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The diffuse Extragalactic Background Light (EBL) contains unique information about the epochs of formation and the history of evolution of galaxies. Unfortunately, direct measurements are subject to large systematic uncertainties due to the difficulties in the accurate model-based subtraction of the bright foregrounds. An alternative approach is based on the detection and identification of EBL absorption features in high-energy spectra of objects of known redshift. Here we exploit this method on the blazars H 2356-309 (z=0.165) and 1ES 1101-232 (z=0.186), newly discovered at TeV energies by the H.E.S.S. Collaboration. They are the most distant sources with measured spectra known so far at these energies. Their hard spectra provide the most stringent upper limit to date on the EBL in the Opt–NIR band, which appears significantly lower than expected from the current \"direct\" estimates and very close to the absolute lower limit represented by the integrated light of resolved galaxies. In addition to important cosmological implications, this result shows that the intergalactic space is more transparent to gamma-rays than previously thought, expanding the horizon of the TeV Universe.

The goal of early autism screening is earlier treatment. We pilot-tested a 12-week, low-intensity treatment with seven symptomatic infants ages 7–15 months. Parents mastered the intervention and maintained skills after treatment ended. Four comparison groups were matched from a study of infant siblings. The treated group of infants was significantly more symptomatic than most of the comparison groups at 9 months of age but was significantly less symptomatic than the two most affected groups between 18 and 36 months. At 36 months, the treated group had much lower rates of both ASD and DQs under 70 than a similarly symptomatic group who did not enroll in the treatment study. It appears feasible to identify and enroll symptomatic infants in parent-implemented intervention before 12 months, and the pilot study outcomes are promising, but testing the treatment’s efficacy awaits a randomized trial.

Visualization experiments are performed to investigate the development of instability waves within the boundary layer on a slender cone under high Mach number conditions. The experimental facility is a reflected-shock wind tunnel, allowing both low (Mach-8 flight equivalent) and high-enthalpy conditions to be simulated. Second-mode instability waves are visualized using a high-speed schlieren set-up, with pulse bursting of the light source allowing the propagation speed of the wavepackets to be unambiguously resolved. This, in combination with wavelength information derived from the images, enables the calculation of the disturbance frequencies. At the lower-enthalpy conditions, we concentrate on the late laminar and transitional regions of the flow. General characteristics are revealed through time-resolved and ensemble-averaged spectra on both smooth and porous ceramic surfaces of the cone. Analysis of the development of individual wavepackets is then performed. It is found that the wavepacket structures evolve from a ‘rope-like’ appearance to become more interwoven as the disturbance nears breakdown. The wall-normal disturbance distributions of both the fundamental and first harmonic, which initially have local maxima at the wall and near $y/{\\it\\delta}=0.7$ –0.75, exhibit an increase in signal energy close to the boundary-layer edge during this evolution. The structure angle of the disturbances also undergoes subtle changes as the wavepacket develops prior to breakdown. Experiments are also performed at high-enthalpy ( $h_{0}\\approx 12~\\text{MJ}~\\text{kg}^{-1}$ ) conditions in the laminar regime, and the visualization technique is shown to be capable of resolving wavepacket propagation speeds and frequencies at such conditions. The visualizations reveal a somewhat different wall-normal distribution to the low-enthalpy case, with the disturbance energy concentrated much more towards the wall. This is attributed to the highly cooled nature of the wall at high enthalpy.

Background The aim of this study was to assess validation evidence for a sedation scale for dogs. We hypothesized that the chosen sedation scale would be unreliable when used by different raters and show poor discrimination between sedation protocols. A sedation scale (range 0–21) was used to score 62 dogs scheduled to receive sedation at two veterinary clinics in a prospective trial. Scores recorded by a single observer were used to assess internal consistency and construct validity of the scores. To assess inter-rater reliability, video-recordings of sedation assessment were randomized and blinded for viewing by 5 raters untrained in the scale. Videos were also edited to allow assessment of inter-rater reliability of an abbreviated scale (range 0–12) by 5 different raters. Results Both sedation scales exhibited excellent internal consistency and very good inter-rater reliability (full scale, intraclass correlation coefficient [ICC single ] = 0.95; abbreviated scale, ICC single  = 0.94). The full scale discriminated between the most common protocols: dexmedetomidine-hydromorphone (median [range] of sedation score, 11 [1–18], n  = 20) and acepromazine-hydromorphone (5 [0–15], n  = 36, p  = 0.02). Conclusions The hypothesis was rejected. Full and abbreviated scales showed excellent internal consistency and very good reliability between multiple untrained raters. The full scale differentiated between levels of sedation.

The unique properties and atomic thickness of two-dimensional (2D) materials enable smaller and better nanoelectromechanical sensors with novel functionalities. During the last decade, many studies have successfully shown the feasibility of using suspended membranes of 2D materials in pressure sensors, microphones, accelerometers, and mass and gas sensors. In this review, we explain the different sensing concepts and give an overview of the relevant material properties, fabrication routes, and device operation principles. Finally, we discuss sensor readout and integration methods and provide comparisons against the state of the art to show both the challenges and promises of 2D material-based nanoelectromechanical sensing.

MicroRNAs (miRNAs) are small non-coding RNAs of ∼20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located ∼2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.

Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary--albeit often ineffective--treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity.

We investigate the relationship between a thousand-year history of violent conflict in Europe and various reconstructions of temperature and precipitation. We find that conflict was more intense during colder period, just like Zhang et al. (Clim Change 76:459-477, 2006) found for China. This relationship weakens in the industrialized era, and is not robust to the details of the climate reconstruction or to the sample period. As the correlation is negative and weakening, it appears that global warming would not lead to an increase in violent conflict in temperature climates.

A robust understanding of the impact of anthropogenic activities on high-altitude tropical aquatic ecosystems is key for the conservation and protection of the Tropical Andean biodiversity hot spot. We present the results of a multiproxy study of lake sediments from the high Andean páramo of El Cajas National Park, a UNESCO biosphere reserve in Ecuador. The main site, Laguna Pallcacocha, is well known for recording El Niño–driven clastic flood layers that are triggered by high-intensity rainfall anomalies from the eastern Pacific. The second site, Laguna El Ocho, does not contain clastic laminations, providing a control. The records show abrupt shifts in diatom assemblages ca. AD 1991 in both high-elevation Andean lakes accompanied by local changes in páramo composition that suggest a sudden nutrient enrichment of the environment. The diatom assemblages from Laguna Pallcacocha, in relation to the clastic input events, are remarkably stable and do not show evident El Niño signals at the analysed resolution. Based on comparison with the nonlaminated El Ocho record, we deduce the main source of this nutrient enrichment to be the construction of a heavily transited road that runs through the park, while climate warming played secondary role by amplifying its effects.

Very high energy γ-rays probe the long-standing mystery of the origin of cosmic rays. Produced in the interactions of accelerated particles in astrophysical objects, they can be used to image cosmic particle accelerators. A first sensitive survey of the inner part of the Milky Way with the High Energy Stereoscopic System (HESS) reveals a population of eight previously unknown firmly detected sources of very high energy γ-rays. At least two have no known radio or x-ray counterpart and may be representative of a new class of \"dark\" nucleonic cosmic ray sources.