Poly (ADP-ribose) Interacts With Phosphorylated α-Synuclein in Post Mortem PD Samples

Poly (ADP-ribose) (PAR) is a negatively charged polymer that is biosynthesized by Poly (ADP-ribose) Polymerase-1 (PARP-1) and regulates various cellular processes. Alpha-synuclein (αSyn) is an intrinsically disordered protein (IDP) that has been directly implicated with driving the onset and progression of Parkinson’s disease (PD). The mechanisms by which α-synuclein (αSyn) elicits its neurotoxic effects remain unclear, though it is well established that the main components of Lewy bodies (LBs) and Lewy neurites (LNs) in PD patients are aggregated hyperphosphorylated (S129) forms of αSyn (pαSyn). In the present study, we used immunofluorescence-based assays to explore if PARP-1 enzymatic product (PAR) promotes the aberrant cytoplasmic accumulation of pαSyn. We also performed quantitative measurements using in situ proximity ligation assays (PLA) on a transgenic murine model of α-synucleinopathy (M83-SNCA∗A53T) and post mortem PD/PDD patient samples to characterize PAR–pαSyn interactions. Additionally, we used bioinformatic approaches and site-directed mutagenesis to identify PAR-binding regions on αSyn. In summary, our studies show that PAR–pαSyn interactions are predominantly observed in PD-relevant transgenic murine models of αSyn pathology and post mortem PD/PDD patient samples. Moreover, we confirm that the interactions between PAR and αSyn involve electrostatic forces between negatively charged PAR and lysine residues on the N-terminal region of αSyn

Systematic Analysis of Cis-Elements in Unstable mRNAs Demonstrates that CUGBP1 Is a Key Regulator of mRNA Decay in Muscle Cells

BACKGROUND: Dramatic changes in gene expression occur in response to extracellular stimuli and during differentiation. Although transcriptional effects are important, alterations in mRNA decay also play a major role in achieving rapid and massive changes in mRNA abundance. Moreover, just as transcription factor activity varies between different cell types, the factors influencing mRNA decay are also cell-type specific. PRINCIPAL FINDINGS: We have established the rates of decay for over 7000 transcripts expressed in mouse C2C12 myoblasts. We found that GU-rich (GRE) and AU-rich (ARE) elements are over-represented in the 3'UTRs of short-lived mRNAs and that these mRNAs tend to encode factors involved in cell cycle and transcription regulation. Stabilizing elements were also identified. By comparing mRNA decay rates in C2C12 cells with those previously measured for pluripotent and differentiating embryonic stem (ES) cells, we identified several groups of transcripts that exhibit cell-type specific decay rates. Further, whereas in C2C12 cells the impact of GREs on mRNA decay appears to be greater than that of AREs, AREs are more significant in ES cells, supporting the idea that cis elements make a cell-specific contribution to mRNA stability. GREs are recognized by CUGBP1, an RNA-binding protein and instability factor whose function is affected in several neuromuscular diseases. We therefore utilized RNA immunoprecipitation followed by microarray (RIP-Chip) to identify CUGBP1-associated transcripts. These mRNAs also showed dramatic enrichment of GREs in their 3'UTRs and encode proteins linked with cell cycle, and intracellular transport. Interestingly several CUGBP1 substrate mRNAs, including those encoding the myogenic transcription factors Myod1 and Myog, are also bound by the stabilizing factor HuR in C2C12 cells. Finally, we show that several CUGBP1-associated mRNAs containing 3'UTR GREs, including Myod1, are stabilized in cells depleted of CUGBP1, consistent with the role of CUGBP1 as a destabilizing factor. CONCLUSIONS: Taken together, our results systematically establish cis-acting determinants of mRNA decay rates in C2C12 myoblast cells and demonstrate that CUGBP1 associates with GREs to regulate decay of a wide range of mRNAs including several that are critical for muscle development

MOA-2019-BLG-008Lb : a new microlensing detection of an object at the planet/brown dwarf boundary

Funding: R.A.S. and E.B. gratefully acknowledge support from NASA grant 80NSSC19K0291. Y.T. and J.W. acknowledge the support of DFG priority program SPP 1992 “Exploring the Diversity of Extrasolar Planets” (WA 1047/11-1). K.H. acknowledges support from STFC grant ST/R000824/1. J.C.Y. acknowledges support from NSF grant No. AST-2108414. Work by C.H. was supported by the grants of the National Research Foundation of Korea (2019R1A2C2085965 and 2020R1A4A2002885). D.M.B. acknowledges the support of the NYU Abu Dhabi Research Enhancement Fund under grant RE124. This work was partly supported by the National Science Foundation of China (grant Nos. 11333003, 11390372, and 11761131004 to S.M.). The MOA project is supported by JSPS KAKENHI grant Nos. JSPS24253004, JSPS26247023, JSPS23340064, JSPS15H00781, JP16H06287, and JP17H02871.We report on the observations, analysis and interpretation of the microlensing event MOA-2019-BLG-008. The observed anomaly in the photometric light curve is best described through a binary lens model. In this model, the source did not cross caustics and no finite-source effects were observed. Therefore, the angular Einstein ring radius θE cannot be measured from the light curve alone. However, the large event duration, tE ∼ 80 days, allows a precise measurement of the microlensing parallax πE. In addition to the constraints on the angular radius θ* and the apparent brightness Is of the source, we employ the Besançon and GalMod galactic models to estimate the physical properties of the lens. We find excellent agreement between the predictions of the two galactic models: the companion is likely a resident of the brown dwarf desert with a mass Mp ∼ 30 MJup, and the host is a main-sequence dwarf star. The lens lies along the line of sight to the Galactic bulge, at a distance of ≤4 kpc. We estimate that in about 10 yr the lens and source will be separated by ∼55 mas, and it will be possible to confirm the exact nature of the lensing system by using high-resolution imaging from ground- or space-based observatories.Publisher PDFPeer reviewe

Lactational coumestrol exposure increases ovarian apoptosis in adult rats

This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10 mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81–84. Ovarian weights were reduced significantly at 0.1 and 1.0 mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135–140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health

Kepler K2 Campaign 9: II. First space-based discovery of an exoplanet using microlensing

We report on the discovery of a bound exoplanetary microlensing event from a blind search of data gathered from Campaign 9 of the Kepler K2 mission (K2C9). K2-2016-BLG-0005Lb is a densely sampled, binary caustic-crossing microlensing event with caustic entry and exit points that are resolved in the K2C9 data, enabling the lens-source relative proper motion to be measured. We have fitted a binary microlens model to the K2 dataset, and to simultaneous observations from the Optical Gravitational Lensing Experiment (OGLE-IV), Canada-France-Hawaii Telescope (CFHT), Microlensing Observations in Astrophysics (MOA-2), the Korean Microlensing Telescope Network (KMTNet), and the United Kingdom InfraRed Telescope (UKIRT). Whilst the ground-based data only sparsely sample the binary caustic, they provide a clear detection of parallax that allows us to break completely the microlensing mass-position-velocity degeneracy and measure the planet's mass directly. We find a host mass of $0.58\pm0.03 ~{\rm M}_\odot$ and a planetary mass of $1.1 \pm 0.1 ~{\rm M_J}$. The system lies at a distance of $5.2 \pm 0.2~$kpc from Earth towards the Galactic bulge. The projected physical separation of the planet from its host is found to be $4.2 \pm 0.3~$au which, for circular orbits, corresponds to $a = 4.4^{+1.9}_{-0.4}~$au and period $P = 13^{+9}_{-2}~$yr, making K2-2016-BLG-0005Lb a close Jupiter analogue. Though previous exoplanet microlensing events have included space-based data, this event is the first bound microlensing exoplanet to be discovered from space-based data. Even through a space telescope not designed for microlensing studies, this result highlights the advantages for exoplanet microlensing discovery that come from continuous, high-cadence temporal sampling that is possible from space. (Abridged).Comment: 17 pages. Submitted to MNRA

<i>Kepler K2</i> Campaign 9: II. First space-based discovery of an exoplanet using microlensing

We present K2-2016-BLG-0005Lb, a densely sampled, planetary binary caustic-crossing microlensing event found from a blind search of data gathered from Campaign 9 of the Kepler K2 mission (K2C9). K2-2016-BLG-0005Lb is the first bound microlensing exoplanet discovered from space-based data. The event has caustic entry and exit points that are resolved in the K2C9 data, enabling the lens–source relative proper motion to be measured. We have fitted a binary microlens model to the Kepler data, and to simultaneous observations from multiple ground-based surveys. Whilst the ground-based data only sparsely sample the binary caustic, they provide a clear detection of parallax that allows us to break completely the microlensing mass–position–velocity degeneracy and measure the planet’s mass directly. We find a host mass of 0.58 ± 0.04M⊙ and a planetary mass of 1.1 ± 0.1MJ. The system lies at a distance of 5.2 ± 0.2 kpc from Earth towards the Galactic bulge, more than twice the distance of the previous most distant planet found by Kepler. The sky-projected separation of the planet from its host is found to be 4.2 ± 0.3 au which, for circular orbits, deprojects to a host separation $a = 4.4^{+1.9}_{-0.4}$ au and orbital period $P = 13^{+9}_{-2}$ yr. This makes K2-2016-BLG-0005MLb a close Jupiter analogue orbiting a low-mass host star. According to current planet formation models, this system is very close to the host mass threshold below which Jupiters are not expected to form. Upcoming space-based exoplanet microlensing surveys by NASA’s Nancy Grace Roman Space Telescope and, possibly, ESA’s Euclid mission, will provide demanding tests of current planet formation models

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms