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Scalable architecture in mammalian brains.

Comparison of mammalian brain parts has often focused on differences in absolute size, revealing only a general tendency for all parts to grow together. Attempts to find size-independent effects using body weight as a reference variable obscure size relationships owing to independent variation of body size and give phylogenies of questionable significance. Here we use the brain itself as a size reference to define the cerebrotype, a species-by-species measure of brain composition. With this measure, across many mammalian taxa the cerebellum occupies a constant fraction of the total brain volume (0.13 +/- 0.02), arguing against the hypothesis that the cerebellum acts as a computational engine principally serving the neocortex. Mammalian taxa can be well separated by cerebrotype, thus allowing the use of quantitative neuroanatomical data to test evolutionary relationships. Primate cerebrotypes have progressively shifted and neocortical volume fractions have become successively larger in lemurs and lorises, New World monkeys, Old World monkeys, and hominoids, lending support to the idea that primate brain architecture has been driven by directed selection pressure. At the same time, absolute brain size can vary over 100-fold within a taxon, while maintaining a relatively uniform cerebrotype. Brains therefore constitute a scalable architecture.

Algorithms↗

Dissecting the architecture of a quantitative trait locus in yeast.

Most phenotypic diversity in natural populations is characterized by differences in degree rather than in kind. Identification of the actual genes underlying these quantitative traits has proved difficult. As a result, little is known about their genetic architecture. The failures are thought to be due to the different contributions of many underlying genes to the phenotype and the ability of different combinations of genes and environmental factors to produce similar phenotypes. This study combined genome-wide mapping and a new genetic technique named reciprocal-hemizygosity analysis to achieve the complete dissection of a quantitative trait locus (QTL) in Saccharomyces cerevisiae. A QTL architecture was uncovered that was more complex than expected. Functional linkages both in cis and in trans were found between three tightly linked quantitative trait genes that are neither necessary nor sufficient in isolation. This arrangement of alleles explains heterosis (hybrid vigour), the increased fitness of the heterozygote compared with homozygotes. It also demonstrates a deficiency in current approaches to QTL dissection with implications extending to traits in other organisms, including human genetic diseases.

Alleles↗

In vivo (31)P magnetic resonance spectroscopy and morphometric analysis of the perfused vascular architecture of human glioma xenografts in nude mice.

The relationship between the bioenergetic status of human glioma xenografts in nude mice and morphometric parameters of the perfused vascular architecture was studied using (31)P magnetic resonance spectroscopy (MRS), fluorescence microscopy and two-dimensional digital image analysis. Two tumour lines with a different vascular architecture were used for this study. Intervascular distances and non-perfused area fractions varied greatly between tumours of the same line and tumours of different lines. The inorganic phosphate-nucleoside triphosphate (P(i)/NTP) ratio increased rapidly as mean intervascular distances increased from 100 microm to 300 microm. Two morphometric parameters - the percentage of intervascular distances larger than 200 microm (ivd200) and the non-perfused area fraction at a distance larger than 100 microm from a nearest perfused vessel (area100), - were deduced from these experiments and related to the P(i)/NTP ratio of the whole tumour. It is assumed that an aerobic to anaerobic transition influences the bioenergetic status, i.e. the P(i)/NTP ratio increased linearly with the percentage of ivd200 and the area100.

Animals↗

The genetic architecture of behavioural responses to novelty in mice.

The genetic architectures of 12 behavioural variables measured in adult male mice placed in a novel environment were analysed in a replicated 4 X 4 diallel cross. The results were combined with those obtained in a classical cross involving two of the four strains. Based on the hypothesis of an evolutionary history of stabilising selection for mouse exploratory behaviour, we expected additive genetic effects and ambidirectional dominance. Such genetic architectures were actually found for those exploratory behaviours where epistatic effects were of minor importance. Similar findings emerged for some non-exploratory phenotypes. All behaviours analysed appeared to be polygenically controlled.

Animals↗

Prognostic value of graph theory-based tissue architecture analysis in carcinomas of the tongue.

Several studies on oral squamous cell carcinomas (OSCC) suggest that the clinical value of traditional histologic grading is limited both by poor reproducibility and by low prognostic impact. However, the prognostic potential of a strictly quantitative and highly reproducible assessment of the tissue architecture in OSCC has not been evaluated. Using image analysis, in 193 cases of T1-2 (Stage I-II) OSCC we retrospectively investigated the prognostic impact of two graph theory-derived structural features: the average Delaunay Edge Length (DEL_av) and the average homogeneity of the Ulam Tree (ELH_av). Both structural features were derived from subgraphs of the Voronoi Diagram. The geometric centers of the cell nuclei were computed, generating a two-dimensional swarm of point-like seeds from which graphs could be constructed. The impact on survival of the computed values of ELH_av and DEL_av was estimated by the method of Kaplan and Meier, with relapse-free survival and overall survival as end-points. The prognostic values of DEL_av and ELH_av as computed for the invasive front, the superficial part of the carcinoma, the total carcinoma, and the normal-appearing oral mucosa were compared. For DEL_av, significant prognostic information was found in the invasive front (p < 0.001). No significant prognostic information was found in superficial part of the carcinoma (p = 0.34), in the carcinoma as a whole (p = 0.35), or in the normal-appearing mucosa (p = 0.27). For ELH_av, significant prognostic information was found in the invasive front (p = 0.01) and, surprisingly, in putatively normal mucosa (p = 0.03). No significant prognostic information was found in superficial parts of the carcinoma (p = 0.34) or in the total carcinoma (p = 0.11). In conclusion, strictly quantitative assessment of tissue architecture in the invasive front of OSCC yields highly prognostic information.

Aged↗

Architecture and material properties of diatom shells provide effective mechanical protection.

Diatoms are the major contributors to phytoplankton blooms in lakes and in the sea and hence are central in aquatic ecosystems and the global carbon cycle. All free-living diatoms differ from other phytoplankton groups in having silicified cell walls in the form of two 'shells' (the frustule) of manifold shape and intricate architecture whose function and role, if any, in contributing to the evolutionary success of diatoms is under debate. We explored the defence potential of the frustules as armour against predators by measuring their strength. Real and virtual loading tests (using calibrated glass microneedles and finite element analysis) were performed on centric and pennate diatom cells. Here we show that the frustules are remarkably strong by virtue of their architecture and the material properties of the diatom silica. We conclude that diatom frustules have evolved as mechanical protection for the cells because exceptional force is required to break them. The evolutionary arms race between diatoms and their specialized predators will have had considerable influence in structuring pelagic food webs and biogeochemical cycles.

Animals↗

Architecture of floral branch systems in maize and related grasses.

The external appearance of flowering plants is determined to a large extent by the forms of flower-bearing branch systems, known as inflorescences, and their position in the overall structure of the plant. Branches and branching patterns are produced by tissues called shoot apical meristems. Thus, inflorescence architecture reflects meristem number, arrangement and activity, and the duration of meristem activity correlates with branch length. The inflorescences of maize, unlike those of related grasses such as rice and sorghum, predominantly lack long branches, giving rise to the tassel and familiar corncob. Here we report the isolation of the maize ramosa1 gene and show that it controls inflorescence architecture. Through its expression in a boundary domain near the nascent meristem base, ramosa1 imposes short branch identity as branch meristems are initiated. A second gene, ramosa2, acts through ramosa1 by regulating ramosa1 gene expression levels. ramosa1 encodes a transcription factor that appears to be absent in rice, is heterochronically expressed in sorghum, and may have played an important role in maize domestication and grass evolution.

Alleles↗

Tetrapod-like middle ear architecture in a Devonian fish.

Few fossils show the incipient stages of complex morphological transformations. For example, the earliest stages in the remodelling of the spiracular tract and suspensorium (jaw suspension) of osteolepiform fishes into the middle ear of tetrapods have remained elusive. The most primitive known tetrapods show a middle ear architecture that is very different from osteolepiforms such as Eusthenopteron, with little indication of how this transformation took place. Here we present an analysis of tetrapod middle ear origins that is based on a detailed study of Panderichthys, the immediate sister taxon of tetrapods. We show that the spiracular region is radically transformed from osteolepiforms and represents the earliest stages in the origin of the tetrapod middle ear architecture. The posterior palatoquadrate of Panderichthys is completely tetrapod-like and defines a similarly tetrapod-like spiracular tract. The hyomandibula has lost its distal portion, representing a previously unrecognized advance towards a stapes-like morphology. This spiracular specialization suggests that the middle ear of early tetrapods evolved initially as part of a spiracular breathing apparatus.

Animals↗

A trehalose metabolic enzyme controls inflorescence architecture in maize.

Inflorescence branching is a major yield trait in crop plants controlled by the developmental fate of axillary shoot meristems. Variations in branching patterns lead to diversity in flower-bearing architectures (inflorescences) and affect crop yield by influencing seed number or harvesting ability. Several growth regulators such as auxins, cytokinins and carotenoid derivatives regulate branching architectures. Inflorescence branching in maize is regulated by three RAMOSA genes. Here we show that one of these genes, RAMOSA3 (RA3), encodes a trehalose-6-phosphate phosphatase expressed in discrete domains subtending axillary inflorescence meristems. Genetic and molecular data indicate that RA3 functions through the predicted transcriptional regulator RAMOSA1 (RA1). We propose that RA3 regulates inflorescence branching by modification of a sugar signal that moves into axillary meristems. Alternatively, the fact that RA3 acts upstream of RA1 supports a hypothesis that RA3 itself may have a transcriptional regulatory function.

Gene Expression Regulation, Enzymologic↗

Transforming the architecture of compound eyes.

Eyes differ markedly in the animal kingdom, and are an extreme example of the evolution of multiple anatomical solutions to light detection and image formation. A salient feature of all photoreceptor cells is the presence of a specialized compartment (disc outer segments in vertebrates, and microvillar rhabdomeres in insects), whose primary role is to accommodate the millions of light receptor molecules required for efficient photon collection. In insects, compound eyes can have very different inner architectures. Fruitflies and houseflies have an open rhabdom system, in which the seven rhabdomeres of each ommatidium are separated from each other and function as independent light guides. In contrast, bees and various mosquitoes and beetle species have a closed system, in which rhabdomeres within each ommatidium are fused to each other, thus sharing the same visual axis. To understand the transition between open and closed rhabdom systems, we isolated and characterized the role of Drosophila genes involved in rhabdomere assembly. Here we show that Spacemaker, a secreted protein expressed only in the eyes of insects with open rhabdom systems, acts together with Prominin and the cell adhesion molecule Chaoptin to choreograph the partitioning of rhabdomeres into an open system. Furthermore, the complete loss of spacemaker (spam) converts an open rhabdom system to a closed one, whereas its targeted expression to photoreceptors of a closed system markedly reorganizes the architecture of the compound eyes to resemble an open system. Our results provide a molecular atlas for the construction of microvillar assemblies and illustrate the critical effect of differences in a single structural protein in morphogenesis.

Adhesiveness↗

Functional interaction between PML and SATB1 regulates chromatin-loop architecture and transcription of the MHC class I locus.

The function of the subnuclear structure the promyelocytic leukaemia (PML) body is unclear largely because of the functional heterogeneity of its constituents. Here, we provide the evidence for a direct link between PML, higher-order chromatin organization and gene regulation. We show that PML physically and functionally interacts with the matrix attachment region (MAR)-binding protein, special AT-rich sequence binding protein 1 (SATB1) to organize the major histocompatibility complex (MHC) class I locus into distinct higher-order chromatin-loop structures. Interferon gamma (IFNgamma) treatment and silencing of either SATB1 or PML dynamically alter chromatin architecture, thus affecting the expression profile of a subset of MHC class I genes. Our studies identify PML and SATB1 as a regulatory complex that governs transcription by orchestrating dynamic chromatin-loop architecture.

Cell Line↗

Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders.

Problematic alcohol use (PAU) and anxiety disorders (ANX) frequently co-occur, implying shared genetic and neurobiological foundations. However, the directionality of potential causal relationships and the specific mechanisms underlying the overlap remain unclear. Thus, we investigated the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. We analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. We used MiXeR to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. We used FUMA to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types, and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets was also evaluated. Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg&#x2009;=&#x2009;0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX. These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively. Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus. We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.

Journal Article↗

OCT2 pre-positioning facilitates cell fate transition and chromatin architecture changes in humoral immunity.

During the germinal center (GC) reaction, B cells undergo profound transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Mapping chromatin accessibility during the humoral immune response, we show that OCT2 was the dominant transcription factor linked to differential accessibility of GC regulatory elements. Silent chromatin regions destined to become GC-specific super-enhancers (SEs) contained pre-positioned OCT2-binding sites in naive B cells (NBs). These preloaded SE 'seeds' featured spatial clustering of regulatory elements enriched in OCT2 DNA-binding motifs that became heavily loaded with OCT2 and its GC-specific coactivator OCAB in GC B cells (GCBs). SEs with high abundance of pre-positioned OCT2 binding preferentially formed long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions were dependent on recruitment of OCAB. Pre-positioning key regulators at SEs may represent a broadly used strategy for facilitating rapid cell fate transitions.

Animals↗

Crystal engineering of a versatile building block toward the design of novel inorganic-organic coordination architectures.

Six novel inorganic-organic coordination supramolecular networks based on a versatile linking unit 4-pyridylthioacetate (pyta) and inorganic Co(II), Cu(II), Ag(I), Zn(II), Mn(II) and Pb(II) salts have been prepared in water medium and structurally characterized by single-crystal X-ray diffraction analysis. Reaction of CoCl(2).6H(2)O with Hpyta afforded a neutral mononuclear complex [Co(pyta)(2)(H(2)O)(4)](1), which exhibits a two-dimensional (2-D) layered architecture through intermolecular O-HO interactions. Reaction of CuCl(2.2H(2)O with Hpyta yielded a neutral one-dimensional (1-D) coordination polymer [[Cu(pyta)(2)(H(2)O].0.5H(2)O](n)(2) consisting of rectangle molecular square units, which show a three-dimensional (3-D) supramolecular network through S...S and O-H...O weak interactions. However, when AgNO(3), Zn(OAc)(2).2H(2)O or MnCl(2).4H(2)O salts were used in the above self-assembled processes, the neutral 2-D coordination polymers [Ag(pyta)](n)(3), [[Zn(pyta)(2)].4H(2)O](n)(4) or [[Mn(pyta)(2)(H(2)O)]](n)(5) with different topologies were obtained, respectively. While substituting the transition metal ions used in 1-5 with Pb(OAc)(2).3H(2)O, a one-dimensional coordination polymer [Pb(pyta)(2)](n)(6), which shows a novel 2-fold interpenetrating 2-D supramolecular architecture through weak SS interactions, was isolated. It is interesting to note that the building block pyta anion exhibits different configurations and coordination modes in the solid structures of complexes 1-6. These results indicate that the versatile nature of this flexible ligand, together with the coordination preferences of the metal centers, play a critical role in construction of these novel coordination polymers or supramolecules. The spectral and thermal properties of these new materials have also been investigated.

Journal Article↗

The effect of molecular architecture on the grain growth kinetics of AnBn star block copolymers.

To investigate the effect of molecular architecture on the grain growth kinetics of star block copolymers, a series of AnBn miktoarm star block copolymers with different numbers of arms (n = 1, 2, 4 and 16) was studied. Across this entire series of materials, all the A arms are polystyrene (PS) blocks from the same anionically synthesized batch, and thus all the A arms are identical. Likewise, all the B arms are polyisoprene (PI) blocks from the same anionically synthesized batch, and thus all the B arms are identical. All the stars employed in this study are therefore composed of the same A and B arms liked together in symmetric numbers. The coarsening kinetics of grain growth was monitored in real space by transmission electron microscopy (TEM), followed by subsequent micrograph image analysis. It was found that the molecular architecture influenced the grain growth kinetics of these AnBn star copolymers dramatically. The grain coarsening kinetics was found to follow a scaling law as V approximately t(beta), where V is the characteristic grain volume and t is time. The exponent, beta, was found to be about 0.2 for the diblock copolymer (n = 1) and 0.4 for all three of the star block copolymers (n = 2, 4 and 16) in the series. It is postulated that the difference in grain growth rate between the diblock and the various stars is due to a reduction in molecular entanglements resulting from chain stretching near the junction points in the stars.

Journal Article↗

Novel dithioether-silver(I) coordination architectures: structural diversities by varying the spacers and terminal groups of ligands.

An investigation into the dependence of the framework formation of coordination architectures on ligand spacers and terminal groups was reported based on the self-assembly of AgClO4 and eight structurally related flexible dithioether ligands, RS(CH2)nSR (Lan, R = ethyl group; Lbn, R = benzyl group, n= 1-4). Eight novel metal-organic architectures, [Ag(La1)3/2ClO4]n (1a), [Ag2(La2)2(ClO4)2]2 (2a), [AgLa3ClO4]n (3a), {[Ag(La4)2]ClO4}n (4a), [AgLb1ClO4]2 (1b), [Ag(Lb2)2]ClO4 (2b), {[Ag(Lb3)3/2(ClO4)1/2](ClO4)1/2}n (3b) and [Ag(Lb4)3/2ClO4]n(4b), were synthesized and structurally characterized by X-ray crystallography. Structure diversities were observed for these complexes: 1a forms a 2-D (6,3) net, while 2a is a discrete tetranuclear complex, in which the AgI ion adopts linear and tetrahedral coordination modes, and the S donors in each ligand show monodentate terminal and mu2-S bridging coordination fashions; 3a has a chiral helical chain structure in which two homo-chiral right-handed single helical chains (Ag-La3-)n are bound together through mu2-S donors, and simultaneously gives rise to left-handed helical entity (Ag-S-)n. In 4a, left- and right-handed helical chains formed by the ligands bridging AgI centers are further linked alternately by single-bridging ligands to form a non-chiral 2-D framework. 1b has a dinuclear structure showing obvious ligand-sustained Ag-Ag interaction, while 2b is a mononuclear complex; 3b is a 3-D framework formed by ClO4- linking the 2-D (6,3) framework, which is similar to that of 1a, and 4b has a single, double-bridging chain structure in which 14-membered dinuclear ring units formed through two ligands bridging two AgI ions are further linked by single-bridging ligands. In addition, a systematic structural comparison of these complexes and other reported AgClO4 complexes of analogous dithioether ligands indicates that the ligand spacers and terminal groups take essential roles on the framework formation of the AgI complexes, and this present feasible ways for adjusting the structures of such complexes by modifying the ligand spacers and terminal groups.

Journal Article↗

Metallasupramolecular architectures, an overview of functional properties and applications.

The synthesis of metallasupramolecular architectures, such as two-dimensional squares, triangles and polygons, and three-dimensional cages and polyhedra, has attracted much interest in the past decade. These structures are designed to have novel specific shapes and dimensions with interesting functional properties. In this overview the functional properties of metallasupramolecular architectures are highlighted with emphasis on potential applications such as catalysis, cavity-directed synthesis and sensing, that can be performed with these materials.

Journal Article↗

Calix[4]phyrin based redox architectures: towards new molecular tools for electrochemical sensing.

New redox active molecular macrocyclic architectures characterized by a direct connection between dipyrrin, tripyrrin and ferrocenyl fragments have been synthesized and characterized. Contrarily to fully conjugated porphyrins, in which four pyrrole moieties contribute to the overall aromatic pi-electronic system and behave as a unique electroactive species, calixphyrins can be regarded as an assembly of independent redox active pyrrole and conjugated oligopyrrole fragments linked through sp(3) hybridized meso carbon atoms. The disruption of the conjugation pathway not only multiplies the number of redox centres throughout the molecule but also leads to a large variety of molecular architectures with specific physico-chemical properties. These novel ferrocene containing hybrid macrocycles exhibit especially attractive electronic and structural features suited for use as molecular sensing tools. An efficient voltammetric sensing of exogenic electron rich anionic species could especially be performed using a metallo-calix[4]phyrin-(1.1.1.1) through the displacement of the labile axial binding site, the perturbation of the Fc(0/+) redox couple being directly related to complexed species features.

Journal Article↗