MicroRNA inhibition using antimiRs in acute human brain tissue sections

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 μmol L-1 and 90% reduction at 3 μmol L-1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effects in live human brain tissues. The findings lend further support to the preclinical development of a therapy that targets miR-134 and offer a flexible platform for the preclinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain

CPEB4–CLOCK crosstalk during temporal lobe epilepsy

Objective: Posttranscriptional mechanisms are increasingly recognized as important contributors to the formation of hyperexcitable networks in epilepsy. Messenger RNA (mRNA) polyadenylation is a key regulatory mechanism governing protein expression by enhancing mRNA stability and translation. Previous studies have shown large-scale changes in mRNA polyadenylation in the hippocampus of mice during epilepsy development. The cytoplasmic polyadenylation element-binding protein CPEB4 was found to drive epilepsy-induced poly(A) tail changes, and mice lacking CPEB4 develop a more severe seizure and epilepsy phenotype. The mechanisms controlling CPEB4 function and the downstream pathways that influence the recurrence of spontaneous seizures in epilepsy remain poorly understood. Methods: Status epilepticus was induced in wild-type and CPEB4-deficient male mice via an intra-amygdala microinjection of kainic acid. CLOCK binding to the CPEB4 promoter was analyzed via chromatin immunoprecipitation assay and melatonin levels via high-performance liquid chromatography in plasma. Results: Here, we show increased binding of CLOCK to recognition sites in the CPEB4 promoter region during status epilepticus in mice and increased Cpeb4 mRNA levels in N2A cells overexpressing CLOCK. Bioinformatic analysis of CPEB4-dependent genes undergoing changes in their poly(A) tail during epilepsy found that genes involved in the regulation of circadian rhythms are particularly enriched. Clock transcripts displayed a longer poly(A) tail length in the hippocampus of mice post-status epilepticus and during epilepsy. Moreover, CLOCK expression was increased in the hippocampus in mice post-status epilepticus and during epilepsy, and in resected hippocampus and cortex of patients with drug-resistant temporal lobe epilepsy. Furthermore, CPEB4 is required for CLOCK expression after status epilepticus, with lower levels in CPEB4-deficient compared to wild-type mice. Last, CPEB4-deficient mice showed altered circadian function, including altered melatonin blood levels and altered clustering of spontaneous seizures during the day. Significance: Our results reveal a new positive transcriptional–translational feedback loop involving CPEB4 and CLOCK, which may contribute to the regulation of the sleep–wake cycle during epilepsy.H2020 Marie Skłodowska-Curie Actions, Grant/Award Number:766124 and 796600; Irish Research Council, Grant/Award Number:GOIPD/2020/806; Programa de Atracción de Talento de la Comunidad de Madrid, Grant/Award Number: 2020-T2/BMD- 20180; Science Foundation Ireland, Grant/Award Number:16/RC/3948 and 17/CDA/4708;Spanish Ministry of Economy and Competitiveness/Ministry of Science, Innovation and Universities, Grant/Award Number: PID2021- 123141OB- I0

Optimized Photometric Redshifts for the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS)

We present the first comprehensive release of photometric redshifts (photo- z's) from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey (CANDELS) team. We use statistics based upon the Quantile-Quantile (Q-Q) plot to identify biases and signatures of underestimated or overestimated errors in photo- z probability density functions (PDFs) produced by six groups in the collaboration; correcting for these effects makes the resulting PDFs better match the statistical definition of a PDF. After correcting each group’s PDF, we explore three methods of combining the different groups’ PDFs for a given object into a consensus curve. Two of these methods are based on identifying the minimum f-divergence curve, i.e., the PDF that is closest in aggregate to the other PDFs in a set (analogous to the median of an array of numbers). We demonstrate that these techniques yield improved results using sets of spectroscopic redshifts independent of those used to optimize PDF modifications. The best photo- z PDFs and point estimates are achieved with the minimum f-divergence using the best four PDFs for each object (mFDa4) and the hierarchical Bayesian (HB4) methods, respectively. The HB4 photo- z point estimates produced σ NMAD = 0.0227/0.0189 and ∣Δz/(1 + z)∣ &gt; 0.15 outlier fraction = 0.067/0.019 for spectroscopic and 3D Hubble Space Telescope redshifts, respectively. Finally, we describe the structure and provide guidance for the use of the CANDELS photo- z catalogs, which are available at https://archive.stsci.edu/prepds/candels/.</p

CANDELS Visual Classifications: Scheme, Data Release, and First Results

We have undertaken an ambitious program to visually classify all galaxies in the five CANDELS fields down to H \u3c 24.5 involving the dedicated efforts of over 65 individual classifiers. Once completed, we expect to have detailed morphological classifications for over 50,000 galaxies spanning 0 \u3c z \u3c 4 over all the fields, with classifications from 3 to 5 independent classifiers for each galaxy. Here, we present our detailed visual classification scheme, which was designed to cover a wide range of CANDELS science goals. This scheme includes the basic Hubble sequence types, but also includes a detailed look at mergers and interactions, the clumpiness of galaxies, k-corrections, and a variety of other structural properties. In this paper, we focus on the first field to be completed—GOODS-S, which has been classified at various depths. The wide area coverage spanning the full field (wide+deep+ERS) includes 7634 galaxies that have been classified by at least three different people. In the deep area of the field, 2534 galaxies have been classified by at least five different people at three different depths. With this paper, we release to the public all of the visual classifications in GOODS-S along with the Perl/Tk GUI that we developed to classify galaxies. We present our initial results here, including an analysis of our internal consistency and comparisons among multiple classifiers as well as a comparison to the Sérsic index. We find that the level of agreement among classifiers is quite good (\u3e70% across the full magnitude range) and depends on both the galaxy magnitude and the galaxy type, with disks showing the highest level of agreement (\u3e50%) and irregulars the lowest (k-corrections between the V-band and H-band observations and find that a small fraction (84 galaxies in total) are classified as being very different between these two bands. These galaxies typically have very clumpy and extended morphology or are very faint in the V-band

Optimized Photometric Redshifts for the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey (CANDELS)

We present the first comprehensive release of photometric redshifts (photo-z's) from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey (CANDELS) team. We use statistics based upon the Quantile-Quantile (Q--Q) plot to identify biases and signatures of underestimated or overestimated errors in photo-z probability density functions (PDFs) produced by six groups in the collaboration; correcting for these effects makes the resulting PDFs better match the statistical definition of a PDF. After correcting each group's PDF, we explore three methods of combining the different groups' PDFs for a given object into a consensus curve. Two of these methods are based on identifying the minimum f-divergence curve, i.e., the PDF that is closest in aggregate to the other PDFs in a set (analogous to the median of an array of numbers). We demonstrate that these techniques yield improved results using sets of spectroscopic redshifts independent of those used to optimize PDF modifications. The best photo-z PDFs and point estimates are achieved with the minimum f-divergence using the best 4 PDFs for each object (mFDa4) and the Hierarchical Bayesian (HB4) methods, respectively. The HB4 photo-z point estimates produced $\sigma_{\rm NMAD} = 0.0227/0.0189$ and $|\Delta z/(1+z)| > 0.15$ outlier fraction = 0.067/0.019 for spectroscopic and 3D-HST redshifts, respectively. Finally, we describe the structure and provide guidance for the use of the CANDELS photo-z catalogs, which are available at https://archive.stsci.edu/hlsp/candels.Comment: 35 pages, 19 figures, submitted to ApJ, data available at https://archive.stsci.edu/hlsp/candel

The Evolution of the Galaxy Rest-Frame Ultraviolet Luminosity Function Over the First Two Billion Years

We present a robust measurement and analysis of the rest-frame ultraviolet (UV) luminosity function at z=4-8. We use deep Hubble Space Telescope imaging over the CANDELS/GOODS fields, the Hubble Ultra Deep Field and the Year 1 Hubble Frontier Field deep parallel observations. These surveys provides an effective volume of 0.6-1.2 x 10^6 Mpc^3 over this epoch, allowing us to perform a robust search for faint (M_UV=-18) and bright (M_UV < -21) galaxies. We select candidate galaxies using a well-tested photometric redshift technique with careful screening of contaminants, finding a sample of 7446 galaxies at 3.51000 galaxies at z~6-8. We measure the luminosity function using a Markov Chain Monte Carlo analysis to measure robust uncertainties. At the faint end our results agree with previous studies, yet we find a higher abundance of UV-bright galaxies at z>6, with M* ~ -21 at z>5, different than that inferred based on previous trends at lower redshift. At z=8, a single power-law provides an equally good fit to the UV luminosity function, while at z=6 and 7, an exponential cutoff at the bright-end is moderately preferred. We compare to semi-analytical models, and find that the lack of evolution in M* is consistent with models where the impact of dust attenuation on the bright-end of the luminosity function decreases at higher redshift. We measure the evolution of the cosmic star-formation rate density, correcting for dust attenuation, and find that it declines as (1+z)^(-4.3 +/- 0.5) at z>4, consistent with observations at z>9. Our observations are consistent with a reionization history that starts at z>10, completes at z>6, and reaches a midpoint (x_HII = 0.5) at 6.7<z<9.4. Finally, our observations predict that the abundance of bright z=9 galaxies is likely higher than previous constraints, though consistent with recent estimates of bright z~10 galaxies. [abridged]Comment: Re-submitted to the Astrophysical Journal after first referee's report. 34 pages, 21 figures, 7 tables. The source file includes a machine readable table of our full galaxy sampl

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns