Translating genetic and preclinical findings into autism therapies

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by social deficits and repetitive/restrictive interests. ASD is associated with multiple comorbidities, including intellectual disability, anxiety, and epilepsy. Evidence that ASD is highly heritable has spurred major efforts to unravel its genetics, revealing possible contributions from hundreds of genes through rare and common variation and through copy-number changes. In this perspective, we provide an overview of the current state of ASD genetics and of how genetic research has spurred the development of in vivo and in vitro models using animals and patient cells to evaluate the impact of genetic mutations on cellular function leading to disease. Efforts to translate these findings into successful therapies have yet to bear fruit. We discuss how the valuable insight into the disorder provided by these new models can be used to better understand ASD and develop future clinical trials

The Density of States and the Spectral Shift Density of Random Schroedinger Operators

In this article we continue our analysis of Schroedinger operators with a random potential using scattering theory. In particular the theory of Krein's spectral shift function leads to an alternative construction of the density of states in arbitrary dimensions. For arbitrary dimension we show existence of the spectral shift density, which is defined as the bulk limit of the spectral shift function per unit interaction volume. This density equals the difference of the density of states for the free and the interaction theory. This extends the results previously obtained by the authors in one dimension. Also we consider the case where the interaction is concentrated near a hyperplane.Comment: 1 figur

Screening and identification of lactic acid bacteria isolated from sorghum silage processes in west Algeria

The lactic acid bacteria (LAB) isolated from sorghum (Sorghum bicolor. L.) silage were identified during different periods of evolution of sorghum silage in west Algeria. Morphological, physiological, biochemical and technological techniques were used to characterize lactic acid bacteria isolates. A total number of 27 representatives of lactic acid bacterial strains were retained and among them four dominant genus were identified as Lactobacillus (44%), Lactococcus (14.81%), Weissella (29.62%) and Leuconostoc (11.11%). The representative species identified were Lactobacillus brevis (25%), Lactobacillus pentosus (3.7%), Lactobacillus manihotivorans (11.11%), and Lactobacillus fermentum (3.7%). Lactococcus lactis subsp. lactis biovar. diacetylactis (14.81%), Weissella cibaria (7.2%), Weissella minor (11.11%), Weissella soli (3.7%), Weissella viridescense (7.2%) and Leuconostoc mesenteroides subsp. mesenteroides (11.11%). Only two strains of lactic acid bacteria were amylolytic. These results will enable future research on the relationship between LAB species and silage fermentation quality.Keywords: Lactic acid bacteria, identification, silage, sorghum, evolution, amylolytic, technology, speciesAfrican Journal of Biotechnology Vol. 12(14), pp. 1703-170

Global Bounds for the Lyapunov Exponent and the Integrated Density of States of Random Schr\"odinger Operators in One Dimension

In this article we prove an upper bound for the Lyapunov exponent $\gamma(E)$ and a two-sided bound for the integrated density of states $N(E)$ at an arbitrary energy $E>0$ of random Schr\"odinger operators in one dimension. These Schr\"odinger operators are given by potentials of identical shape centered at every lattice site but with non-overlapping supports and with randomly varying coupling constants. Both types of bounds only involve scattering data for the single-site potential. They show in particular that both $\gamma(E)$ and $N(E)-\sqrt{E}/\pi$ decay at infinity at least like $1/\sqrt{E}$. As an example we consider the random Kronig-Penney model.Comment: 9 page

Unconventional Transcriptional Response to Environmental Enrichment in a Mouse Model of Rett Syndrome

Background: Rett syndrome (RTT) is an X-linked postnatal neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2) and one of the leading causes of mental retardation in females. RTT is characterized by psychomotor retardation, purposeless hand movements, autistic-like behavior and abnormal gait. We studied the effects of environmental enrichment (EE) on the phenotypic manifestations of a RTT mouse model that lacks MeCP2 (Mecp2 2/y). Principal Findings: We found that EE delayed and attenuated some neurological alterations presented by Mecp2 2/y mice and prevented the development of motor discoordination and anxiety-related abnormalities. To define the molecular correlate of this beneficial effect of EE, we analyzed the expression of several synaptic marker genes whose expression is increased by EE in several mouse models. Conclusions/Significance: We found that EE induced downregulation of several synaptic markers, suggesting that th

The Effect Of Ni And Cu Catalysts On The Growth Of Graphene Under Different Ethanol Flow Rates Using Atmospheric Pressure Chemical Vapor Deposition

Graphene was grown on both nickel (Ni) and copper (Cu) catalysts by atmospheric pressure chemical vapor deposition (APCVD) technique at various ethanol flow rates. Raman spectroscopy and field emission scanning electron microscopy (FESEM) were used to study morphological and structural properties of APCVD grown graphene. The crystallite size, defect intensity, distance between defects and the graphene thickness were estimated based on Raman spectra analysis. For the same growth conditions, Ni catalyst promote the formation of more graphene layers as compare to Cu. This because of the higher carbon solubility in Ni as compared to Cu which leads to different growth mechanisms

Optimisation of Cooking Time for Two Varieties of Foodstuffs using Single- and Double-Cavity Cooking Pots

The increase in the shortage of firewood due to deforestation, skyrocketing of electricity tariffs and fuel pump prices in recent times have propelled scientists to search for alternative measures of cooking that can reduce electric energy and fuel consumption. Double-cavity cooking pots have emerged in recent times to reduce the prolonged duration arising from the sequential cooking of different foodstuffs/ dishes using a single-cavity pot. However, experimental reports are rarely available to sensitise users about the advantages of using the double-cavity pot. The present work describes a simple and informative experimental report that compares the cooking time for two varieties of foodstuffs (rice and beans) using single- and double-cavity pots. It was found that the average time rate of cooking in the double-cavity pot was 1.33 ◦ C/min less than in the single-cavity pot. The total time taken to concurrently cook equal masses of rice and beans in separate cavities of the double-cavity pot was found to be 9.98 min less than that of the single-cavity pot. The double-cavity pot proved to be economically viable by reducing the cooking time, electric energy, and fuel consumption that arise from the successional cooking of a variety of foodstuffs using the single-cavity pot

Isolation of MECP2-null Rett Syndrome patient hiPS cells and isogenic controls through X-chromosome inactivation

Rett syndrome (RTT) is a neurodevelopmental autism spectrum disorder that affects girls due primarily to mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). The majority of RTT patients carry missense and nonsense mutations leading to a hypomorphic MECP2, while null mutations leading to the complete absence of a functional protein are rare. MECP2 is an X-linked gene subject to random X-chromosome inactivation resulting in mosaic expression of mutant MECP2. The lack of human brain tissue motivates the need for alternative human cellular models to study RTT. Here we report the characterization of a MECP2 mutation in a classic female RTT patient involving rearrangements that remove exons 3 and 4 creating a functionally null mutation. To generate human neuron models of RTT, we isolated human induced pluripotent stem (hiPS) cells from RTT patient fibroblasts. RTT-hiPS cells retained the MECP2 mutation, are pluripotent and fully reprogrammed, and retained an inactive X-chromosome in a nonrandom pattern. Taking advantage of the latter characteristic, we obtained a pair of isogenic wild-type and mutant MECP2 expressing RTT-hiPS cell lines that retained this MECP2 expression pattern upon differentiation into neurons. Phenotypic analysis of mutant RTT-hiPS cell-derived neurons demonstrated a reduction in soma size compared with the isogenic control RTT-hiPS cell-derived neurons from the same RTT patient. Analysis of isogenic control and mutant hiPS cell-derived neurons represents a promising source for understanding the pathogenesis of RTT and the role of MECP2 in human neurons

RAB1A Haploinsufficiency Phenocopies the 2p14-p15 Microdeletion and Is Associated With Impaired Neuronal Differentiation

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C\u3eT [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T\u3eC [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome