H2O)4]·4H2O, P·1, Z = 1, '4Ln' recorded here in a 153 K determination, for Ln = Ho, consolidating the assignment of its domain of existence to be Ho–Er, Y, and 'polymeric mononuclear' [Ln(salH)3(H2O)2](∞|∞)·2H2O, '4Ln,' recorded here for Ln = Tb–Er, Yb, Lu, Y. The 6Gd hexahydrate shows paramagnetic f7 magnetic behaviour. The reaction conditions leading to the isolation of a particular structural type of lanthanoid salicylate could not be reliably identified, indicating that a fine balance exists in the preferential crystallization of the lanthanoid salicylate hydrate phases. The discovery of the monomeric class has applications for the species acting as a corrosion inhibitor in dilute aqueous solution