Novel therapeutic approaches for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3Δex7/8 astrocytes have significantly lower basal spontaneous Ca2+ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca2+ signaling, Cln3Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 loss disrupts neuronal synaptic activity causing increased glutamate release, which astrocytes are unequipped to regulate due to reductions in Ca2+ signaling and energy metabolism. Therefore, a therapeutic capable of targeting several molecular deficits associated with JNCL would be an ideal. Cyclic AMP (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation, glutamate transporter expression, and neuron survival. We investigated whether three distinct phosphodiesterase-4 (PDE4) inhibitors could mitigate disease pathology in the Cln3Δex7/8 mouse model. cAMP levels were significantly reduced in the Cln3Δex7/8 brain, which were restored by PF-06266047. PDE4 inhibitors significantly improved motor function, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression with no evidence of toxicity. These studies revealed neuroprotective effects of PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential. However, PDE4 inhibitors do not provide a long-term treatment for JNCL because the CLN3 mutation is still present. Therefore, we explored a gene delivery approach for JNCL utilizing two self-complementary AAV9 (scAAV9) constructs with the MeCP2 and β-actin promoters to drive low versus high transgene expression and to test efficacy in the Cln3Δex7/8 model. Only the scAAV9/MeCP2-hCLN3 construct corrected motor deficits and attenuated glia activation and lysosomal pathology, possibly resulting from preferential viral promoter usage by neurons. This is the first demonstration of a systemic delivery route to restore CLN3 in vivo using scAAV9 and highlights the importance of promoter selection for disease modification. Collectively, these projects provide novel insights into CLN3 pathology and identify two promising modes of therapeutic advancement for this fatal lysosomal storage disease

A New Look at the Incidence of Slipped Capital Femoral Epiphysis in New Mexico

Past epidemiological studies demonstrated a nearly fivefold lower incidence of slipped capital femoral epiphysis (SCFE) in New Mexico compared with Connecticut. A recent study demonstrated some regional variability but did not address this earlier finding. We sought to reexamine the incidence of SCFE in New Mexico to improve the understanding of the epidemiology and ultimately the disorder itself

Adolescents with Idiopathic Scoliosis are Not Osteoporotic

In the past, prior studies have associated adolescent idiopathic scoliosis (AIS) to abnormalities in bone mineral density (BMD) such as osteoporosis\u27 or \u27osteopenia\u27 based on their adult definitions, but in reality very few AIS patients have clinically abnormal BMD. Fracture risk has not been correlated to Z-scores in pediatric populations, so the terms \u27osteoporosis\u27 and \u27osteopenia\u27 can not be applied to AIS. Our study examined adolescents with and without scoliosis of varying weights to better understand the relationship of BMD to body mass index (BMI). This cross-sectional retrospective study compared the dual photon X-ray absorptiometry (DXA) scans of hips and distal femora of 49 adolescents with idiopathic scoliosis and 40 normal control adolescents. Z-scores were compared using student\u27s t-test or simple linear regression procedures to discover correlations between Z-scores and clinical and demographic variables. In both populations, there was a strong correlation with z-scores and BMI (p\u3c.001). Scoliosis had the effect of lowering the Z-score as if the individual had \u27lost\u27 3.4 BMI units. Essentially, thin subjects had lower BMD and heavy subjects had higher BMD. The impact of scoliosis reducing BMI scores by 3.4 units puts thin subjects in the \u27low for age\u27 level while the effect is negligible in heavier subjects. There were no subjects in either group that met the International Society of Clinical Densitometry (ICSD) definition for \u27osteoporosis.\u27\u2

Implementation of a part-of-speech ontology : morphemic units of Bantu languages

In a previous article (Faaß et al, 2012), a first attempt was made at documenting and encoding morphemic units of two South African Bantu languages, i.e. Northern Sotho and Zulu, with the aim of describing and storing the morphemic units of these two languages in a single relational database, structured as a hierarchical ontology. As a follow-up, the current article describes the implementation of our part-of-speech ontology. We give a detailed description of the morphemes and categories contained in the database, highlighting the need and reasons for a flexible ontology which will provide for both language specific and general linguistic information. By giving a detailed account of the methodology for the population of the database, we provide linguists from other Bantu languages with a road map for extending the database to also include their languages of specialization.This paper has been written in the framework of the project Scientific eLexicography for Africa (SeLA) working towards the development of electronic dictionaries and terminology databases for the (South) African Bantu Languages.The German ministry for education and research (BMBF, Funding number 55516493.http://www.njas.helsinki.fiam2016African Language

Towards a part-of-speech ontology : encoding morphemic units of two South African Bantu languages

This article describes the design of an electronic knowledge base, namely a morpho-syntactic database structured as an ontology of linguistic categories, containing linguistic units of two related languages of the South African Bantu group: Northern Sotho and Zulu. These languages differ significantly in their surface orthographies, but are very similar on the lexical and sub-lexical levels. It is therefore our goal to describe the morphemes of these languages in a single common database in order to outline and interpret commonalities and differences in more detail. Moreover, the relational database which is developed defines the underlying morphemic units (morphs) for both languages. It will be shown that the electronic part-ofspeech ontology goes hand in hand with part-of-speech tagsets that label morphemic units. This database is designed as part of a forthcoming system providing lexicographic and linguistic knowledge on the official South African Bantu languages.The German Ministry for Education and Research (BMBF, Funding number 55516493http://www.njas.helsinki.fi/am201

Exploring the links between star formation and minor companions around isolated galaxies

Previous studies have shown that galaxies with minor companions exhibit an elevated star formation rate. We reverse this inquiry, constructing a volume-limited sample of \simL\star (Mr \leq -19.5 + 5 log h) galaxies from the Sloan Digital Sky Survey that are isolated with respect to other luminous galaxies. Cosmological simulations suggest that 99.8% of these galaxies are alone in their dark matter haloes with respect to other luminous galaxies. We search the area around these galaxies for photometric companions. Matching strongly star forming (EW(H{\alpha})\geq 35 \AA) and quiescent (EW(H{\alpha})< 35 \AA) samples for stellar mass and redshift using a Monte Carlo resampling technique, we demonstrate that rapidly star-forming galaxies are more likely to have photometric companions than other galaxies. The effect is relatively small; about 11% of quiescent, isolated galaxies have minor photometric companions at radii \leq 60 kpc h$^{-1}$ kpc while about 16% of strongly star-forming ones do. Though small, the cumulative difference in satellite counts between strongly star-forming and quiescent galaxies is highly statistically significant (PKS = 1.350 \times10$^{-3}$) out to to radii of \sim 100 h$^{-1}$ kpc. We discuss explanations for this excess, including the possibility that \sim 5% of strongly star-forming galaxies have star formation that is causally related to the presence of a minor companion.Comment: 7 pages, 6 figures, submitted to MNRA

Compilación de un corpus para la enseñanza de la traducción médica

Fundamento: la traducción médica cuenta con un sinnúmero de fuentes documentales; la mayor dificultad radica en saber evaluarlas. El corpus es una herramienta idónea para hacerlo de forma confiable y rápida, así como para definir objetivos de aprendizaje basados en la tipología textual y orientados a la práctica profesional. Objetivo: compilar un corpus electrónico que responda a los requerimientos de la práctica profesional para asumir la traducción médica especializada.Métodos: investigación pedagógica realizada en la provincia de Cienfuegos, cuyas unidades de análisis estuvieron conformadas por el registro de trabajo de los traductores del Centro Provincial de Información de Ciencias Médicas y traductores especializados en esta área, a los cuales se les aplicó un cuestionario para determinar con exactitud sus necesidades de consulta, que condicionaron los criterios de diseño del corpus. Se analizó un conjunto de textos extraídos de fuentes altamente acreditadas a partir de los cuales se realizó la selección y compilación final. Posteriormente se procedió a la validación del corpus como herramienta documental para la enseñanza de la traducción médica especializada. Resultados: concentración de encargos de traducción en los temas: tumores malignos, hipertensión, cardiopatías, diabetes mellitus y neumonías. Tipología textual predominante: evaluativa y transmisión de actualidad inmediata, con abundancia de artículos originales y revisiones. Los criterios de diseño del corpus fueron: no anotado, documentado, especializado, textual, monitor y comparable. Conclusiones: el corpus es un apoyo útil para mostrar las particularidades léxicas, terminológicas, semánticas, discursivas y contextuales de la comunicación biomédica, permite definir objetivos de aprendizaje y problemas de traducción.</p

Orbiting Circum-galactic Gas as a Signature of Cosmological Accretion

We use cosmological SPH simulations to study the kinematic signatures of cool gas accretion onto a pair of well-resolved galaxy halos. Cold-flow streams and gas-rich mergers produce a circum-galactic component of cool gas that generally orbits with high angular momentum about the galaxy halo before falling in to build the disk. This signature of cosmological accretion should be observable using background-object absorption line studies as features that are offset from the galaxy's systemic velocity by ~100 km/s. Accreted gas typically co-rotates with the central disk in the form of a warped, extended cold flow disk, such that the observed velocity offset is in the same direction as galaxy rotation, appearing in sight lines that avoid the galactic poles. This prediction provides a means to observationally distinguish accreted gas from outflow gas: the accreted gas will show large one-sided velocity offsets in absorption line studies while radial/bi-conical outflows will not (except possibly in special polar projections). This rotation signature has already been seen in studies of intermediate redshift galaxy-absorber pairs; we suggest that these observations may be among the first to provide indirect observational evidence for cold accretion onto galactic halos. Cold mode halo gas typically has ~3-5 times more specific angular momentum than the dark matter. The associated cold mode disk configurations are likely related to extended HI/XUV disks seen around galaxies in the local universe. The fraction of galaxies with extended cold flow disks and associated offset absorption-line gas should decrease around bright galaxies at low redshift, as cold mode accretion dies out.Comment: 15 pages, 9 figures, edited to match published version. Includes expanded discussion, with primary results unchange

Deletion Mutants of the Attenuated Recombinant ASF Virus, BA71ΔCD2, Show Decreased Vaccine Efficacy

African swine fever (ASF) has become the major threat to the global swine industry. Lack of available commercial vaccines complicates the implementation of global control strategies. So far, only live attenuated ASF viruses (ASFV) have demonstrated solid protection efficacy at the experimental level. The implementation of molecular techniques has allowed the generation of a collection of deletion mutants lacking ASFV-specific virulence factors, some of them with promising potential as vaccine candidates against the pandemic genotype II ASFV strain currently circulating in Africa, Europe, Asia and Oceania. Despite promising results, there is room for improvement, mainly from the biosafety point of view. Aiming to improve the safety of BA71∆CD2, a cross-protective recombinant live attenuated virus (LAV) lacking the ASFV CD2v gene (encoding β-glucuronidase as a reporter gene) available in our laboratory, three new recombinants were generated using BA71∆CD2 as a template: the single mutant BA71∆CD2 f, this time containing the fluorescent mCherry reporter gene instead of CD2v, and two double recombinants lacking CD2v and either the lectin gene (EP153R) or the uridine kinase (UK) gene (DP96R). Comparative in vivo experiments using BA71∆CD2 f, BA71∆CD2DP96R and BA71∆CD2EP153R recombinant viruses as immunogens, demonstrated that deletion of either DP96R or EP153R from BA71∆CD2 f decreases vaccine efficacy and does not improve safety. Our results additionally confirm ASFV challenge as the only available method today to evaluate the protective efficacy of any experimental vaccine. We believe that understanding the fine equilibrium between attenuation and inducing protection in vivo deserves further study and might contribute to more rational vaccine designs in the future

Distinctive phytohormonal and metabolic profiles of Arabidopsis thaliana and Eutrema salsugineum under similar soil drying

Main conclusions: Arabidopsis and Eutrema show similar stomatal sensitivity to drying soil. In Arabidopsis, larger metabolic adjustments than in Eutrema occurred, with considerable differences in the phytohormonal responses of the two species. Although plants respond to soil drying via a series of concurrent physiological and molecular events, drought tolerance differs greatly within the plant kingdom. While Eutrema salsugineum (formerly Thellungiella salsuginea) is regarded as more stress tolerant than its close relative Arabidopsis thaliana, their responses to soil water deficit have not previously been directly compared. To ensure a similar rate of soil drying for the two species, daily soil water depletion was controlled to 5–10% of the soil water content. While partial stomatal closure occurred earlier in Arabidopsis (Day 4) than Eutrema (from Day 6 onwards), thereafter both species showed similar stomatal sensitivity to drying soil. However, both targeted and untargeted metabolite analysis revealed greater response to drought in Arabidopsis than Eutrema. Early peaks in foliar phytohormone concentrations and different sugar profiles between species were accompanied by opposing patterns in the bioactive cytokinin profiles. Untargeted analysis showed greater metabolic adjustment in Arabidopsis with more statistically significant changes in both early and severe drought stress. The distinct metabolic responses of each species during early drought, which occurred prior to leaf water status declining, seemed independent of later stomatal closure in response to drought. The two species also showed distinct water usage, with earlier reduction in water consumption in Eutrema (Day 3) than Arabidopsis (Day 6), likely reflecting temporal differences in growth responses. We propose Arabidopsis as a promising model to evaluate the mechanisms responsible for stress-induced growth inhibition under the mild/moderate soil drying that crop plants are typically exposed to