Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling

Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP+. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease

Massive stars exploding in a He-rich circumstellar medium. V. Observations of the slow-evolving SN Ibn OGLE-2012-SN-006

We present optical observations of the peculiar Type Ibn supernova (SN Ibn) OGLE-2012-SN-006, discovered and monitored by the OGLE-IV survey, and spectroscopically followed by PESSTO at late phases. Stringent pre-discovery limits constrain the explosion epoch with fair precision to JD = 2456203.8 +- 4.0. The rise time to the I-band light curve maximum is about two weeks. The object reaches the peak absolute magnitude M(I) = -19.65 +- 0.19 on JD = 2456218.1 +- 1.8. After maximum, the light curve declines for about 25 days with a rate of 4 mag per 100d. The symmetric I-band peak resembles that of canonical Type Ib/c supernovae (SNe), whereas SNe Ibn usually exhibit asymmetric and narrower early-time light curves. Since 25 days past maximum, the light curve flattens with a decline rate slower than that of the 56Co to 56Fe decay, although at very late phases it steepens to approach that rate. An early-time spectrum is dominated by a blue continuum, with only a marginal evidence for the presence of He I lines marking this SN Type. This spectrum shows broad absorptions bluewards than 5000A, likely O II lines, which are similar to spectral features observed in super-luminous SNe at early epochs. The object has been spectroscopically monitored by PESSTO from 90 to 180 days after peak, and these spectra show the typical features observed in a number of SN 2006jc-like events, including a blue spectral energy distribution and prominent and narrow (v(FWHM) ~ 1900 km/s) He I emission lines. This suggests that the ejecta are interacting with He-rich circumstellar material. The detection of broad (10000 km/s) O I and Ca II features likely produced in the SN ejecta (including the [O I] 6300A,6364A doublet in the latest spectra) lends support to the interpretation of OGLE-2012-SN-006 as a core-collapse event.Comment: 16 pages, 9 figures, 4 tables. Accepted by MNRA

A Significantly off-center Ni56 Distribution for the Low-Luminosity Type Ia Supernova SN 2016brx from the 100IAS survey

We present nebular-phase spectra of the Type Ia supernova (SN Ia) 2016brx, a member of the 1991bg-like subclass that lies at the faint end of the SN Ia luminosity function. Nebular spectra are available for only three other 1991bg-like SNe, and their Co line centers are all within <~ 500 km/s of each other. In contrast, the nebular Co line center of SN 2016brx is blue-shifted by >1500 km/s compared to them and by ~1200 km/s compared to the rest frame. This is a significant shift relative to the narrow nebular line velocity dispersion of <~ 2000 km/s of these SNe. The large range of nebular line shifts implies that the Ni56 in the ejecta of SN 1991bg-like events is off-center by ~1000 km/s rather than universally centrally confined as previously suggested. With the addition of SN 2016brx, the Co nebular line shapes of 1991bg-like objects appear to connect with the brighter SNe Ia that show double-peak profiles, hinting at a continuous distribution of line profiles among SNe Ia. One class of models to produce both off-center and bi-modal Ni56 distributions is collisions of white dwarfs with unequal and equal masses.Comment: Minor Changes. Accepted by MNRAS Lette

Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells

During the pregnancy associated syndrome preeclampsia (PE), there is increased release of placental syncytiotrophoblast extracellular vesicles (STBEVs) and free foetal haemoglobin (HbF) into the maternal circulation. In the present study we investigated the uptake of normal and PE STBEVs by primary human coronary artery endothelial cells (HCAEC) and the effects of free HbF on this uptake. Our results show internalization of STBEVs into primary HCAEC, and transfer of placenta specific miRNAs from STBEVs into the endoplasmic reticulum and mitochondria of these recipient cells. Further, the transferred miRNAs were functional, causing a down regulation of specific target genes, including the PE associated gene fms related tyrosine kinase 1 (FLT1). When co-treating normal STBEVs with HbF, the miRNA deposition is altered from the mitochondria to the ER and the cell membrane becomes ruffled, as was also seen with PE STBEVs. These findings suggest that STBEVs may cause endothelial damage and contribute to the endothelial dysfunction typical for PE. The miRNA mediated effects on gene expression may contribute to the oxidative and endoplasmic reticulum stress described in PE, as well as endothelial reprogramming that may underlay the increased risk of cardiovascular disease reported for women with PE later in life

HII Region Metallicity Constraints Near the Site of the Strongly Lensed Supernova "SN Refsdal" at Redshift 1.49

T. Yuan, C. Kobayashi, and L. J. Kewley, “HII Region Metallicity Constraints Near the Site of the Strongly Lensed Supernova "SN Refsdal" at Redshift 1.49”, The Astrophysical Journal Letters, Vol. 804(1), April 2015. © 2015. The American Astronomical Society.We present the local HII region metallicity near the site of the recently discovered multiply lensed supernova (SN; "SN Refsdal") at redshift 1.49. "SN Refsdal" is located at the outer spiral arm ($\sim$7 kpc) of the lensed host galaxy, which we have previously reported to exhibit a steep negative galactocentric metallicity gradient. Based on our updated near-infrared integral field spectroscopic data, the gas-phase metallicity averaged in an intrinsic radius of $\sim$ 550 pc surrounding an HII region $\sim$ 200 pc away from the SN site is 12 + log(O/H)$_{\rm PP04N2}$ $\le$ 8.67. The metallicity averaged over nine HII regions at similar galactocentric distances ($\sim$5-7 kpc) as "SN Refsdal" is constrained to be 12 + log(O/H)$_{\rm PP04N2}$ $\le$ 8.11. Given the fortuitous discovery of "SN Refsdal" in an advantageously lensed face-on spiral, this is the first observational constraint on the local metallicity environment of an SN site at redshift $z>1$.Peer reviewe

Adaptation and Preadaptation of Salmonella enterica to Bile

Bile possesses antibacterial activity because bile salts disrupt membranes, denature proteins, and damage DNA. This study describes mechanisms employed by the bacterium Salmonella enterica to survive bile. Sublethal concentrations of the bile salt sodium deoxycholate (DOC) adapt Salmonella to survive lethal concentrations of bile. Adaptation seems to be associated to multiple changes in gene expression, which include upregulation of the RpoS-dependent general stress response and other stress responses. The crucial role of the general stress response in adaptation to bile is supported by the observation that RpoS− mutants are bile-sensitive. While adaptation to bile involves a response by the bacterial population, individual cells can become bile-resistant without adaptation: plating of a non-adapted S. enterica culture on medium containing a lethal concentration of bile yields bile-resistant colonies at frequencies between 10−6 and 10−7 per cell and generation. Fluctuation analysis indicates that such colonies derive from bile-resistant cells present in the previous culture. A fraction of such isolates are stable, indicating that bile resistance can be acquired by mutation. Full genome sequencing of bile-resistant mutants shows that alteration of the lipopolysaccharide transport machinery is a frequent cause of mutational bile resistance. However, selection on lethal concentrations of bile also provides bile-resistant isolates that are not mutants. We propose that such isolates derive from rare cells whose physiological state permitted survival upon encountering bile. This view is supported by single cell analysis of gene expression using a microscope fluidic system: batch cultures of Salmonella contain cells that activate stress response genes in the absence of DOC. This phenomenon underscores the existence of phenotypic heterogeneity in clonal populations of bacteria and may illustrate the adaptive value of gene expression fluctuations

Changes in circulating microRNA levels can be identified as early as day 8 of pregnancy in cattle

<div><p>Poor reproductive performance remains a major issue in the dairy industry, with low conception rates having a significant impact on milk production through extended calving intervals. A major limiting factor is the lack of reliable methods for early pregnancy diagnosis. Identification of animals within a herd that fail to conceive within 3 weeks after insemination would allow early re-insemination and shorten calving intervals. In a previous study, we found an increase in plasma miR-26a levels in Day 16-pregnant relative to non-pregnant heifers, however changes in miRNA levels that early during pregnancy were very small which likely prevented the identification of robust biomarkers. In this study, we extended our analyses to a wider interval during pregnancy (Days 8 to 60, n = 11 heifers) with the rationale that this may facilitate the identification of additional early pregnancy miRNA biomarkers. Using small RNA sequencing we identified a total of 77 miRNAs that were differentially expressed on Day 60 relative to Day 0 of pregnancy. We selected 14 miRNAs for validation by RT-qPCR and confirmed significant differences in the expression of let-7f, let-7c, miR-30c, miR-101, miR-26a, miR-205 and miR-143 between Days 0 and 60. RT-qPCR profiling throughout Days 0, 8, 16 and 60 of pregnancy showed a distinct increase in circulating levels of miR-26a (3.1-fold, P = 0.046) as early as Day 8 of pregnancy. In summary, in contrast to earlier stages of pregnancy (≤ Day 24), marked differences in the levels of multiple miRNAs can be detected in circulation by Day 60 in cattle. Retrospective analyses showed miR-26a levels to be increased in circulation as early as Day 8, sooner than previously reported in any species, suggesting a biological role for this miRNA in the very early events of pregnancy.</p></div

First year of energetic particle measurements in the inner heliosphere with Solar Orbiter's Energetic Particle Detector

Context. Solar Orbiter strives to unveil how the Sun controls and shapes the heliosphere and fills it with energetic particle radiation. To this end, its Energetic Particle Detector (EPD) has now been in operation, providing excellent data, for just over a year. Aims. EPD measures suprathermal and energetic particles in the energy range from a few keV up to (near-) relativistic energies (few MeV for electrons and about 500 MeV nuc−1 for ions). We present an overview of the initial results from the first year of operations and we provide a first assessment of issues and limitations. In addition, we present areas where EPD excels and provides opportunities for significant scientific progress in understanding how our Sun shapes the heliosphere. Methods. We used the solar particle events observed by Solar Orbiter on 21 July and between 10 and 11 December 2020 to discuss the capabilities, along with updates and open issues related to EPD on Solar Orbiter. We also give some words of caution and caveats related to the use of EPD-derived data. Results. During this first year of operations of the Solar Orbiter mission, EPD has recorded several particle events at distances between 0.5 and 1 au from the Sun. We present dynamic and time-averaged energy spectra for ions that were measured with a combination of all four EPD sensors, namely: the SupraThermal Electron and Proton sensor (STEP), the Electron Proton Telescope (EPT), the Suprathermal Ion Spectrograph (SIS), and the High-Energy Telescope (HET) as well as the associated energy spectra for electrons measured with STEP and EPT. We illustrate the capabilities of the EPD suite using the 10 and 11 December 2020 solar particle event. This event showed an enrichment of heavy ions as well as 3He, for which we also present dynamic spectra measured with SIS. The high anisotropy of electrons at the onset of the event and its temporal evolution is also shown using data from these sensors. We discuss the ongoing in-flight calibration and a few open instrumental issues using data from the 21 July and the 10 and 11 December 2020 events and give guidelines and examples for the usage of the EPD data. We explain how spacecraft operations may affect EPD data and we present a list of such time periods in the appendix. A list of the most significant particle enhancements as observed by EPT during this first year is also provided.Ministerio de Economía y CompetitividadAgencia Estatal de Investigació

Active commuting to and from university, obesity and metabolic syndrome among Colombian university students

Background: There is limited evidence concerning how active commuting (AC) is associated with health benefits in young. The aim of the study was to analyze the relationship between AC to and from campus (walking) and obesity and metabolic syndrome (MetS) in a sample of Colombian university students. Methods: A total of 784 university students (78.6% women, mean age = 20.1 ± 2.6 years old) participated in the study. The exposure variable was categorized into AC (active walker to campus) and non-AC (non/infrequent active walker to campus: car, motorcycle, or bus) to and from the university on a typical day. MetS was defined in accordance with the updated harmonized criteria of the International Diabetes Federation criteria. Results: The overall prevalence of MetS was 8.7%, and it was higher in non-AC than AC to campus. The percentage of AC was 65.3%. The commuting distances in this AC from/to university were 83.1%, 13.4% and 3.5% for < 2 km, 2- 5 km and > 5 km, respectively. Multiple logistic regressions for predicting unhealthy profile showed that male walking commuters had a lower probability of having obesity [OR = 0.45 (CI 95% 0.25–0.93)], high blood pressure [OR = 0.26 (CI 95% 0.13–0.55)] and low HDL cholesterol [OR = 0.29 (CI 95% 0.14–0.59)] than did passive commuters. Conclusions: Our results suggest that in young adulthood, a key life-stage for the development of obesity and MetS, AC could be associated with and increasing of daily physical activity levels, thereby promoting better cardiometabolic health.This study was part of the project entitled “Body Adiposity Index and Biomarkers of Endothelial and Cardiovascular Health in Adults”, which was funded by Centre for Studies on Measurement of Physical Activity, School of Medicine and Health Sciences, Universidad del Rosario (Code N° FIUR DNBG001) and Universidad de Boyacá (Code N° RECT 60)

The Dark Energy Spectroscopic Instrument (DESI)

We present the status of the Dark Energy Spectroscopic Instrument (DESI) and its plans and opportunities for the coming decade. DESI construction and its initial five years of operations are an approved experiment of the US Department of Energy and is summarized here as context for the Astro2020 panel. Beyond 2025, DESI will require new funding to continue operations. We expect that DESI will remain one of the world's best facilities for wide-field spectroscopy throughout the decade. More about the DESI instrument and survey can be found at https://www.desi.lbl.gov