Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and ...disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.
A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein ...Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed “autosis,” has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia–ischemia in vivo. A chemical screen of ∼5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na ⁺,K ⁺-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na ⁺,K ⁺-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na ⁺,K ⁺-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.
We compare the magnetic field orientation for the young giant molecular cloud Vela C inferred from 500 m polarization maps made with the BLASTPol balloon-borne polarimeter to the orientation of ...structures in the integrated line emission maps from Mopra observations. Averaging over the entire cloud we find that elongated structures in integrated line-intensity or zeroth-moment maps, for low-density tracers such as 12CO and 13CO J → 1 - 0, are statistically more likely to align parallel to the magnetic field, while intermediate- or high-density tracers show (on average) a tendency for alignment perpendicular to the magnetic field. This observation agrees with previous studies of the change in relative orientation with column density in Vela C, and supports a model where the magnetic field is strong enough to have influenced the formation of dense gas structures within Vela C. The transition from parallel to no preferred/perpendicular orientation appears to occur between the densities traced by 13CO and by C18O J → 1 - 0. Using RADEX radiative transfer models to estimate the characteristic number density traced by each molecular line, we find that the transition occurs at a molecular hydrogen number density of approximately 103 cm−3. We also see that the Centre Ridge (the highest column density and most active star-forming region within Vela C) appears to have a transition at a lower number density, suggesting that this may depend on the evolutionary state of the cloud.
Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee ...has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research.
Depuis la parution des Lignes directrices sur l’insuffisance cardiaque (IC) de la Société canadienne de cardiologie en 2006, les soins aux patients atteints de ce trouble ont connu d’importants changements. Au cours de la dernière décennie, le Comité des lignes directrices sur l’IC a publié des mises à jour périodiques. Toutefois, en raison des changements importants qui sont survenus, le Comité des lignes directrices a jugé qu’il était nécessaire de procéder à une réévaluation exhaustive des recommandations sur la prise en charge de l’IC afin de produire un ensemble complet de lignes directrices à jour. Les membres des comités primaire et secondaire sur l’IC de la Société canadienne de cardiologie, ainsi que des spécialistes externes, ont passé en revue la littérature pertinente afin d’indiquer aux cliniciens la marche à suivre. Les lignes directrices de 2017 donnent des indications sur le diagnostic et la prise en charge (autosoins, traitements pharmacologiques et non pharmacologiques, dispositifs et orientation des patients) destinées à faciliter la prise de décisions quotidiennes en matière de soins aux patients atteints d’IC. Parmi les questions abordées figurent notamment les cotes de risque, les différences de prise en charge selon qu’il s’agit d’IC à fraction d’éjection préservée ou réduite, l’activité physique et la réadaptation, les dispositifs implantables, la revascularisation, la dysfonction ventriculaire droite, l’anémie et la carence en fer, le syndrome cardiorénal, l’apnée du sommeil, les cardiomyopathies, l’IC pendant la grossesse, la cardio-oncologie et la myocardite. Le comité a apporté une attention particulière aux stratégies et aux traitements visant à prévenir l’IC, à l’organisation des soins aux patients atteints d’IC, à la prise en charge des comorbidités, ainsi qu’à des questions pratiques concernant les délais d’orientation du patient et les soins de suivi. La reconnaissance et le traitement de l’IC au stade avancé, et notamment le choix des thérapies à ce stade et les considérations en matière de fin de vie, représentent un autre aspect important de cette mise à jour. Enfin, le comité reconnaît les lacunes dans les données probantes qui subsistent et devront être comblées par les recherches futures.
A small-scale, transportable membrane upgrading system designed to purify biogas was tested at two food waste digesters and one dairy digester. The system had a rated capacity of 100 Nm3 h−1 raw ...biogas making it suitable for the many small-scale biogas production facilities being developed across California. The membrane removed a majority of the carbon dioxide from the biogas with performance matching expected targets. The membrane system also removed trace levels of aldehydes, ketones, siloxanes, halocarbons, and sulfur-containing compounds from the biogas, mainly because the pre-cleaning steps removed these contaminants from the gas stream. The average composition of upgraded biomethane produced by the membrane system satisfied the trace contaminant requirements for pipeline injection in California. Residual air in the biogas was not removed efficiently by the membrane system which prevented methane concentrations from reaching levels sufficient to meet the heating value requirements for pipeline injection. Dedicated upgrading plants could carefully eliminate air leakage to address this issue, and/or mix propane into the biomethane to achieve the target heating value. An economic model developed for small scale biogas production facilities predicted that capital costs for a typical small-scale membrane separation plant exceed $2.46 million and projects only become financially viable over a 15 year return period when natural gas prices exceed $21.92 GJ−1. Current market prices for petroleum natural gas are far below this level, and so financial incentives will be required to make small-scale biogas projects using membrane separation technology viable in the near term.
•A small-scale membrane separation unit was tested for biogas upgrading in California.•Pre-cleaning steps removed most trace contaminants but breakthrough occurred.•Air injection used at most sites prevented upgrading gas to pipeline quality.•Upgrading at small-scales requires subsidies to be economically feasible.
Adsorption of the two oxyanions, arsenate (As(V)) and arsenite (As(III)), on a common goethite-based granular porous adsorbent is studied in the presence of major co-existing ions in groundwater ...(i.e., phosphate, silicic acid, sulfate, carbonate, magnesium, and calcium) and predicted using the extended triple layer model (ETLM), a dipole modified single-site triple layer surface complexation model consistent with spectroscopic and molecular evidence. Surface species of all ions were selected according to the previous ETLM studies and published experimental spectroscopic/theoretical molecular information. The adsorption equilibrium constants for all ions were determined using adsorption data obtained in single-solute systems. The adsorption equilibrium constants referenced to the site-occupancy standard state (indicated by Kθ) were compared with those for goethite in the literature if available. The values of these constants for the goethite-based adsorbent are found to be close to the values for goethite previously studied. These “constrained” adsorption equilibrium constants determined in single-solute systems were used in the ETLM to predict the competitive interactions of As(III, V) with the co-existing ions in binary-solute systems. The ETLM is capable of predicting As(III, V) adsorption in the presence of oxyanions (phosphate, silicic acid, sulfate, and carbonate). This study presents the first successful and systematic prediction of the competitive interactions of As(III, V) with these oxyanions using the ETLM. The ETLM prediction of surface (and aqueous) speciation also provides insights into the distinct adsorption behavior of As(III, V) in the presence of the oxyanions. Magnesium and calcium significantly enhanced As(V) adsorption at higher pH values, while they had little effect on As(III) adsorption. The enhanced adsorption of As(V), however, could not be predicted by the ETLM using the surface species proposed in previous ETLM studies. Further studies are necessary to identify ternary complexes, especially at high pH. Adsorption isotherms of As(V), a dominant form of arsenic in adsorptive water treatment systems, in the presence of the co-existing ions under relevant conditions of water treatment systems are also obtained and predicted by the ETLM to study and compare the effect of the co-existing ions on As(V) removal.
Biogas is a renewable energy source composed of methane, carbon dioxide, and other trace compounds produced from anaerobic digestion of organic matter. A variety of feedstocks can be combined with ...different digestion techniques that each yields biogas with different trace compositions. California is expanding biogas production systems to help meet greenhouse gas reduction goals. Here, we report the composition of six California biogas streams from three different feedstocks (dairy manure, food waste, and municipal solid waste). The chemical and biological composition of raw biogas is reported, and the toxicity of combusted biogas is tested under fresh and photochemically aged conditions. Results show that municipal waste biogas contained elevated levels of chemicals associated with volatile chemical products such as aromatic hydrocarbons, siloxanes, and certain halogenated hydrocarbons. Food waste biogas contained elevated levels of sulfur-containing compounds including hydrogen sulfide, mercaptans, and sulfur dioxide. Biogas produced from dairy manure generally had lower concentrations of trace chemicals, but the combustion products had slightly higher toxicity response compared to the other feedstocks. Atmospheric aging performed in a photochemical smog chamber did not strongly change the toxicity (oxidative capacity or mutagenicity) of biogas combustion exhaust.
Why some women look young for their age Gunn, David A; Rexbye, Helle; Griffiths, Christopher E M ...
PloS one,
12/2009, Volume:
4, Issue:
12
Journal Article
Peer reviewed
Open access
The desire of many to look young for their age has led to the establishment of a large cosmetics industry. However, the features of appearance that primarily determine how old women look for their ...age and whether genetic or environmental factors predominately influence such features are largely unknown. We studied the facial appearance of 102 pairs of female Danish twins aged 59 to 81 as well as 162 British females aged 45 to 75. Skin wrinkling, hair graying and lip height were significantly and independently associated with how old the women looked for their age. The appearance of facial sun-damage was also found to be significantly correlated to how old women look for their age and was primarily due to its commonality with the appearance of skin wrinkles. There was also considerable variation in the perceived age data that was unaccounted for. Composite facial images created from women who looked young or old for their age indicated that the structure of subcutaneous tissue was partly responsible. Heritability analyses of the appearance features revealed that perceived age, pigmented age spots, skin wrinkles and the appearance of sun-damage were influenced more or less equally by genetic and environmental factors. Hair graying, recession of hair from the forehead and lip height were influenced mainly by genetic factors whereas environmental factors influenced hair thinning. These findings indicate that women who look young for their age have large lips, avoid sun-exposure and possess genetic factors that protect against the development of gray hair and skin wrinkles. The findings also demonstrate that perceived age is a better biomarker of skin, hair and facial aging than chronological age.
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