The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Gestión del conocimiento como apoyo para la mejora de procesos software en las micro, pequeñas y medianas empresas

Ante la significativa información generada durante la ejecución de los programas de mejora de procesos software (SPI), las organizaciones se han visto obligadas a cambiar su filosofía y plan de trabajo para mantener y convertir dicha información en conocimiento, de tal forma que permita adaptar e integrar cambios rápidamente y de esta forma mantenerse dentro del mercado competitivo. En este artículo se presentan algunos de los antecedentes más significativos en la definición e implementación de la gestión del conocimiento (KM) en programas SPI adaptados a las micro, pequeñas y medianas empresas desarrolladoras de software – MiPyMEs DS, ya que dicha gestión repre-senta una filosofía de verdadero capital organizativo para empresas que adelanten proyectos de mejoramiento de software. Se analiza la conveniencia de la implementación del KM en los programas o proyectos SPI partiendo de los objetivos principales de la gestión del conocimiento y su adaptación a dichos proyectos de acuerdo a las necesi-dades identificadas, especialmente en lo referente a la documentación y manipulación de los productos tangibles e intangibles generados en un SPI.Organisations have been forced to change their philosophy due to the vast amount of information made available when running software process improvement (SPI) programmes and working in a way leading to maintaining and converting this information into knowledge in order to adapt and integrate changes quickly and thereby ensuring re-maining in the competitive market. This article presents some of the most significant antecedents in defining and im-plementing knowledge management (KM) in SPI programmes which have been adapted for use in small software companies, as such management represents a philosophy of true organisational capital for companies involved in software improvement projects. The advisability of implementing KM in SPI programmes or projects arising from pri-mary knowledge management targets is analysed, as is its adaptation for such projects according to identified needs, especially related to documenting and manipulating tangible and intangible products produced in an SPI pro-gramme

Knowledge management as a support mechanism for improving software programmes in micro, small and medium-sized companies

Organisations have been forced to change their philosophy due to the vast amount of information made available when running software process improvement (SPI) programmes and working in a way leading to maintaining and converting this information into knowledge in order to adapt and integrate changes quickly and thereby ensuring re-maining in the competitive market. This article presents some of the most significant antecedents in defining and im-plementing knowledge management (KM) in SPI programmes which have been adapted for use in small software companies, as such management represents a philosophy of true organisational capital for companies involved in software improvement projects. The advisability of implementing KM in SPI programmes or projects arising from pri-mary knowledge management targets is analysed, as is its adaptation for such projects according to identified needs, especially related to documenting and manipulating tangible and intangible products produced in an SPI pro-gramme

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury

Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor β (TGFβ) pathway, osteopontin encoded by the SPP1 gene and latent TGFβ binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFβ and TGFβ-associated pathways. We identified that increased TGFβ resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFβ and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury.

Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor β (TGFβ) pathway, osteopontin encoded by the SPP1 gene and latent TGFβ binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFβ and TGFβ-associated pathways. We identified that increased TGFβ resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFβ and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury

<div><p>Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor β (TGFβ) pathway, osteopontin encoded by the <i>SPP1</i> gene and latent TGFβ binding protein 4 (<i>LTBP4</i>). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFβ and TGFβ-associated pathways. We identified that increased TGFβ resulted in reduced expression of <i>Anxa1</i> and <i>Anxa6</i>, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of <i>Ltbp4</i> in dystrophic muscle also directly modulated sarcolemmal resealing, and <i>Ltbp4</i> alleles acted in concert with <i>Anxa6</i>, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFβ and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy.</p></div

<i>Spp1</i> ablation in <i>mdx</i> muscle is associated with decreased TGFβ gene expression and signaling.

<p><b>A)</b> Heat-map of qPCR analysis of gene expression, normalized to control muscles, showed downregulation of genes associated with the TGFβ pathway and atrophic remodeling in <i>mdx</i>/<i>Spp1</i>^<i>-/-</i> dystrophic muscle (<i>tibialis anterior</i>). All genes shown in the heatmap were significantly different (*). <b>B)</b> Percentage of phosphorylated-Smad3-positive nuclei within myofibers (myonuclei; arrowheads) was significantly decreased in <i>quadriceps</i> (representative immunofluorescence panels) and <i>diaphragm</i> muscles of <i>mdx/Spp1</i>^<i>-/-</i> mice when compared to <i>mdx</i> mice. Box plots, Tukey distribution; heat-map, z-test average values of fold change to control (ctrl); n = 4 mice/group; *, P<0.05 vs <i>mdx</i> control, 1way ANOVA + Bonferroni.</p

Excess osteopontin exacerbates sarcolemmal injury and delays repair cap formation.

<p>The sarcolemmal wounding assay was performed on <i>flexor digitorus brevis</i> muscles from WT muscle in the presence or absence of recombinant osteopontin (rOPN; 10μl at 1μg/μl). <b>A)</b> The extent of sarcolemmal damage, monitored as FM4-64 area, was greater in rOPN-treated myofibers compared to vehicle-treated control, both over time and at end-point (arrows). <b>B)</b> Repair cap formation, monitored by GFP-tagged annexin A1 (GFP-ANXA1) was delayed in rOPN-treated myofibers (arrowheads). Repair cap diameter at end-point was smaller in treated compared to control myofibers (arrowheads). Over time image series represents stacked consecutive images of the injured site at 10° orientation to reveal the extent of dye accumulation or repair cap formation (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007070#pgen.1007070.s002" target="_blank">S1B Fig</a>). FM4-64 and ANXA1-GFP pictures were acquired simultaneously. Marked line plots, avg±sem; box plots, Tukey distribution; n = 50 myofibers (5 mice)/group; #, P<0.05 vs vehicle, 2way ANOVA + Bonferroni; *, P<0.05 vs vehicle, unpaired t-test with Welch’s correction.</p

Excess osteopontin and TGFβ activation inhibits <i>Anxa1</i> and <i>Anxa6</i> gene expression.

<p><b>A)</b> Model depicting the feed-forward loop in which osteopontin promotes TGFβ, which in turn promotes <i>Spp1</i>/osteopontin expression. <i>Slug/Snail</i> expression, downstream of TGFβ activation, results in <i>Anxa1/Anxa6</i> gene repression. <b>B)</b> Diagram of putative E-box elements upstream of transcriptional start site (TSS) of <i>Anxa1</i> and <i>Anxa6</i> genes in the murine genome. <b>C)</b> qPCR analysis of C2C12 cells after treatment with recombinant osteopontin (rOPN) or rOPN plus the TGFβ inhibitor SB431452. rOPN increased <i>Slug/Snail</i> expression, and this was reversed in the presence of SB431452. <b>D)</b> Correspondingly, ChIP-qPCR showed that the E-box occupancy of the <i>Anxa1</i> and <i>Anxa6</i> promoters by the SLUG/SNAIL protein complex was increased by rOPN, and this was reversed in the presence of SB431452. <b>E)</b> <i>Anxa1 and Anxa6</i> promoter occupancy by SLUG/SNAIL was decreased in the myofiber fraction of <i>mdx/Spp1</i>^<i>-/-</i> muscle compared to control <i>mdx</i> muscle (<i>gastrocnemius</i>). <b>F)</b> PF573228, a chemical inhibitor of OPN-driven signaling leading to <i>Mzf1-Tgfb1</i> axis activation, ablated rOPN-induced upregulation of <i>Slug</i>, <i>Snail</i>, <i>Mzf1</i>, and <i>Tgfb1</i>. <b>G)</b> Accordingly, PF573228 blunted rOPN-dependent increase in SLUG/SNAIL occupancy on <i>Anxa1/6</i> E-boxes in C2C12 myoblasts. <b>H)</b> <i>Mzf1</i>, transcriptional regulator linking the OPN and TGFβ signaling cascades, was downregulated in both hindlimb (<i>quadriceps</i>) and respiratory (<i>diaphragm</i>) muscles of <i>mdx/Spp1</i>^<i>-/-</i> compared to <i>mdx</i>. Histograms, single values & avg±sem; n = 8 independent replicates/group for C2C12 myoblast analyses, n = 4 mice/group for <i>mdx</i>/<i>Spp1</i>^<i>-/-</i> mice analyses; (C-D; E-G) *, P<0.05 vs vehicle, 1way ANOVA + Bonferroni; (D) *, P<0.05 vs <i>mdx</i> control, unpaired t-test with Welch’s correction.</p

Relative contribution of <i>Anxa6</i> and <i>Ltbp4</i> alleles on muscle injury in vivo.

<p><b>A)</b> Three days post-injury, the number of dye⁺ myofibers (red) in injured <i>tibialis anterior</i> muscles was increased in single homozygous mice, either A6^severe or L4^severe, compared to double homozygous A6^mild/L4^mild muscle, which displayed the fewest dye+ fibers. Doubly homozygous animals A6^severe/L4^severe had the greatest number of dye⁺ fibers. <b>B)</b> The same pattern was seen when measuring injury area from cardiotoxin injected gastrocnemius muscles measured 7 days post-injury. <b>C)</b> Scarring monitored by Masson’s trichrome staining (left panels; arrows) and hydroxyproline content (right chart) was also greatest in doubly mutant (A6^severe/L4^severe<i>) gastrocnemius</i> muscles 7 days post-injury. <b>D)</b> 24 hours after cardiotoxin-injury of hindlimb muscles, serum CK levels were increased in single homozygous mice A6^severe or L4^severe, and further increased in double homozygous A6^severe/L4^{sever<i>e</i>} animals. <b>E)</b> Seven days after cardiotoxin injury, <i>Slug</i>, <i>Snail</i> were upregulated while <i>Anxa1</i>, and <i>Anxa6</i> expression levels were significantly downregulated in muscle in the presence of homozygous L4^severe allele (<i>tibialis anterior</i>) indicating that the L4^severe allele impacts <i>Anxa1/Anxa6</i> expression likely via <i>Slug/Snail</i> regulation. *, P<0.05 vs A6^mild/L4^mild, +, P<0.05 vs A6^severe/L4^mild and A6^mild/L4^severe groups, 1way ANOVA + Bonferroni.</p