Transfer of Fully Convolutional Policy-Value Networks Between Games and Game Variants

In this paper, we use fully convolutional architectures in AlphaZero-like self-play training setups to facilitate transfer between variants of board games as well as distinct games. We explore how to transfer trained parameters of these architectures based on shared semantics of channels in the state and action representations of the Ludii general game system. We use Ludii's large library of games and game variants for extensive transfer learning evaluations, in zero-shot transfer experiments as well as experiments with additional fine-tuning time

Solvent Minimized Synthesis of Amides by Reactive Extrusion

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid–liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product)

The Transiting System GJ1214: High-Precision Defocused Transit Observations and a Search for Evidence of Transit Timing Variation

Aims: We present 11 high-precision photometric transit observations of the transiting super-Earth planet GJ1214b. Combining these data with observations from other authors, we investigate the ephemeris for possible signs of transit timing variations (TTVs) using a Bayesian approach. Methods: The observations were obtained using telescope-defocusing techniques, and achieve a high precision with random errors in the photometry as low as 1mmag per point. To investigate the possibility of TTVs in the light curve, we calculate the overall probability of a TTV signal using Bayesian methods. Results: The observations are used to determine the photometric parameters and the physical properties of the GJ1214 system. Our results are in good agreement with published values. Individual times of mid-transit are measured with uncertainties as low as 10s, allowing us to reduce the uncertainty in the orbital period by a factor of two. Conclusions: A Bayesian analysis reveals that it is highly improbable that the observed transit times is explained by TTV, when compared with the simpler alternative of a linear ephemeris.Comment: Submitted to A&

Why magnesium sulfate 'coverage' only is not enough to reduce eclampsia: Lessons learned in a middle-income country

Objectives: Determine the eclampsia prevalence and factors associated with eclampsia and recurrent seizures in Suriname and evaluate quality-of-care indicator ‘magnesium sulfate (MgSO4) coverage’. Study design: A two-year prospective nationwide cohort study was conducted in Suriname and included women with eclampsia at home or in a healthcare facility. Main outcome measures: We calculated the prevalence by the number of live births obtained from vital registration. Risk factor denominator data concerned hospital births. Descriptive statistics and multivariate regression analysis were performed. Results: Seventy-two women with eclampsia (37/10.000 live births) were identified, including two maternal deaths (case-fatality 2.8%). Nulliparity, African-descent and adolescence were associated with eclampsia. Adolescents with eclampsia had significantly lower BPs (150/100 mmHg) than adult women (168/105 mmHg). The first seizure occurred antepartum in 54% (n = 39/72), intrapartum in 19% (n = 14/72) and postpartum in 26% (n = 19/72). Recurrent seizures were observed in 60% (n = 43/72). MgSO4 was administered to 99% (n = 69/70) of women; however 26% received no loading dosage and, in 22% of cases MgSO4 duration was <24 h, i.e. guideline adherence existed in only 43%. MgSO4 was ceased during CS in all women (n = 40). Stable BP was achieved before CS in 46%. The median seizure-to-delivery interval was 27 h, and ranged from four to 36 h. Conclusion: Solely ‘MgSO4 coverage’ is not a reliable quality-of-care indicator, as it conceals inadequate MgSO4 dosage and timing, discontinuation during CS, stabilization before delivery, and seizure-to-delivery interval. These other quality-of-care indicators need attention from the international community in order to reduce the prevalence of eclampsia

Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles

BACKGROUND: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. METHODS: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. RESULTS: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake. CONCLUSIONS: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS

Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles

Background: The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. Methods: Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged-matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT-qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. Results: An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti-CD63 immuno-blocking of vesicle uptake. Conclusions: ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS

Overexpression of the Mitochondrial T3 Receptor p43 Induces a Shift in Skeletal Muscle Fiber Types

In previous studies, we have characterized a new hormonal pathway involving a mitochondrial T3 receptor (p43) acting as a mitochondrial transcription factor and consequently stimulating mitochondrial activity and mitochondrial biogenesis. We have established the involvement of this T3 pathway in the regulation of in vitro myoblast differentiation.We have generated mice overexpressing p43 under control of the human α-skeletal actin promoter. In agreement with the previous characterization of this promoter, northern-blot and western-blot experiments confirmed that after birth p43 was specifically overexpressed in skeletal muscle. As expected from in vitro studies, in 2-month old mice, p43 overexpression increased mitochondrial genes expression and mitochondrial biogenesis as attested by the increase of mitochondrial mass and mt-DNA copy number. In addition, transgenic mice had a body temperature 0.8°C higher than control ones and displayed lower plasma triiodothyronine levels. Skeletal muscles of transgenic mice were redder than wild-type animals suggesting an increased oxidative metabolism. In line with this observation, in gastrocnemius, we recorded a strong increase in cytochrome oxidase activity and in mitochondrial respiration. Moreover, we observed that p43 drives the formation of oxidative fibers: in soleus muscle, where MyHC IIa fibers were partly replaced by type I fibers; in gastrocnemius muscle, we found an increase in MyHC IIa and IIx expression associated with a reduction in the number of glycolytic fibers type IIb. In addition, we found that PGC-1α and PPARδ, two major regulators of muscle phenotype were up regulated in p43 transgenic mice suggesting that these proteins could be downstream targets of mitochondrial activity. These data indicate that the direct mitochondrial T3 pathway is deeply involved in the acquisition of contractile and metabolic features of muscle fibers in particular by regulating PGC-1α and PPARδ

Human Muscle Satellite Cells as Targets of Chikungunya Virus Infection

BACKGROUND: Chikungunya (CHIK) virus is a mosquito-transmitted alphavirus that causes in humans an acute infection characterised by fever, polyarthralgia, head-ache, and myalgia. Since 2005, the emergence of CHIK virus was associated with an unprecedented magnitude outbreak of CHIK disease in the Indian Ocean. Clinically, this outbreak was characterized by invalidating poly-arthralgia, with myalgia being reported in 97.7% of cases. Since the cellular targets of CHIK virus in humans are unknown, we studied the pathogenic events and targets of CHIK infection in skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistology on muscle biopsies from two CHIK virus-infected patients with myositic syndrome showed that viral antigens were found exclusively inside skeletal muscle progenitor cells (designed as satelllite cells), and not in muscle fibers. To evaluate the ability of CHIK virus to replicate in human satellite cells, we assessed virus infection on primary human muscle cells; viral growth was observed in CHIK virus-infected satellite cells with a cytopathic effect, whereas myotubes were essentially refractory to infection. CONCLUSIONS/SIGNIFICANCE: This report provides new insights into CHIK virus pathogenesis, since it is the first to identify a cellular target of CHIK virus in humans and to report a selective infection of muscle satellite cells by a viral agent in humans

Myogenic Cell Transplantation in Genetic and Acquired Diseases of Skeletal Muscle

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-04-29, accepted 2021-06-16, epub 2021-08-02Publication status: PublishedThis article will review myogenic cell transplantation for congenital and acquired diseases of skeletal muscle. There are already a number of excellent reviews on this topic, but they are mostly focused on a specific disease, muscular dystrophies and in particular Duchenne Muscular Dystrophy. There are also recent reviews on cell transplantation for inflammatory myopathies, volumetric muscle loss (VML) (this usually with biomaterials), sarcopenia and sphincter incontinence, mainly urinary but also fecal. We believe it would be useful at this stage, to compare the same strategy as adopted in all these different diseases, in order to outline similarities and differences in cell source, pre-clinical models, administration route, and outcome measures. This in turn may help to understand which common or disease-specific problems have so far limited clinical success of cell transplantation in this area, especially when compared to other fields, such as epithelial cell transplantation. We also hope that this may be useful to people outside the field to get a comprehensive view in a single review. As for any cell transplantation procedure, the choice between autologous and heterologous cells is dictated by a number of criteria, such as cell availability, possibility of in vitro expansion to reach the number required, need for genetic correction for many but not necessarily all muscular dystrophies, and immune reaction, mainly to a heterologous, even if HLA-matched cells and, to a minor extent, to the therapeutic gene product, a possible antigen for the patient. Finally, induced pluripotent stem cell derivatives, that have entered clinical experimentation for other diseases, may in the future offer a bank of immune-privileged cells, available for all patients and after a genetic correction for muscular dystrophies and other myopathies

Non-tuberculous mycobacterial pulmonary infections

Submitted by Sandra Infurna ([email protected]) on 2019-05-14T13:52:47Z No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-05-14T14:00:46Z (GMT) No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5)Made available in DSpace on 2019-05-14T14:00:46Z (GMT). No. of bitstreams: 1 ACC_Caravalho_IOC_2018.pdf: 454431 bytes, checksum: 86468a62313ad15880a6ccff685e3090 (MD5) Previous issue date: 2018University of Dundee. Hospital and Medical School. Scottish Centre for Respiratory Research. Dundee, United Kingdom.Mayo Clinic College of Medicine. Rochester, MN, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil.Hospital Universitario de Monterrey. Centro de Investigación, Prevención y Tratamiento de Infecciones Respiratorias. Monterrey, Nuevo León UANL, Mexico.Centro Hospitalar Vila Nova de Gaia. Respiratory Department. Espinho, Portugal.Non-tuberculous mycobacterial (NTM) infections are increasingly rapidly worldwide. The reason for this phenomenon is unclear, but may include the ageing population, the increasing use of immunosuppressive drugs, the increasing prevalence of diseases that confer susceptibility to NTM, such as COPD and bronchiectasis, and growing testing for NTM. Awareness of the NTM related diseases is rising but is still suboptimal. Guidelines from the American Thoracic Society and Infectious Diseases Society of America have provided a framework for evaluating disease and evaluating care. Compliance with these guidelines is, however, very poor globally. NTM infections are amongst the most challenging cases that respiratory and infectious diseases physicians face. The challenges include intrinsic antibiotic resistance, complex drug regimens, poor tolerability and significant side effects associated with therapy and poor response rates. The decision to initiate treatment is therefore often difficult and requires careful evaluation of benefits and risks. Optimal management of NTM infections requires multidisciplinary care with close collaboration between physicians, microbiologists, physiotherapist/allied health professionals, primary care physicians and the patient. There remains a need for greater research into the epidemiology, clinical evaluation and treatment of NTM pulmonary disease. Randomised clinical trials are now being conducted which may provide useful data on the effectiveness of some new and existing therapies. In this review, we discuss the growing importance of NTM pulmonary disease and the opportunities for progress in clinical research for these conditions