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Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.

Using exact computer arithmetic, it is possible to determine the (exact) solution of a numerical model without any rounding error. For such purposes, a corresponding system of equations should be exactly defined, either directly or by rationalising the numerically given input data. In the latter case, there is an initial round-off error, but this does not propagate during the solution process. If this system is exactly solved first and then using floating-point arithmetic, the convergence of the numerical method easily follows. As an example, the IRM-CG, which is an alternative to the Conjugate Gradient (CG) method and a special case of the more general Iterated Ritz Method (IRM), is verified. The method is not based on conjugacy; therefore, restarting strategies are not required, while an overrelaxation factor and preconditioning like techniques could be easily adopted. The exact arithmetic approach is introduced by means of a simple example and is then applied to small structural engineering problems. The perturbation of the displacement increment and the different condition numbers of the system matrix are used to check the stability of the algorithm. Interestingly, a large difference in the number of steps between the exact and numerical approaches is detected, even for well-conditioned systems. According to the tests, the IRM-CG may be considered to be stable and useful for not well-posed or well-posed but ill-conditioned models. Because the computer demands and execution time grow enormously with the number of unknowns using this strategy, three possibilities for larger systems are also provided., (© 2020 The Author(s).)

Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity., (Copyright © 2015, American Association for the Advancement of Science.)

A new functional gene database, FOAM (Functional Ontology Assignments for Metagenomes), was developed to screen environmental metagenomic sequence datasets. FOAM provides a new functional ontology dedicated to classify gene functions relevant to environmental microorganisms based on Hidden Markov Models (HMMs). Sets of aligned protein sequences (i.e. 'profiles') were tailored to a large group of target KEGG Orthologs (KOs) from which HMMs were trained. The alignments were checked and curated to make them specific to the targeted KO. Within this process, sequence profiles were enriched with the most abundant sequences available to maximize the yield of accurate classifier models. An associated functional ontology was built to describe the functional groups and hierarchy. FOAM allows the user to select the target search space before HMM-based comparison steps and to easily organize the results into different functional categories and subcategories. FOAM is publicly available at http://portal.nersc.gov/project/m1317/FOAM/., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Porous hybrid organo-silica monoliths have been prepared inside pretreated 100 μm id UV transparent fused-silica capillaries using simultaneous sol-gel transition and polymerization of 3-(methacryloyloxy)propyl trimethoxysilane in the presence of toluene as a porogen. The sol-gel reaction was catalyzed by hydrochloric acid while various photoinitiators including azobisisobutyronitrile, 2,2-dimethoxy-2-phenylacetophenone, and Irgacure 819 were used for the photopolymerization carried out under irradiation with UV light at a wavelength of 254 or 365 nm. The chromatographic performance of photopolymerized monolithic columns in RP liquid chromatographic mode was assessed with respect to the following metrics: column efficiency, methylene and steric selectivity, effect of silanol groups, van Deemter plot, permeability, and pore size distribution. Columns with an efficiency of up to 77 000 plates/m for benzene has been achieved at a flow velocity of 0.47 mm/s. The performance of photopolymerized hybrid monolithic column was compared to the performance of columns prepared via thermally initiated polymerization., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)