Crawling in Rogue's dungeons with (partitioned) A3C

Rogue is a famous dungeon-crawling video-game of the 80ies, the ancestor of its gender. Rogue-like games are known for the necessity to explore partially observable and always different randomly-generated labyrinths, preventing any form of level replay. As such, they serve as a very natural and challenging task for reinforcement learning, requiring the acquisition of complex, non-reactive behaviors involving memory and planning. In this article we show how, exploiting a version of A3C partitioned on different situations, the agent is able to reach the stairs and descend to the next level in 98% of cases.Comment: Accepted at the Fourth International Conference on Machine Learning, Optimization, and Data Science (LOD 2018

Highly heterogeneous Late Mesozoic lithospheric mantle beneath the North China Craton: evidence from Sr–Nd–Pb isotopic systematics of mafic igneous rocks

The lithospheric mantle beneath the North China Craton changed dramatically in its geophysical and geochemical characteristics from Palaeozoic to Cenozoic times. This study uses samples of Mesozoic basalts and mafic intrusions from the North China Craton to investigate the nature of this mantle in Mesozoic times. Sr-Nd-Pb isotopic data demonstrate that the Late Mesozoic lithospheric mantle was extremely heterogeneous. In the central craton or the Luzhong region, it is slightly Sr-Nd isotopically enriched, beneath the Taihangshan region it has an EMI character (87Sr/86Sri = 0.7050-0.7066; εNd = -17--10), and beneath the Luxi-Jiaodong region, it possesses EM2-like characteristics (87Sr/86Sri up to 0.7114). Compositional variation with time is also apparent in the Mesozoic lithospheric mantle. Our data suggest that the old lithospheric mantle was modified during Mesozoic times by a silicic melt, where beneath the Luxi-Jiaodong region it was severely modified, but in the Luzhong and Taihangshan regions the effects were much less marked. The silicic melt may have been the product of partial melting of crustal materials brought into the mantle by the subducted slab during the formation of circum-cratonic orogenic belts. This Mesozoic mantle did not survive for a long time, and was replaced by a Cenozoic mantle with depleted geochemical characteristics. © 2004 Cambridge University Press.published_or_final_versio

Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release

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Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Clinical guidance on pharmacotherapy for the treatment of attention-deficit hyperactivity disorder (ADHD) for people with intellectual disability.

INTRODUCTION: ADHD causes significant distress and functional impairment in multiple domains of daily life. Therefore, diagnosis and treatment are important to improve the quality of life of people. The pharmacotherapy for ADHD is well established but needs systematic evaluation in Intellectual Disability (ID) populations. AREAS COVERED: This paper reviews the ADHD pharmacological treatment in people with ID using the PRISMA guidance for scoping reviews to help identify the nature and strength of evidence. EXPERT OPINION: In the last 20 years, seven randomized controlled trials have evaluated pharmacotherapies for ADHD in people with ID; five looking at methylphenidate. Generally, studies were underpowered; all but two had less than 25 participants. Of the two larger trials one was single blinded and therefore open to bias. Only two used a parallel-group method, the remainder were mostly short crossover trials; not ideal when measuring behavioral and psychological parameters which are long standing. The remaining evidence is made up of observational studies. Methylphenidate and atomoxetine, particularly at higher doses, have shown clear benefits in people with ID. Most people with ID tolerated ADHD medications well. Benefits were seen in behavioral and/or cognitive domains. The evidence base is limited, though promising, for dexamfetamine, clonidine, and guanfacine

The VMC survey XXVIII. Improved measurements of the proper motion of the Galactic globular cluster 47 Tucanae

We use deep multi-epoch point-spread function (PSF) photometry taken with the Visible and Infrared Survey Telescope for Astronomy (VISTA) to measure and analyze the proper motions of stars within the Galactic globular cluster 47 Tucanae (47 Tuc, NGC 104). The observations are part of the ongoing near-infrared VISTA survey of the Magellanic Cloud system (VMC). The data analyzed in this study correspond to one VMC tile, which covers a total sky area of 1.77 deg(2). Absolute proper motions with respect to similar to 9070 background galaxies are calculated from a linear regression model applied to the positions of stars in 11 epochs in the K-s filter. The data extend over a total time baseline of about 17 months. We found an overall median proper motion of the stars within 47 Tuc of (mu alpha cos(delta), mu(delta)) = (+5.89 +/- 0.02 (statistical) +/- 0.13 (systematic), -2.14 +/- 0.02 (statistical) +/- 0.08 (systematic)) mas yr(-1), based on the measurements of similar to 35 000 individual sources between 5’ and 42’ from the cluster center. We compared our result to the proper motions from the newest US Naval Observatory CCD Astrograph Catalog (UCAC5), which includes data from the Gaia data release 1. Selecting cluster members (similar to 2700 stars), we found a median proper motion of (mu(alpha)cos(delta), mu(delta)) = (+5.30 +/- 0.03 (statistical) +/- 0.70 (systematic), -2.70 +/- 0.03 (statistical) +/- 0.70 (systematic)) mas yr(-1). Comparing the results with measurements in the literature, we found that the values derived from the VMC data are consistent with the UCAC5 result, and are close to measurements obtained using the Hubble Space Telescope. We combined our proper motion results with radial velocity measurements from the literature and reconstructed the orbit of 47 Tuc, finding that the cluster is on an orbit with a low ellipticity and is confined within the inner similar to 7.5 kpc of the Galaxy. We show that the use of an increased time baseline in combination with PSF-determined stellar centroids in crowded regions significantly improves the accuracy of the method. In future works, we will apply the methods described here to more VMC tiles to study in detail the kinematics of the Magellanic Clouds

The VMC Survey. XXXII. Pre-main-sequence populations in the Large Magellanic Cloud

Context Detailed studies of intermediate- and low-mass pre-main-sequence (PMS) stars outside the Galaxy have so far been conducted only for small targeted regions harbouring known star formation complexes. The VISTA Survey of the Magellanic Clouds (VMC) provides an opportunity to study PMS populations down to solar masses on a galaxy-wide scale. Aims Our goal is to use near-infrared data from the VMC survey to identify and characterise PMS populations down to ∼ 1 M� across the Magellanic Clouds. We present our colour−magnitude diagram method, and apply it to a ∼ 1.5 deg2 pilot field located in the Large Magellanic Cloud. Methods The pilot field is divided into equal-size grid elements. We compare the stellar population in every element with the population in nearby control fields by creating Ks/(Y−Ks) Hess diagrams; the observed density excesses over the local field population are used to classify the stellar populations. Results Our analysis recovers all known star formation complexes in this pilot field (N 44, N 51, N 148, and N 138) and for the first time reveals their true spatial extent. In total, around 2260 PMS candidates with ages . 10 Myr are found in the pilot field. PMS structures, identified as areas with a significant density excess of PMS candidates, display a power-law distribution of the number of members with a slope of −0.86 ± 0.12. We find a clustering of the young stellar populations along ridges and filaments where dust emission in the far-infrared (FIR) (70 µm – 500 µm) is bright. Regions with young populations lacking massive stars show a lower degree of clustering and are usually located in the outskirts of the star formation complexes. At short FIR wavelengths (70 µm, 100 µm) we report a strong dust emission increase in regions hosting young massive stars, which is less pronounced in regions populated only by less massive (. 4 M�) PMS stars

Clinical and genetic spectrum of a Chinese cohort with SCN4A gene mutations

Skeletal muscle sodium channelopathies due to SCN4A gene mutations have a broad clinical spectrum. However, each phenotype has been reported in few cases of Chinese origin. We present detailed phenotype and genotype data from a cohort of 40 cases with SCN4A gene mutations seen in neuromuscular diagnostic service in Huashan hospital, Fudan University. Cases were referred from 6 independent provinces from 2010 to 2018. A questionnaire covering demographics, precipitating factors, episodes of paralysis and myotonia was designed to collect the clinical information. Electrodiagnostic studies and muscle MRI were retrospectively analyzed. The clinical spectrum of patients included: 6 Hyperkalemic periodic paralysis (15%), 18 Hypokalemic periodic paralysis (45%), 7 sodium channel myotonia (17.5%), 4 paramyotonia congenita (10%) and 5 heterozygous asymptomatic mutation carriers (12.5%). Review of clinical information highlights a significant delay to diagnosis (median 15 years), reports of pain and myalgia in the majority of patients, male predominance, circadian rhythm and common precipitating factors. Electrodiagnostic studies revealed subclinical myotonic discharges and a positive long exercise test in asymptomatic carriers. Muscle MRI identified edema and fatty infiltration in gastrocnemius and soleus. A total of 13 reported and 2 novel SCN4A mutations were identified with most variants distributed in the transmembrane helix S4 to S6, with a hotspot mutation p.Arg675Gln accounting for 32.5% (13/40) of the cohort. Our study revealed a higher proportion of periodic paralysis in SCN4A-mutated patients compared with cohorts from England and the Netherlands. It also highlights the importance of electrodiagnostic studies in diagnosis and segregation studies

The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis.

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents