The NetHack learning environment

Progress in Reinforcement Learning (RL) algorithms goes hand-in-hand with the development of challenging environments that test the limits of current methods. While existing RL environments are either sufficiently complex or based on fast simulation, they are rarely both. Here, we present the NetHack Learning Environment (NLE), a scalable, procedurally generated, stochastic, rich, and challenging environment for RL research based on the popular single-player terminal-based roguelike game, NetHack. We argue that NetHack is sufficiently complex to drive long-term research on problems such as exploration, planning, skill acquisition, and language-conditioned RL, while dramatically reducing the computational resources required to gather a large amount of experience. We compare NLE and its task suite to existing alternatives, and discuss why it is an ideal medium for testing the robustness and systematic generalization of RL agents. We demonstrate empirical success for early stages of the game using a distributed Deep RL baseline and Random Network Distillation exploration, alongside qualitative analysis of various agents trained in the environment. NLE is open source and available at https://github.com/facebookresearch/nle

Object-based Visual SLAM: How Object Identity Informs Geometry

Presented at the IV Workshop de Visao Computacional (WVC), 17-19 November 2008, Bauru, Brazil.Objects are rich information sources about the environment. A 3D model of the objects, together with their semantic labels, can be used for camera localization as well as for cognitive reasoning about the environment. However, traditional frameworks for scene reconstruction usually map a cloud of points using structure-from-motion techniques, but do not provide objects representation. On the other side, robotics object-based mapping mainly focus on adding cognitive representations to a metric or topologic map built using traditional SLAM techniques. In this work we propose a framework for environment modeling by representing the objects in the scene, detected by an object recognition and segmentation technique. The key idea is to incorporate the resulting image segments and labels into a global inference engine in order to build simple geometric models for the objects. For now, we consider the perfect object recognition case, where we know the exact object identities, testing our approach using coarsely hand-annotated images captured by a robot carrying an omnidirectional camera. We found that the resultant object locations and sizes are fully compatible with what is expected, and the inferred robot trajectory is improved when compared to that recovered using odometry only

A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation

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Functional characterization of two novel mutations in scn5a associated with brugada syndrome identified in Italian patients

Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention

Urine-Derived Stem Cells Express 571 Neuromuscular Disorders Causing Genes, Making Them a Potential in vitro Model for Rare Genetic Diseases

Background: Neuromuscular disorders (NMDs) are a heterogeneous group of genetic diseases, caused by mutations in genes involved in spinal cord, peripheral nerve, neuromuscular junction, and muscle functions. To advance the knowledge of the pathological mechanisms underlying NMDs and to eventually identify new potential drugs paving the way for personalized medicine, limitations regarding the availability of neuromuscular disease-related biological samples, rarely accessible from patients, are a major challenge. Aim: We characterized urinary stem cells (USCs) by in-depth transcriptome and protein profiling to evaluate whether this easily accessible source of patient-derived cells is suitable to study neuromuscular genetic diseases, focusing especially on those currently involved in clinical trials. Methods: The global transcriptomics of either native or MyoD transformed USCs obtained from control individuals was performed by RNA-seq. The expression of 610 genes belonging to 16 groups of disorders (http://www.musclegenetable.fr/) whose mutations cause neuromuscular diseases, was investigated on the RNA-seq output. In addition, protein expression of 11 genes related to NMDs including COL6A, EMD, LMNA, SMN, UBA1, DYNC1H1, SOD1, C9orf72, DYSF, DAG1, and HTT was analyzed in native USCs by immunofluorescence and/or Western blot (WB). Results: RNA-seq profile of control USCs shows that 571 out of 610 genes known to be involved in NMDs, are expressed in USCs. Interestingly, the expression levels of the majority of NMD genes remain unmodified following USCs MyoD transformation. Most genes involved in the pathogenesis of all 16 groups of NMDs are well represented except for channelopathies and malignant hyperthermia related genes. All tested proteins showed high expression values, suggesting consistency between transcription and protein representation in USCs. Conclusion: Our data suggest that USCs are human cells, obtainable by non-invasive means, which might be used as a patient-specific cell model to study neuromuscular disease-causing genes and that they can be likely adopted for a variety of in vitro functional studies such as mutation characterization, pathway identification, and drug screening

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism

Mycobacteria Attenuate Nociceptive Responses by Formyl Peptide Receptor Triggered Opioid Peptide Release from Neutrophils

In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

Studio molecolare e cellulare dell'inibitore PKI55 in condizioni normali e patologiche

Il gruppo di ricerca risulta composto sia da medici che da biologi e mostra competenze differenziate utili per la completa caratterizzazione, in condizioni normali e patologiche, della proteina PKI55, da noi recentemente identificata come nuovo inibitore della PKC (Selvatici, 2003). Le diverse competenze contribuiranno allo studio dei meccanismi genetici, molecolari e cellulari del ruolo della PKI55 e di peptidi sintetici da essa derivati: a) in patologie caratterizzate da deregolata attivazione della PKC, come ad esempio l’ischemia cerebrale; b) in modelli animali in vivo, per studiare il loro potenziale ruolo antinfiammatorio. Esperimenti preliminari in vitro dimostrano che PKI55 e peptidi non sono tossici. L’uso di piccoli peptidi, in sostituzione dell’intera proteina, ha vantaggi pratici, relativi a sintesi e conservazione, e di sicurezza, relativi a tossicità e aspecificità. Infatti, numerosi sono gli inibitori della PKC studiati, tuttavia la bassa selettività e l’alta tossicità ne hanno finora impedito l’utilizzo clinico. Riteniamo che le metodiche sperimentali e gli strumenti a disposizione consentiranno di estendere le conoscenze su PKI55 e peptidi e a contribuire alla formazione degli specializzandi

Uso di oligoribonucleotidi antisenso (AONs) per il ripristino dell'espressione della distrofina

La distrofia muscolare di Duchenne (DMD) è una malattia rara dovuta a mutazioni che interrompono la traduzione proteica producendo una proteina tronca che viene rapidamente degradata. Colpisce 1 su 3500 maschi nati vivi e attualmente non esiste una cura specifica. Da tempo il gruppo di ricerca si occupa di un approccio terapeutico basato sull’utilizzo di oligoribonucleotidi antisenso (AONs) che legandosi a specifiche sequenze esoniche correggono il difetto molecolare DMD e permettono la sintesi di distrofina più corta ma funzionale. La maggiore difficoltà è ottenere il trasporto degli AONs al gene target senza che essi vengano degradati. Scopo del progetto è quello di utilizzare AONs coniugati a differenti nanoparticelle polimeriche e valutarne l’effetto terapeutico in cellule di pazienti affetti. Saranno eseguiti studi di farmacocinetica per verificare il trasporto e la quantità di AONs presente all’interno delle cellule trattate e sarà studiato se dopo il trattamento con AONs viene modificata anche la trascrizione di altre proteine del sarcolemma. L’esperienza del gruppo di ricerca nell’uso degli AONs e i precedenti lavori su animali da laboratorio (topi mdx) potranno contribuire al raggiungimento degli obiettivi proposti