Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Diversity, host specialization, and geographic structure of filarial nematodes infecting Malagasy bats

We investigated filarial infection in Malagasy bats to gain insights into the diversity of these parasites and explore the factors shaping their distribution. Samples were obtained from 947 individual bats collected from 52 sites on Madagascar and representing 31 of the 44 species currently recognized on the island. Samples were screened for the presence of micro-and macro-parasites through both molecular and morphological approaches. Phylogenetic analyses showed that filarial diversity in Malagasy bats formed three main groups, the most common represented by Litomosa spp. infecting Miniopterus spp. (Miniopteridae); a second group infecting Pipistrellus cf. hesperidus (Vespertilionidae) embedded within the Litomosoides cluster, which is recognized herein for the first time from Madagascar; and a third group composed of lineages with no clear genetic relationship to both previously described filarial nematodes and found in M. griveaudi, Myotis goudoti, Neoromicia matroka (Vespertilionidae), Otomops madagascariensis (Molossidae), and Paratriaenops furculus (Hipposideridae). We further analyzed the infection rates and distribution pattern of Litomosa spp., which was the most diverse and prevalent filarial taxon in our sample. Filarial infection was disproportionally more common in males than females in Miniopterus spp., which might be explained by some aspect of roosting behavior of these cave-dwelling bats. We also found marked geographic structure in the three Litomosa clades, mainly linked to bioclimatic conditions rather than host-parasite associations. While this study demonstrates distinct patterns of filarial nematode infection in Malagasy bats and highlights potential drivers of associated geographic distributions, future work should focus on their alpha taxonomy and characterize arthropod vectors

Endobiont Viruses Sensed by the Human Host – Beyond Conventional Antiparasitic Therapy

Wide-spread protozoan parasites carry endosymbiotic dsRNA viruses with uncharted implications to the human host. Among them, Trichomonas vaginalis, a parasite adapted to the human genitourinary tract, infects globally ∼250 million each year rendering them more susceptible to devastating pregnancy complications (especially preterm birth), HIV infection and HPV-related cancer. While first-line antibiotic treatment (metronidazole) commonly kills the protozoan pathogen, it fails to improve reproductive outcome. We show that endosymbiotic Trichomonasvirus, highly prevalent in T. vaginalis clinical isolates, is sensed by the human epithelial cells via Toll-like receptor 3, triggering Interferon Regulating Factor -3, interferon type I and proinflammatory cascades previously implicated in preterm birth and HIV-1 susceptibility. Metronidazole treatment amplified these proinflammatory responses. Thus, a new paradigm targeting the protozoan viruses along with the protozoan host may prevent trichomoniasis-attributable inflammatory sequelae

The strengths and difficulties questionnaire as a predictor of parent-reported diagnosis of autism spectrum disorder and attention deficit hyperactivity disorder

notes: PMCID: PMC3848967This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The Strengths and Difficulties Questionnaire (SDQ) is widely used as an international standardised instrument measuring child behaviour. The primary aim of our study was to examine whether behavioral symptoms measured by SDQ were elevated among children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) relative to the rest of the population, and to examine the predictive value of the SDQ for outcome of parent-reported clinical diagnosis of ASD/ADHD. A secondary aim was to examine the extent of overlap in symptoms between children diagnosed with these two disorders, as measured by the SDQ subscales. A cross-sectional secondary analysis of data from the Millennium Birth Cohort (n = 19,519), was conducted. Data were weighted to be representative of the UK population as a whole. ADHD or ASD identified by a medical doctor or health professional were reported by parents in 2008 and this was the case definition of diagnosis; (ADHD n = 173, ASD n = 209, excluding twins and triplets). Study children's ages ranged from 6.3-8.2 years; (mean 7.2 years). Logistic regression was used to examine the association between the parent-reported clinical diagnosis of ASD/ADHD and teacher and parent-reported SDQ subscales. All SDQ subscales were strongly associated with both ASD and ADHD. There was substantial co-occurrence of behavioral difficulties between children diagnosed with ASD and those diagnosed with ADHD. After adjustment for other subscales, the final model for ADHD, contained hyperactivity/inattention and impact symptoms only and had a sensitivity of 91% and specificity of 90%; (AUC) = 0.94 (95% CI, 0.90-0.97). The final model for ASD was composed of all subscales except the 'peer problems' scales, indicating of the complexity of behavioural difficulties that may accompany ASD. A threshold of 0.03 produced model sensitivity and specificity of 79% and 93% respectively; AUC = 0.90 (95% CI, 0.86-0.95). The results support changes to DSM-5 removing exclusivity clauses.ESRCNational Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

A Hydrodynamic Model of Alfvénic Wave Heating in a Coronal Loop and Its Chromospheric Footpoints

Alfv\'enic waves have been proposed as an important energy transport mechanism in coronal loops, capable of delivering energy to both the corona and chromosphere and giving rise to many observed features, of flaring and quiescent regions. In previous work, we established that resistive dissipation of waves (ambipolar diffusion) can drive strong chromospheric heating and evaporation, capable of producing flaring signatures. However, that model was based on a simplified assumption that the waves propagate instantly to the chromosphere, an assumption which the current work removes. Via a ray tracing method, we have implemented traveling waves in a field-aligned hydrodynamic simulation that dissipate locally as they propagate along the field line. We compare this method to and validate against the magnetohydrodynamics code Lare3D. We then examine the importance of travel times to the dynamics of the loop evolution, finding that (1) the ionization level of the plasma plays a critical role in determining the location and rate at which waves dissipate; (2) long duration waves effectively bore a hole into the chromosphere, allowing subsequent waves to penetrate deeper than previously expected, unlike an electron beam whose energy deposition rises in height as evaporation reduces the mean-free paths of the electrons; (3) the dissipation of these waves drives a pressure front that propagates to deeper depths, unlike energy deposition by an electron beam.Comment: Accepted to Ap

Fragile X Mental Retardation Protein and cerebral expression of metabotropic glutamate receptor subtype 5 in men with fragile X syndrome: A pilot study

Multiple lines of evidence suggest that a deficiency of Fragile X Mental Retardation Protein (FMRP) mediates dysfunction of the metabotropic glutamate receptor subtype 5 (mGlu

Dynamic star formation in the massive DR21 filament

The formation of massive stars is a highly complex process in which it is not clear whether the star-forming gas is in global gravitational collapse or in an equilibrium state, supported by turbulence. By studying one of the most massive and dense star-forming regions in the Galaxy at a distance of less than 3 kpc, the filament containing the well-known sources DR21 and DR21(OH), we expect to find observational signatures that allow to discriminate between the two views. We use molecular line data from our 13CO 1-0, CS 2-1, and N2H+ 1-0 survey of the Cygnus X region obtained with the FCRAO and high-angular resolution observations of CO, CS, HCO+, N2H+, and H2CO, obtained with the IRAM 30m telescope. We observe a complex velocity field and velocity dispersion in the DR21 filament in which regions of highest column-density, i.e. dense cores, have a lower velocity dispersion than the surrounding gas and velocity gradients that are not (only) due to rotation. Infall signatures in optically thick line profiles of HCO+ and 12CO are observed along and across the whole DR21 filament. From modelling the observed spectra, we obtain a typical infall speed of 0.6 km/s and mass accretion rates of the order of a few 10^-3 Msun/yr for the two main clumps constituting the filament. These massive (4900 and 3300 Msun) clumps are both gravitationally contracting. All observed kinematic features in the DR21 filament can be explained if it is formed by the convergence of flows at large scales and is now in a state of global gravitational collapse. Whether this convergence of flows originated from self-gravity at larger scales or from other processes can not be settled with the present study. The observed velocity field and velocity dispersion are consistent with results from (magneto)-hydrodynamic simulations where the cores lie at the stagnation points of convergent turbulent flows.Comment: Astronomy and Astrophysics, in pres

Econometric analysis to evaluate the effect of community-based health insurance on reducing informal self-care in Burkina Faso

Objective This study examines the role of community-based health insurance (CBHI) in influencing health-seeking behaviour in Burkina Faso, West Africa. Community-based health insurance was introduced in Nouna district, Burkina Faso, in 2004 with the goal to improve access to contracted providers based at primary- and secondary-level facilities. The paper specifically examines the effect of CBHI enrolment on reducing the prevalence of seeking modern and traditional methods of self-treatment as the first choice in care among the insured population

Dark Matter from Minimal Flavor Violation

We consider theories of flavored dark matter, in which the dark matter particle is part of a multiplet transforming nontrivially under the flavor group of the Standard Model in a manner consistent with the principle of Minimal Flavor Violation (MFV). MFV automatically leads to the stability of the lightest state for a large number of flavor multiplets. If neutral, this particle is an excellent dark matter candidate. Furthermore, MFV implies specific patterns of mass splittings among the flavors of dark matter and governs the structure of the couplings between dark matter and ordinary particles, leading to a rich and predictive cosmology and phenomenology. We present an illustrative phenomenological study of an effective theory of a flavor SU(3)_Q triplet, gauge singlet scalar.Comment: 10 pages, 2 figures; v2: references added, minor changes to collider analysis, conclusions unchange