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Int J Biol Sci 2006; 2(2):38-47. doi:10.7150/ijbs.2.38
Retinoic acid signaling and the evolution of chordates
Ferdinand Marlétaz1, Linda Z. Holland2, Vincent Laudet1, Michael Schubert1
1. Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR5161/INRA 1237/ENS Lyon, IFR128 BioSciences/Lyon-Gerland, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France
2. Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA 92093-0202, USA
Marlétaz F, Holland LZ, Laudet V, Schubert M. Retinoic acid signaling and the evolution of chordates. Int J Biol Sci 2006; 2(2):38-47. doi:10.7150/ijbs.2.38. Available from http://www.ijbs.com/v02p0038.htm
In chordates, which comprise urochordates, cephalochordates and vertebrates, the vitamin A-derived morphogen retinoic acid (RA) has a pivotal role during development. Altering levels of endogenous RA signaling during early embryology leads to severe malformations, mainly due to incorrect positional codes specifying the embryonic anteroposterior body axis. In this review, we present our current understanding of the RA signaling pathway and its roles during chordate development. In particular, we focus on the conserved roles of RA and its downstream mediators, the Hox genes, in conveying positional patterning information to different embryonic tissues, such as the endoderm and the central nervous system. We find that some of the control mechanisms governing RA-mediated patterning are well conserved between vertebrates and invertebrate chordates, such as the cephalochordate amphioxus. In contrast, outside the chordates, evidence for roles of RA signaling is scarce and the evolutionary origin of the RA pathway itself thus remains elusive. In sum, to fully understand the evolutionary history of the RA pathway, future research should focus on identification and study of components of the RA signaling cascade in non-chordate deuterostomes (such as hemichordates and echinoderms) and other invertebrates, such as insects, mollusks and cnidarians.
Keywords: amphioxus, anteroposterior patterning, Branchiostoma, deuterostomes, Hox, invertebrate-to-vertebrate transition, phylogeny
Among bilaterian animals, the deuterostomes include the hemichordates, the echinoderms and the chordates. The chordates can further be subdivided into urochordates (=tunicates), cephalochordates and vertebrates (Fig. 1A). Since human beings have often wondered about their own origins, it is not surprising that there have been many studies aimed at understanding the evolutionary history of chordates (i.e. the origin of chordates and the diversification of vertebrates). The main characters that evolved at the base of the chordates are a notochord and a dorsal hollow nerve cord [1], while definite neural crest cells and placodes arose at the base of the vertebrates [2]. However, the evolutionary origins of these structures have been controversial, mainly because of difficulties in determining homologies between chordate-specific characters and structures in non-chordate deuterostomes (i.e. in hemichordates and echinoderms) as well as between the vertebrate-specific characters and structures in invertebrate chordates.
The development of many chordate- and vertebrate-specific characters is controlled, directly or indirectly, by retinoic acid (RA), a vitamin A-derived morphogen. In chordate embryos, too much or too little RA during early embryogenesis causes malformations, which are mainly due to a mispatterning of the embryo along the anteroposterior body axis. RA signaling is mediated by RA binding to retinoic acid receptors (RARs), which form heterodimers with retinoid X receptors (RXRs) [3]. During chordate development, important functions of RA signaling are mediated by Hox genes, at least some of which are direct targets of RA [4-6]. In many animals, including most deuterostomes, Hox genes mediate anteroposterior positional patterning of the embryo [7, 8]. Moreover, in vertebrates, Hox genes have been suggested to play important roles in the patterning of all embryonic tissue layers [7, 9].
Ever since it became clear that the genetic mechanisms controlling key features of embryonic development are highly conserved between organisms as diverse as fruit flies and mice, comparisons of the developmental mechanisms in different organisms have been used to address questions about animal evolution, particularly about the invertebrate-to-vertebrate transition in chordates [10]. Using this so-called "evo-devo" approach, this review discusses the developmental roles of RA signaling among chordates in regard to chordate origins and vertebrate evolution. The focus is on the roles of RA- and Hox-dependent patterning during development and their conservation during chordate evolution. We show that some of the control mechanisms governing RA-mediated patterning are quite conserved among vertebrates and between vertebrates and invertebrate chordates, such as the cephalochordate amphioxus. In contrast, evidence for roles of RA signaling outside the chordates and the evolutionary origin of RA signaling itself still remain elusive.
Deuterostome phylogeny and components of the RA signaling pathway in deuterostomes. A) Deuterostome phylogeny. Echinoderms and hemichordates together establish the sister group of chordates. The urochordates (=tunicates) include ascidians and appendicularians. Urochordates and cephalochordates are invertebrate chordates. The vertebrates include agnathan groups (hagfish and lampreys) as well as the gnathostome chondrichthyans (cartilaginous fish), actinopterygians (ray-finned fish) and sarcopterygians (lobe-finned fish and tetrapods). Within chordates, the phylogenetic relationships between cephalochordates and urochordates and between hagfish and lampreys are still disputed and their respective positions within the tree are thus shown as polytomies. Two important events during deuterostome evolution are the origin of chordates and the origin of vertebrates. The two rounds of extensive gene duplications early during vertebrate diversification are highlighted with green boxes labeled 'R'. B) Components of the RA pathway in deuterostomes. Deuterostome groups, for which a whole genome sequencing (WGS) project has already been finished are indicated with a turquoise "+", those, for which a WGS project is underway, are marked with a turquoise "(+)". If known, the exact number of RAR, Raldh and Cyp26 genes in the genome of a specific deuterostome group is indicated, the certain presence of a gene is marked with "+" and the lack of data is highlighted by "?".
2. The retinoic acid signaling pathway
Retinoic acid (RA) is a natural morphogen synthesized from vitamin A (retinol), and it has been known for over fifty years that either too much or too little RA during early development is teratogenic mainly due to anteroposterior patterning defects [3]. In general, excess RA posteriorizes, while RA deficiency anteriorizes chordate embryos [3, 11-14]. Endogenous RA is synthesized in two steps: the first is the reversible oxidation of retinol to retinal performed by alcohol dehydrogenases (ADHs or RDHs/SDRs) and the second is the oxidation of retinal to retinoic acid, which is carried out by retinaldehyde dehydrogenases (RALDHs). Conversely, endogenous RA is degraded by CYP26 enzymes. RA signaling levels are also regulated by binding of retinol to cellular retinol binding proteins (CRBPs) and of RA to retinoic acid binding proteins (CRABPs) (Fig. 2A) [13, 15]. The roles of these proteins in regulating RA signaling in vertebrates have been elucidated with gene knock-outs. For example, individual knock-outs of three of the four Raldh genes (i.e. the knock-outs of Raldh1, 2 and 3) have been described in the mouse, but only that of Raldh2 exhibits clear developmental defects. In these mice, the anteroposterior axis is shortened and the embryos, which die before birth, have defects in the heart, limbs and head, which are reminiscent of vitamin A deprivation phenotypes [16]. In the RA degradation pathway, knock-out of Cyp26a1, one of the three mouse Cyp26 genes, is also lethal before birth and affects anteroposterior patterning as well as hindbrain and tail development [17, 18]. This Cyp26a1 phenotype is comparable to the teratogenic effects of excess RA, suggesting that Cyp26 genes in general may help restrict the distribution of endogenous RA to RA target tissues. Moreover, analysis of Cyp26a1 and Raldh2 double knock-out mice has shown that RA and not one of its metabolic derivatives is the major (if not the only) active retinoid during development [19].
Synthesis, degradation and mode of action of retinoic acid (RA). A) The metabolic pathway for synthesis and degradation of endogenous RA is shown. RA is synthesized by oxidation of retinal by retinaldehyde dehydrogenases (RALDHs). In a reversible reaction, retinal is synthesized from retinol (vitamin A) by either aldehyde dehydrogenases (ADHs) or short-chain dehydrogenase/reductases (RDHs/SDRs). Cellular retinol binding proteins (CRBPs) can bind retinol, whereas cellular retinoic acid binding proteins (CRABPs) can bind RA. Finally, endogenous RA is degraded by CYP26 enzymes. B) The RAR/RXR heterodimer mediates the effects of RA. In the absence of ligand (RA), the RAR/RXR heterodimer is bound to DNA and co-repressors. This complex induces transcriptional repression through histone deacetylation. Binding of the ligand (RA) induces conformational changes and the binding of co-activators leading to histone acetylation and activation of transcription.
RA signaling is mediated by RA binding to retinoic acid receptors (RARs), which form heterodimers with retinoid X receptors (RXRs). This complex in turn binds to retinoic acid response elements (RAREs) in the regulatory regions of target genes [13, 15]. Only a few direct targets of RA signaling have been described. These include the RARs themselves, Hox genes, some other transcription factors, such as HNF-3α and Cdx1, plus genes involved in retinoic acid metabolism (e.g. CRABP1 and 2) [5]. In the mouse, there are 3 RARs and 3 RXRs (α, β and γ). Although knock-out of any one of these has only minor, tissue-specific effects on morphogenesis due most likely to functional redundancy among them, compound mutants with two or three of the genes inactivated are much more severely affected with defects in anteroposterior patterning of pharyngeal endoderm, hindbrain and neural crest cells [3].
In general, RAR and RXR proteins share a common organization of functional domains: an amino terminal A/B region containing a transcriptional activation domain (AF-1), a centrally located C region corresponding to the DNA binding domain (DBD) plus a weak dimerization domain and the E region, which includes the ligand binding domain (LBD), a strong dimerization interface and a surface allowing binding of transcriptional co-regulators [3, 20, 21]. In the absence of ligand, the RAR/RXR heterodimer is constitutively bound to DNA on RAREs and associated with co-repressor complexes that induce transcriptional silencing by deacetylating histones associated with the target sequences thus increasing chromatin condensation (Fig. 2B). These co-repressors include the related proteins SMRT and NcoR [20-22]. Binding of RA to the RAR ligand binding pocket induces a conformational change of the LBD that creates a surface allowing the association of co-activators and the release of co-repressors. The co-activators (e.g. TIF2 and SRC-1 of the p160 co-activator family) subsequently mediate histone acetylation resulting in decondensation of the chromatin and activation of target gene expression (Fig. 2B) [20-22].
Among the known targets of the RAR/RXR heterodimer are the Hox genes [5]. Hox genes encode transcription factors that contain a highly conserved DNA binding domain of 60 amino acids, the homeodomain [7, 8]. Hox genes are usually linked in a cluster and their order on the chromosome correlates with both their temporal and spatial expression during embryogenesis [7-9, 23]. This so-called collinear expression is crucial for conveying anteroposterior positional patterning information to the embryo during development and is conserved in many animals, including most deuterostomes [7-9, 23]. However, when genomic Hox clustering has been lost, as for example in tunicates, temporal collinearity is lacking and spatial collinearity is only approximate [24, 25]. In vertebrates, Hox genes are direct targets of RA signaling [5] and RA signaling is involved in regulation of collinear Hox expression along the anteroposterior body axis of the developing embryo. For example, in mice, the deletion of a single RARE from the Hoxa1 cis-regulatory region disrupts the establishment of the anterior boundary of Hoxa1 as well as the normal expression pattern of Hoxa2 in the hindbrain [26]. Moreover, the Hox cluster also contains several other RAREs, which are largely conserved among vertebrates and at least to some extent between vertebrates and the cephalochordate amphioxus [4, 6]. For example, both the amphioxus and vertebrate Hox1 genes have a conserved RARE in their cis-regulatory region [4]. In addition, although clustering of Hox genes has been lost in tunicates, ascidian Hox1 expression is strongly upregulated after RA treatment [27] suggesting that, as in amphioxus and vertebrates, Hox genes in tunicates might also be direct targets of RA signaling.
3. Retinoic acid signaling in invertebrate deuterostomes
Early during vertebrate diversification, the total number of genes has been markedly increased by two rounds of whole genome duplications [28]. Thus, while vertebrates have 3 or more RARs, there are single RARs in invertebrate chordates, such as amphioxus and tunicates [14, 29]. A comprehensive search of the sea urchin genome sequence (www.ncbi.nlm.nih.gov/genome/guide/sea_urchin) also reveals the presence of a single RAR (Fig. 3). Although less is known about the RA signaling pathway in invertebrate deuterostomes than in vertebrates, it seems likely that the overall pathway is very much the same in amphioxus and vertebrates and somewhat different in tunicates (for example, RAR does not regulate its own expression in tunicates, but it does in both amphioxus and vertebrates [29]). Raldh and Cyp26 genes have been identified in the genomes of both amphioxus (ftp.ncbi.nih.gov/pub/TraceDB/branchiostoma_floridae) and tunicates (www.ensembl.org/Ciona_intestinalis) (Fig. 1B) [30]. Unfortunately, too little is known about RA signaling in echinoderms, such as sea urchins, for a comparison with chordates [31-33]. Moreover, for hemichordates, the sister group of echinoderms, it is not known if there is an RAR, and roles for RA signaling during hemichordate development have yet to be established. Even so, bioinformatic analyses of the sea urchin genome sequence (www.ncbi.nlm.nih.gov/genome/guide/sea_urchin) and of hemichordate EST data (ftp.ncbi.nih.gov/pub/TraceDB/saccoglossus_kowalevskii) suggest that both Raldh and Cyp26 genes are present in echinoderms and hemichordates (Fig. 1B). Interestingly, these analyses also revealed a putative RARE (a so-called DR5 element) about 3770 base pairs upstream (5') of the sea urchin Hox1 gene. Thus, at least some components of the RA signaling cascade were probably already present in the last common ancestor of deuterostomes.
Phylogeny of deuterostome retinoic acid receptors (RARs). The tree shows the phylogenetic relationships between RARs from the sea urchin Strongylocentrotus purpuratus, the ascidian tunicate Ciona intestinalis, the cephalochordate Branchiostoma floridae, pufferfish (Takifugu rubripes) and humans (Homo sapiens). The RAR sequences were added to an alignment of nuclear hormone receptors [34] and conserved sites (335 positions) were subsequently selected for phylogenetic reconstruction using PhyML (WAG + Γ8 + I) [61]. 100 bootstrap replicates were carried out to determine the robustness of the obtained phylogenetic tree. In the tree, the RAR subfamily as a whole is strongly supported (bootstrap support 95%) and within the RARs the sea urchin sequence is at the base (with a moderate support of 70%). The respective branching of the cephalochordate and tunicate RARs is not resolved (bootstrap support of 49%). Nonetheless, the invertebrate chordate sequences are positioned between the sea urchin RAR and the duplicated RARs of vertebrates, which form a single clade that is very strongly supported (100%). This analysis shows that a RAR gene is present in the genome of echinoderms and suggests that, despite the lack of data from hemichordates, the presence of RAR is an ancestral character of deuterostomes.
In addition, these results raise two very important questions about the evolution of the RA signaling network: (1) If molecular components of the RA pathway are present in non-chordate deuterostomes, what are their functional roles during development? (2) If molecular traces of the RA pathway exist in all deuterostomes, when did RA signaling first evolve? In the last common ancestor of deuterostomes, in the urbilaterian ancestor of deuterostomes and protostomes or even earlier during animal evolution? A first tentative step towards answering the second question was recently taken by an extensive phylogenetic analysis of the nuclear hormone receptor superfamily, which includes the RAR and RXR subfamilies [34]. The results obtained from this analysis suggest that a "Proto-RAR" gene was already present in the genome of the last common ancestor of protostomes and deuterostomes and that in protostomes this RAR gene was lost at least in the lineages leading to nematode worms and insects [34].
4. The role of RA signaling in chordate morphogenesis
In vertebrates, the roles of RA signaling in anteroposterior patterning of the central nervous system (CNS) and pharynx have received particular attention [35, 36]. In the CNS, when vertebrate embryos are treated with RA, anterior neural structures (like the forebrain) are lost and posterior structures, such as the hindbrain and spinal cord, are expanded. In addition, expression of genes in the anterior nervous system (like Otx2) is lost and the Hox genes, normally expressed in hindbrain and spinal cord, are upregulated and shifted anteriorly [35]. In lampreys, for example, RA expands expression of Hox3 anteriorly in the hindbrain [37]. Conversely, decreasing RA signaling levels has the opposite effect: anterior neural structures, such as the forebrain and midbrain are expanded posteriorly, as is expression of Otx2 [35]. Loss of at least two of the three RAR genes in mice also leads to mispatterning of the hindbrain, such as defects in segmental (rhombomeric) hindbrain organization, which correlate with an induction of Hox gene expression at more posterior levels of the hindbrain [38]. Thus, in vertebrates, RA signaling influences collinear expression of Hox genes, which in turn is required to set up an anteroposterior patterning code along the neural tube.
Not only is anteroposterior patterning of the CNS affected by RA signaling, but, since hindbrain neural crest carries the Hox code of the CNS with it when it migrates, the Hox code carried by neural crest migrating into the branchial arches is also altered when levels of RA signaling are changed. In mammals, excess RA causes fusion of the first two pharyngeal arches while in RA-deficient mice and rats, pharyngeal structures caudal to the first pharyngeal arch are absent [39-42]. Similarly in vitamin A-deficient quail, the pharynx is extended caudally, the first pouch forms normally, the second one is abnormal and the third and fourth pharyngeal pouches never form [43]. In lampreys, the effects of excess RA are even more severe, with complete deletion of anterior pharyngeal structures [44]. Thus, RA signaling in the pharynx specifies the anteroposterior position of pharyngeal structures [36, 45, 46].
It was initially believed that the effects of exogenous RA on the vertebrate pharynx were solely due to a mispatterning of neural crest cells migrating into the branchial arches [36, 45, 46]. However, this influence of neural crest cells is subordinate to regional patterning within the pharyngeal endoderm itself, since removal of neural crest does not prevent the proper patterning of pharyngeal arches and pouches [47]. Conversely, in the zebrafish, Tbx1 function in the pharyngeal endoderm is required for proper development of neural crest-derived structures in the pharyngeal arches [48, 49]. Interestingly, the defects obtained in the Tbx1 mutant van gogh in zebrafish are similar to those obtained after loss of both RARα and β in mice [38, 48, 49] suggesting that RA signaling may be upstream of Tbx1 in the pharyngeal endoderm. Moreover, treatment of developing mice with an RARβ-specific agonistic ligand has conclusively shown that RARβ-dependent RA signaling in the endoderm is independent of neural crest cells [50]. Thus, while neural crest cells migrating into the branchial arches give rise to several structures, such as the pharyngeal arch cartilage, the initial patterning of the pharynx requires RA signaling within the endoderm [36, 45, 46].
In the cephalochordate amphioxus, RAR is expressed in the hindbrain and anterior spinal cord of the developing CNS [14]. Moreover, in the region of the amphioxus CNS strongly expressing RAR, Hox1, Hox3 and Hox4 are collinearly expressed [51]. RA strongly upregulates RAR expression throughout the CNS, whereas an RA antagonist almost completely downregulates RAR [14]. In addition, RA pushes the anterior limits of Hox1 expression anteriorly in the CNS [12], while RA antagonist shifts the Hox1 domain posteriorly (Fig. 4A) [52]. These data suggest that in cephalochordates, as in vertebrates, RA signaling, probably acting via Hox genes, controls anteroposterior patterning of the developing CNS. Similarly, in the amphioxus general ectoderm, treatments with RA and RA antagonist affect collinear expression of Hox genes. Whereas RA shifts expression of Hox genes (such as Hox1) anteriorly in the general ectoderm, the RA antagonist completely downregulates ectodermal Hox expression (Fig. 4B) [53].
Moreover, in amphioxus, which lacks definitive neural crest, exogenous RA shifts the posterior limit of the pharynx anteriorly, while the application of RA antagonist has the opposite effect [12, 14]. The amphioxus pharyngeal endoderm strongly expresses Pax1/9 and Otx [54, 55] and treatments with RA or an RA antagonist shift the posterior limit of Pax1/9 and Otx expression, respectively, anteriorly or posteriorly [52]. RAR and Hox1 are expressed just posterior to Pax1/9 and Otx in the midgut region of the endoderm suggesting that, as in vertebrates, RA signaling within the endoderm might control anteroposterior pharyngeal patterning in amphioxus [52]. In addition, loss of Hox1 function mimics the effect of a decrease of RA signaling in the amphioxus endoderm [52]. Taken together, these results suggest that in the amphioxus endoderm, RA signaling activates Hox1 in the midgut and that Hox1 in turn mediates the effects of RA signaling by limiting expression of genes that are required for specification of the pharynx (such as Pax1/9 and Otx) to the anterior endoderm [52].
RA signaling controls Hox1 expression in central nervous system (CNS) and general ectoderm of developing amphioxus. A) The rostral limit of Hox1 expression in the CNS (arrowheads) is shifted, respectively, anteriorly and posteriorly by 1x10-6M RA and 1x10-6M RA antagonist (BMS009). Side views of whole mounts of 20-hour amphioxus embryos with anterior to the left. Scale bar=50μm. "x" shows the level of the frontal sections in B). B) In the general ectoderm, the rostral limit of Hox1 (arrowheads) is shifted anteriorly by 1x10-6M RA, whereas treatment with 1x10-6M RA antagonist (BMS009) downregulates Hox1 expression. Frontal sections of 20-hour amphioxus embryos with anterior to the left. Scale bar=50μm. Modified with permission from [52].
A role for RA signaling and Hox genes in neural patterning of tunicates is much less obvious than in amphioxus and vertebrates. In the ascidian Ciona intestinalis, treatment with RA does not affect the expression of RAR suggesting that, as mentioned above, RAR does not regulate its own expression as it does in other chordate groups [29]. In addition, tunicates have lost several Hox genes and both cluster organization and collinear expression have been at least partly lost. For example, the ascidian Ciona intestinalis has lost Hox7, Hox8, Hox9 and Hox11 [24], while the appendicularian Oikopleura dioica has lost Hox3, Hox6, Hox7 and Hox8 [25]. Expression of some of the remaining Hox genes cannot be detected at all in the CNS and the domains of those that are expressed are only approximately collinear [24, 25]. Even so, excess RA affects morphology and even Hox gene expression at least in ascidian tunicates. For example, treatment of embryos with exogenous RA leads to incomplete closure of the anterior neural tube of Ciona intestinalis [29] and expression of the Hox1 gene in the CNS of the tunicate Halocynthia roretzi is shifted anteriorly [11]. Thus, a role for RA signaling via Hox genes in neural patterning of tunicates remains a possibility. In contrast to its effects on the CNS, the effects of RA on pharyngeal structures in tunicates is more similar to that in amphioxus and vertebrates. As in amphioxus, Pax1/9 and Otx genes are expressed in the tunicate pharynx during gill slit formation [56, 57]. Moreover, in the ascidian tunicate Herdmania curvata, RA treatment of juveniles leads to a decrease of Otx expression in pharyngeal tissues and to an eventual loss of the pharyngeal basket by respecification of anterior endoderm to a more posterior fate [57, 58]. Taken together, these data suggest that, in tunicates, as in amphioxus, RA signaling might play roles in patterning and development of the CNS and pharyngeal endoderm. In addition, there is evidence that at least some of the genetic machinery mediating RA signaling in amphioxus and vertebrates (like the Hox genes) might also be important for mediating RA signaling in tunicates. Thus, embryonic patterning mechanisms mediated by RA signaling and Hox genes are present in all chordates.
Evolution of RA- and Hox-dependent patterning mechanisms in deuterostomes. In scenario 1, the putative deuterostome ancestor had a central nervous system (CNS) (located ventrally) and both CNS and general ectoderm were patterned by Hox genes, while a role for RA signaling remains elusive. In this scenario, chordates evolved by dorso-ventral axis inversion and the CNS was secondarily lost in the hemichordate lineage. In scenario 2, the nervous system of the ancestral deuterostome was organized as an ectodermal nerve net. Hox-dependent patterning codes were present in the ectoderm, but again a role for RA signaling remains elusive. Early during chordate evolution, condensation of a central nervous system (CNS) dorsally led to the creation of two RA-Hox patterning hierarchies one in general ectoderm and one in neural ectoderm (i.e. in the CNS). In the vertebrate lineage, neural crest function was elaborated and neural crest cells contribute to patterning and development of the embryo by carrying positional information from the CNS into other tissues, for example in the pharyngeal region.
In contrast to chordates, enteropneust hemichordates do not have a centralized nervous system, but instead a diffuse ectodermal nerve net (i.e. a "skin brain") [59, 60]. As in the cephalochordate amphioxus, Hox genes are collinearly expressed in the hemichordate ectoderm [53, 60]. Whether RA signaling is involved in the control of Hox gene expression in the ectoderm of hemichordates is unknown, but RA does not appear to affect anteroposterior patterning in echinoderms, the sister group of hemichordates [31]. These data suggest that collinear expression of Hox genes was already used for anteroposterior patterning of ectodermal tissues in the last common ancestor of hemichordates and cephalochordates and that a role for RA signaling in controlling collinear expression of Hox genes in the ectoderm evolved very early during chordate evolution. Whether this RA-Hox hierarchy evolved even earlier, in the last common ancestor of all deuterostomes, remains to be determined. Thus, very early during chordate evolution or perhaps even very early during deuterostome diversification, RA signaling was co-opted for controlling Hox-dependent anteroposterior patterning mechanisms during development. In one scenario, the putative deuterostome ancestor had a ventral CNS that was patterned by Hox genes like other tissue layers, such as the general ectoderm (Fig. 5), but the CNS was lost in hemichordates [59]. In the second scenario, the ancestral deuterostome lacked a CNS, and the CNS evolved independently from the ectoderm in protostomes and deuterostomes (Fig. 5) [59]. In this scenario, an ancestral ectodermal patterning mechanism was carried over into the CNS at the base of the chordates, leading to the creation of two independent RA-Hox control hierarchies, one in general ectoderm and one in neural ectoderm (i.e. in the CNS) (Fig. 5). Thus, in invertebrate chordates, RA signaling and Hox genes are involved in anteroposterior patterning of the general ectoderm, the CNS, the endoderm (and possibly even of the mesoderm). During vertebrate evolution, with the functional elaboration of neural crest cells another level of complexity has been added. By migrating through the embryo, neural crest cells carry patterning information acquired at the dorsal neural tube into other tissue layers (Fig. 5). In either case, RA signaling became linked to Hox gene function at least at the base of the chordates. Future research on hemichordates will show whether it evolved even earlier in the deuterostome lineage.
In sum, RA signaling is a key regulator of anteroposterior patterning orchestrated by Hox codes in at least general ectoderm, central nervous system and endoderm of chordates. In contrast to the relative conservation of developmental mechanisms within chordates, evidence for roles of RA outside the chordates and the evolutionary origin of RA signaling itself still remain elusive. In fact, it is unclear when RA-controlled patterning mechanisms first evolved in the animal kingdom and when the RA signaling cascade was co-opted for regulating Hox gene expression. Future research on the evolution of RA signaling should thus focus on the identification of RA signaling components, such as the RA receptor (RAR), in non-chordate deuterostomes (such as hemichordates and echinoderms), protostomes (such as insects and mollusks) and maybe even cnidarians. Furthermore, to fully understand the elaboration of this signaling pathway during evolution, the functional roles of the identified components during development will have to be assessed.
The authors would like to thank Nicholas D. Holland, Cédric Finet, François Bonneton and Yannick Le Parco for helpful comments and critical reading of the manuscript. We are indebted to MENRT, CNRS, ARC and the Région Rhônes-Alpes for financial support. LZH is also supported by NSF grant IOB-0416292 and by MOD grant 1-FY05-108.
The authors have declared that no conflict of interest exists.
Strongylocentrotus purpuratus RAR (XM_774883), Ciona intestinalis RAR (AB210661), Branchiostoma floridae RAR (AF378827), Takifugu rubripes RARα1 (FRUP00000151563), Takifugu rubripes RARα2 (FRUP00000165122), Takifugu rubripes RARβ (FRUP00000079596), Takifugu rubripes RARγ1 (FRUP00000158774), Takifugu rubripes RARγ2 (FRUP00000143282), Homo sapiens RARα (NM_001033603), Homo sapiens RARβ (NM_000965), Homo sapiens RARγ (NM_000966).
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15. Napoli JL. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1999 ;1440:139-162
16. Niederreither K, Subbarayan V, Dolle P, Chambon P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet. 1999 ;21:444-448
17. Abu-Abed S, Dolle P, Metzger D, Beckett B, Chambon P, Petkovich M. The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001 ;15:226-240
18. Sakai Y, Meno C, Fujii H, Nishino J, Shiratori H, Saijoh Y, Rossant J, Hamada H. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 2001 ;15:213-225
19. Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P, Dolle P. Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nat Genet. 2002 ;31:84-88
20. Laudet V, Gronemeyer H. The nuclear receptor facts book. San Diego: Academic Press. 2001
21. Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004 ;3:950-964
22. Zechel C. Synthetic retinoids dissociate coactivator binding from corepressor release. J Recept Signal Transduct Res. 2002 ;22:31-61
23. Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering. Science. 2003 ;301:331-333
24. Ikuta T, Yoshida N, Satoh N, Saiga H. Ciona intestinalis Hox gene cluster: its dispersed structure and residual colinear expression in development. Proc Natl Acad Sci USA. 2004 ;101:15118-15123
25. Seo HC, Edvardsen RB, Maeland AD, Bjordal M, Jensen MF, Hansen A, Flaat M, Weissenbach J, Lehrach H, Wincker P, Reinhardt R, Chourrout D. Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica. Nature. 2004 ;431:67-71
26. Dupe V, Davenne M, Brocard J, Dolle P, Mark M, Dierich A, Chambon P, Rijli FM. In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). Development. 1997 ;124:399-410
27. Ishibashi T, Nakazawa M, Ono H, Satoh N, Gojobori T, Fujiwara S. Microarray analysis of embryonic retinoic acid target genes in the ascidian Ciona intestinalis. Dev Growth Differ. 2003 ;45:249-259
28. Dehal P, Boore JL. Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol. 2005 ;3:e314
29. Nagatomo K, Ishibashi T, Satou Y, Satoh N, Fujiwara S. Retinoic acid affects gene expression and morphogenesis without upregulating the retinoic acid receptor in the ascidian Ciona intestinalis. Mech Dev. 2003 ;120:363-372
30. Nagatomo K, Fujiwara S. Expression of Raldh2, Cyp26 and Hox-1 in normal and retinoic acid-treated Ciona intestinalis embryos. Gene Expr Patterns. 2003 ;3:273-277
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32. Sconzo G, Fasulo G, Romancino D, Cascino D, Giudice G. Effect of retinoic acid and valproate on sea urchin development. Pharmazie. 1996 ;51:175-180
33. Kuno S, Kawamoto M, Okuyama M, Yasumasu I. Outgrowth of pseudopodial cables induced by all-trans retinoic acid in micromere-derived cells isolated from sea urchin embryos. Dev Growth Differ. 1999 ;41:193-199
34. Bertrand S, Brunet FG, Escriva H, Parmentier G, Laudet V, Robinson-Rechavi M. Evolutionary genomics of nuclear receptors: from twenty-five ancestral genes to derived endocrine systems. Mol Biol Evol. 2004 ;21:1923-1937
35. Maden M. Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci. 2002 ;3:843-853
36. Mark M, Ghyselinck NB, Chambon P. Retinoic acid signalling in the development of branchial arches. Curr Opin Genet Dev. 2004 ;14:591-598
37. Murakami Y, Pasqualetti M, Takio Y, Hirano S, Rijli FM, Kuratani S. Segmental development of reticulospinal and branchiomotor neurons in lamprey: insights into the evolution of the vertebrate hindbrain. Development. 2004 ;131:983-995
38. Dupe V, Ghyselinck NB, Wendling O, Chambon P, Mark M. Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse. Development. 1999 ;126:5051-5059
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40. Wendling O, Dennefeld C, Chambon P, Mark M. Retinoid signaling is essential for patterning the endoderm of the third and fourth pharyngeal arches. Development. 2000 ;127:1553-1562
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43. Quinlan R, Gale E, Maden M, Graham A. Deficits in the posterior pharyngeal endoderm in the absence of retinoids. Dev Dyn. 2002 ;225:54-60
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47. Veitch E, Begbie J, Schilling TF, Smith MM, Graham A. Pharyngeal arch patterning in the absence of neural crest. Curr Biol. 1999 ;9:1481-1484
48. Piotrowski T, Nusslein-Volhard C. The endoderm plays an important role in patterning the segmented pharyngeal region in zebrafish (Danio rerio). Dev Biol. 2000 ;225:339-356
49. Piotrowski T, Ahn DG, Schilling TF, Nair S, Ruvinsky I, Geisler R, Rauch GJ, Haffter P, Zon LI, Zhou Y, Foott H, Dawid IB, Ho RK. The zebrafish van gogh mutation disrupts tbx1, which is involved in the DiGeorge deletion syndrome in humans. Development. 2003 ;130:5043-5052
50. Matt N, Ghyselinck NB, Wendling O, Chambon P, Mark M. Retinoic acid-induced developmental defects are mediated by RARβ/RXR heterodimers in the pharyngeal endoderm. Development. 2003 ;130:2083-2093
51. Wada H, Garcia-Fernandez J, Holland PW. Colinear and segmental expression of amphioxus Hox genes. Dev Biol. 1999 ;213:131-141
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53. Schubert M, Holland ND, Escriva H, Holland LZ, Laudet V. Retinoic acid influences anteroposterior positioning of epidermal sensory neurons and their gene expression in a developing chordate (amphioxus). Proc Natl Acad Sci USA. 2004 ;101:10320-10325
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61. Guindon S, Gascuel O. A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol. 2003 ;52:696-704
Ferdinand Marlétaz, B.S., M.A.-I (Ecole Normale Supérieure de Lyon, France), is a graduate student in the Laboratory of Molecular Biology of the Cell at the Ecole Normale Supérieure in Lyon, France. He is currently working on the identification of molecular components of the retinoic acid signaling cascade in invertebrate chordates. He is mainly interested in defining novel characters (morphological or molecular) to improve our current understanding of the phylogenetic relationships between animals.
Linda Z. Holland, B.A., M.A. (Stanford University, Palo Alto, CA, USA), Ph.D. (University of California San Diego, San Diego, CA, USA), is Research Professor in the Marine Biology Research Division, Scripps Institution of Oceanography, University of California San Diego. After receiving her M.A., she worked for fifteen years as a laboratory technician before embarking on her own research on chordate evolution, which led to a Ph.D. and to her current position. She pioneered research on developmental genetics of amphioxus and has been instrumental in the effort to sequence the amphioxus genome. She currently directs a laboratory focused on understanding mechanisms of embryonic patterning in amphioxus as key to understanding how vertebrates evolved from their invertebrate chordate ancestors.
Vincent Laudet, DEA (Université Louis Pasteur, Strasbourg, France), Ph.D. (Molecular Oncology Laboratory, Institut Pasteur, Lille, France), is Professor in the Laboratory of Molecular Biology of the Cell at the Ecole Normale Supérieure in Lyon, France. After his Ph.D., he was recruited as research scientist by the Centre National de la Recherche Scientifique (CNRS) and continued working at the Institut Pasteur in Lille for several years, before being appointed Professor at the Ecole Normale Supérieure in Lyon. He is currently heading a research team working on structure and evolution of nuclear hormone receptors. He is particularly interested in comparative studies on retinoid, steroid and thyroid hormone receptors (using amphioxus, lampreys, zebrafish and mice).
Michael Schubert, Vordiplom (Universität Stuttgart, Germany), Ph.D. (Scripps Institution of Oceanography, University of California San Diego, San Diego, CA, USA), Postdoc (Ecole Normale Supérieure de Lyon, France), is research scientist in the Laboratory of Molecular Biology of the Cell at the Ecole Normale Supérieure in Lyon, France. He is a Fulbright graduate student (San Diego) as well as a DAAD (Lyon) and Marie Curie (Lyon) postdoctoral fellow. In 2004, he was recruited as research scientist by the Centre National de la Recherche Scientifique (CNRS). His current research is mainly focused on the evolution of the retinoic acid signaling cascade in chordates, but more generally he is interested in the evolution of vertebrates from an invertebrate chordate ancestor.
Corresponding address:
V. Laudet, Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR5161/INRA 1237/ENS Lyon, IFR128 BioSciences/Lyon-Gerland, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France. E-mail: Vincent.Laudetfr - Tel: ++33 4 72 72 81 90 - Fax: ++33 4 72 72 80 80
Received 2006-2-13
Accepted 2006-3-15


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Discussion in 'Hire a Freelancer' started by Robert, Apr 18, 2013.
I need a login script with a username and password. I do not need a database as I will not be storing any info. I am basically using this as a gate keeper or access login form.
I would like to be able to type ANYTHING into the username box but if it contains the number "2" it gets redirected to another page and if the username contains the number "3" it would get redirected to a different page.
If I type fish2 it goes to redirect page 1.
If I type fish3 it goes to redirect page 2.
I want to ba able to type ANY username not just fish but if the username contains a "2" it gets redirected one place and if it contains a "3" to another.
I would also like to be able to type ANYTHING in the password box but it would ONLY work if it contains a "!" character.
Please pm cost and time frame or if there are any questions.
This work has been done by BHW member Standard Toaster who did an excellent job and very quick as well!
add me on skype: walcott911 if you need it done.


text:
Underrated: The Case For Malcolm Subban
Madeline Purdue
When the San Jose Sharks scored against the Vegas Golden Knights in less than 30 seconds on Monday night, I audibly sighed and said to my sisters, "It's going to be that kind of game." I was not prepared for the 7-3 beating Vegas was going to put down on the second half of a back-to-back, especially with Malcolm Subban starting both games.
Then came Thursday night's home shutout of the Winnipeg Jets, where Subban record his first career doughnut (Krispy Kremes for all!) with 20 saves in the VGK's 5-0 win over the Jets.
My initial reaction prior to the San Jose game wasn't a dig at Subban's talents or abilities, I just expected the whole team to be tired and leave Subban hanging out on the ice as they have in previous back-to-back situations with him in net.
Obviously, I couldn't have been more wrong.
With starting goaltender Marc-Andre Fleury out with a day-to-day lower body injury, Subban is stepping up to lead the Knights in the last handful of games before playoff season begins. This has some fans worried, as any goal scored against Subban means social media uproar about his time in the game, but the fan base should have more faith in Subban.
Malcolm Subban save percentage in road games as a Golden Knights: .898
Malcolm Subban save percentage in home games as a Golden Knights: .917
— Tyler Bischoff (@Bischoff_Tyler) March 19, 2019
As Puck Daddy editor Greg Wyshynski says in his book Take Your Eye Off the Puck, "If you don't stop one, you get the blame. Every single person in front of you, from the left defenseman to the cotton candy vendor, can fail to do their job, and it'll be your fault."
Such is the case when Subban starts in net for the Knights. That's not to say that Subban is completely blameless in every goal against this season, but he also takes a lot more flack for the ones that go in. I would estimate this reaction is 90 percent due to the fact that Subban plays under, and therefore in compared to, the future hall of famer, no-way-is-he-human, Fleury.
The GOAT, if you will. The other 10 percent comes from the fact that no one likes to see the puck in the back of their team's net and the goaltender is the easiest target to blame it on. As far as back up goalies go, Subban is pretty fantastic and should be appreciated more.
Before going into the nitty-gritty details of Subban's short career thus far, there is one statistic that clearly shows why everyone should want him in the net — he is PERFECT when it comes to shootouts. As in, he has never been scored against when it comes to a shootout. Not once. How many other goalies can say that? That's something Flower can't even boast (since the comparisons between the two are being made, albeit unfairly). On Thursday, Feb. 28, Subban extended his record of shootout goals saved to 18-0 against the Florida Panthers, giving the Knights a much-needed win at the beginning of the Stone Age.
Games don't often go to shootouts, so this stat may seem somewhat irrelevant, but it also translates well into the regulation game. Before that shootout win, I was extremely nervous every time a player got a breakaway to go one-on-one with Subban. Now, I'm calm and collected knowing this is his bread and butter. Shootouts and breakaways are nerve-wracking, and it's 100 percent on the goalie to make the save, but Subban always looks in his element when it happens.
Nice timely save from Subban. pic.twitter.com/K61SJim5xl
— Knights On Ice (@knightsonice) March 19, 2019
When fans should be worried is in the first period of any game Subban starts, as this is when he is scored on the most often. According to SinBin.Vegas, Subban has to get settled into a game before to bursts out of his cocoon like a beautiful butterfly to make those incredible saves. This also means the other team has 20 full minutes to put Vegas in a hole before Subban gets to his game, which is not ideal. In that awful, no-good, very bad game against Calgary earlier this season when the Knights were routed 7-2, the Flames scored 5 of their goals in the first period.
It's not a myth, Malcolm Subban really does get better as games wear on.
1st Period – 21 goals allowed
2nd Period – 12 goals allowed
3rd Period – 9 goals allowed
And it's not just that… https://t.co/MPO4xmPXvz
— SinBin.vegas (@SinBinVegas) March 19, 2019
Considering he has only started 14 games this season, a little rust should be expected. Yes, some of the goals Subban has allowed have been "soft" — meaning he was easily able to stop them but didn't — but he's also only 25 years old. He has a lot of training and growing to do, which can't happen unless he starts more games. The games he has started this year, especially at the beginning, haven't given him a fair chance to show his worth. His first three starts this season came on the road against playoff contending teams. He also started second in a lot of back-to-back games with the team in front of him being less than spectacular. Now, with Fleury out, Subban should be getting better and better as his playing time becomes more consistent and his confidence grows. He's just getting started.
While Fleury's injury seems to have been coincidentally timed as he prepares to welcome baby no. 3 with his wife and less than a dozen games before the playoffs, he will be getting some much-needed rest after a fast 59 starts this season. Don't worry, Flower, SUUUUBBB has it locked down.
My oh my, this is a beauty. pic.twitter.com/DbtUNSMTIj
Former Runnin' Rebel Kris Clyburn Joins Bucks In NBA Summer League
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redpajama_set_name: RedPajamaCommonCrawl


It's been a while since I did an outfit of the day--- so I decided to document mine today!!
I bought some new pieces from Urban Outfitters (I'll be doing a bigger lookbook) and I'm wearing one of the new pieces (the top!) It's been really cold in New York this past week and I've had to layer! I'm wearing a crop top from Urban, as I said, and some Urban Outfitters pants as well. I have some shoes from Miss Guided on and a fur coat from Topshop.


text:
MAGIC MAN WARMS UP FOR INTERNATIONALS
Joao Moreira winning aboard Brazen Beau 2014 Group 1 Coolmore Stakes
Hong Kong's big international race day just got a lot more interesting with champion jockey Joao Moreira back in action and doing what he does best – winning races.
Joao is back riding permanently in Hong Kong after failing a written examination he needed to pass in order to obtain a licence to ride fulltime in Japan.
With Ontrack Racing Tours annual tour to the big Hong Kong International Race Day at Sha Tin only three weeks away, Joao Moreira signalled his readiness for the day when kicking home a hattrick of winners at Sha Tin last Sunday.
One of those three winners was Hot King Prawn who took his record to nine wins from only 10 career starts. From a Hong Kong Sprint perspective, Hot King Prawn led from go to whoa, while Mr Stunning, winner of the Group One Sprint last year, was gallant in defeat. They look the leading two local hopes.
Of the other Hong Kong hopes for the big day, Hong Kong's champion horse Beauty Generation smashed a long standing track record when winning at Sha Tin on Sunday in the Group Two Jockey Club Mile.
With the scorching 1:32.64 time breaking the 10-year-old record held by Good Ba Ba, Beauty Generation firmly placed his stake for the Longines Hong Kong International Mile in the ground – he is clearly the horse to beat.
Trainer John Moore said the performance would put his horse on the map globally, forcing people to stand up and take notice.
"From a trainer's point of view, you worry about if he can make two runs, but he proved himself that he is a champion, he did make two runs and for that reason people not only around Hong Kong but around the world are going to stand up and say there is a very good miler in Hong Kong," he said.


A journalist who has won five Bright Leaf awards regardless of category is automatically a recipient of the Oriental Leaf Award and becomes a member of the Bright Leaf Hall of Fame.
This award is open to both feature and news stories.
The article must be published on an online news website or magazine either stand-alone publications or the online version of a printed newspaper.
The online publication must have been active for at least three (3) years including the current year and must adhere to the highest journalistic principles.
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Entries must be accompanied by a certification from the editorial head of their respective online news platform.
The winning online story will not be considered for the "Agriculture Story of the Year" award.
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Judging will be via points system.
Entries with an average score of 85% and above will be elevated to Phase 2.
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text:
Home Current-Affairs-Daily-Basis NOV18-Current-Affairs 15 November 2018 - Daily Current Affairs
15 November 2018 - Daily Current Affairs
IBTSINDIA.COM - Friday, November 16, 2018 Current-Affairs-Daily-Basis, NOV18-Current-Affairs,
1. Hima Das is UNICEF India's first youth ambassador
The United Nations Children's Fund — India (UNICEF—India) has appointed Asian Games gold-medallist sprinter Hima Das as the country's first ever youth ambassador.
The name of the woman athlete from Assam was announced by the world organization in a tweet on Wednesday evening coinciding with the Children's Day celebrated on November 14.
"I'm honored to be chosen as Unicef India's Youth Ambassador, and I hope I will be able to inspire more children to follow their dreams," Ms. Das responded.
Hima Das made history by becoming India's first ever track and field gold medallist at the IAAF World Championships 2018.
She also clinched a gold medal in Women's 4 x 400 m Relay event at the 2018 Asian Games
She had also won a silver medal in Women's 400m Race event.
She is the daughter of a farmer from the village of Dhing in Assam's Nagaon district.
2. India International Trade Fair 2018 opens in New Delhi
The 38th edition of India International Trade Fair (IITF) 2018 was inaugurated by the Minister of State for Commerce & Industry, C.R. Chaudhary at Pragati Maidan in New Delhi.
The flagship event of India Trade Promotion Organisation (ITPO) will continue from 14th to 27th November 2018.
The partner country is the Islamic Republic of Afghanistan and the focus country is the Federal Democratic Republic of Nepal. The focus state is Jharkhand.
This edition of IITF assumes special significance as it marks the beginning of the150th birth anniversary celebrations of Mahatma Gandhi.
Summits & Conferences
3. PM Modi participates in ASEAN-India Breakfast Summit in Singapore
Prime Minister Narendra Modi today participated in the ASEAN-India Breakfast Summit in Singapore and underlined the need for maritime cooperation and centrality of trade for the prosperity of the strategic Indo-Pacific region.
He also held separate bilateral meetings with the premiers of Singapore, Australia, and Thailand and discussed ways to further strengthen ties, including in areas of trade, defense, and security.
The Association of Southeast Asian Nations (ASEAN) is a regional intergovernmental organization comprising 10 Southeast Asian countries, which promotes intergovernmental cooperation and facilitates economic, political, security, military, educational, and socio-cultural integration among its members and other Asian states.
The ASEAN members are Indonesia, Thailand, Singapore, Malaysia, The Philippines, Vietnam, Myanmar, Cambodia, Brunei, and Laos.
4. PM Modi attends 13th East Asia Summit in Singapore
Prime Minister Narendra Modi on 15th November attended the 13th East Asia Summit in Singapore during which the leaders of the grouping discussed global and regional issues, including maritime cooperation.
It was Prime Minister Modi's 5th East Asia Summit.
India has been participating in the East Asia Summit since its very inception in 2005.
The Twelfth East Asia Summit was held in Pasay, the Philippines in 2017.
East Asia Summit meetings are held after the annual ASEAN leaders' meetings and play an important role in the regional architecture of Asia-Pacific.
The first summit was held in Kuala Lumpur, Malaysia on 14 December 2005.
5. Sanjay Kumar Seth takes oath as chief justice of MP high court
Justice Sanjay Kumar Seth was sworn in as the 24th Chief Justice of the Madhya Pradesh High Court.
State Governor Anandi Ben Patel administered the oath of office to Justice Seth in a ceremony.
He was made acting chief justice after the incumbent Hemant Gupta was elevated to the Supreme Court.
Before becoming a high court judge, he had served as an additional advocate general.
He was enrolled as an advocate on July 24, 1981, and practiced in Jabalpur.
6. Sadananda Gowda takes charge of chemicals and fertilizers ministry
Union minister D V Sadananda Gowda assumed additional charge of the Ministry of Chemicals and Fertilisers.
The move was necessitated following the demise of Ananth Kumar.
He is currently the minister for statistics and programme implementation
7. Ashok Chawla steps down as Yes Bank chairman
Yes Bank chairman Ashok Chawla has stepped down, stating that the current transition period calls for someone who can devote more time and attention.
The resignation comes days after the bank sought RBI's opinion on Chawla continuing in the post after being named in a corruption charge sheet in the Aircel-Maxis case.
Chawla, a former secretary with the ministry of finance, is also the chairman of the National Stock Exchange.
8. India to the top US as second-largest carbon spewer from power: IEA
India will overtake the US to become the world's second-biggest emitter of carbon dioxide from the power sector before 2030 as the nation's electricity demand skyrockets, the International Energy Agency said in its latest World Energy Outlook.
Carbon dioxide emissions from India's power sector are expected to rise to nearly 80 percent by 2040 as power use almost triples, driven in part by air conditioning, the Paris-based IEA said in the report.
China will remain the biggest emitter.
Even with the jump in power demand and emissions, India's per-capita electricity consumption will remain one of the world's lowest, according to the report.
9. Ministry of HRD launches faculty development programmes - LEAP & ARPIT
A unique initiative of online professional development of 15 lakh higher education faculty using the MOOCs platform SWAYAM, Annual Refresher Programme in Teaching (ARPIT) was launched on 13th
The ministry of human resource development also launched Leadership for Academicians Programme (LEAP) which will be implemented through 15 top institutions like IITs, TISS, DU, JNU and IISERs and also include a week training in a foreign campus of the likes of Harvard University, Oxford University, Purdue University and NTU Singapore, among others.
About LEAP programme
LEAP is a three-week flagship leadership development training programme (two-weeks domestic and one-week foreign training for second level academic functionaries in public funded higher education institutions.
LEAP programme will be offered by 15 NIRF top-ranked Indian Institutions namely, IIT Roorkee, IIT Kanpur, NIT Trichy, Indian Institute of Science Education and Research (IISER) Kolkata, Jawaharlal Nehru University, University of Delhi, IIT Bombay and TISS Mumbai, among others.
Objective of LEAP
The objective is to prepare second-tier academic heads who are potentially likely to assume leadership roles in the future.
About ARPIT programme
ARPIT is a 40-hour module with 20 hours of video content offered in a highly flexible format and can be done at one's own pace and time.
There are built-in assessment exercises and activities as part of the academic progression in the course.
At the end of the course, they will be a terminal assessment which can be either online or a written examination.
All faculties who have successfully completed the online refresher course will be certified.
10. Agriculture Minister launches 'Yuva Sahakar' scheme
Agriculture Minister Radha Mohan Singh launched a Rs 1000 crore start-up scheme to encourage youth to join cooperative business ventures in agriculture and allied sectors.
The National Cooperative Development Corporation (NCDC) under the agriculture ministry has come up the Yuva Sahakar-Cooperative Enterprise Support and Innovation Scheme.
The scheme will be linked to Rs 1000 crore 'Cooperative Start-up and Innovation Fund (CSIF) created by the NCDC.
Apart from a subsidy for the entrepreneur, the scheme also makes available an interest subvention of 2% per annum.
NCDC is a statutory organization functioning as an apex financial and developmental institution which supports cooperatives in diverse fields apart from agriculture and allied sectors
11. Six professors win Infosys Prize 2018 for science and research
Six eminent professors have been awarded the Infosys Prize 2018 across different categories of science and research, the software major's science foundation announced on 13th Nov 2018.
The list of winners are –
Category Name of the winner contribution
1. Engineering and Computer Science Navakanta Bhat
(Professor, Indian Institute of Science, Bangalore) Awarded for his work on the design of novel biosensors based on his research in biochemistry and gaseous sensors that push the performance limits of existing metal-oxide sensors.
2. Humanities Kavita Singh
(Professor and Dean, School of Arts & Aesthetics, Jawaharlal Nehru University, New Delhi) Awarded for her study of Mughal, Rajput and Deccan art.
3. Life Sciences Roop Mallik
(Associate Professor, Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai) Awarded for his work on molecular motor proteins, which are crucial for the functioning of living cells.
4. Mathematical Sciences Nalini Anantharaman
(Professor and Chair of Mathematics, Institute for Advanced Study, University of Strasbourg, France) Awarded the prize in Mathematical Sciences for her work related to "Quantum Chaos".
5. Physical Sciences S.K. Satheesh
(Professor, Centre for Atmospheric & Oceanic Sciences, Indian Institute of Science, Bangalore) Awarded for his pioneering scientific work in the field of climate change.
6. Social Sciences Sendhil Mullainathan
(Professor of Computation and Behavioral Science, the University of Chicago in the U.S.) For his path-breaking work in behavioural economics.
"The Infosys Prize seeks to honour the efforts of some of the brightest scientists and researchers and highlight the country's ongoing quest for scientific excellence.
The annual award includes a pure gold medal, a citation and a prize purse worth $100,000 (or its equivalent in Indian rupees), the Infosys Science Foundation (ISF) said in a statement.
12. Former World No. 2 Agnieszka Radwanska announces retirement
Polish tennis player Agnieszka Radwanska said that she has decided to end her 13 year-long career due to health reasons.
"Unfortunately, I am no longer able to train and play the way I used to, and recently my body can't live up to my expectations."
Radwanska, who reached a career-high ranking of second in 2012, complained of health woes last year, including suffering from viruses which she had to fight using antibiotics.
She struggled for form in the 2018 season, falling to 75 in the world rankings after starting the year in the top 30.
Radwanska reached a career-high world singles ranking of number two in 2012 after finishing as runner-up at Wimbledon.
She won the season-ending WTA Finals in 2015.
13. The 10th edition of World Boxing championship begins in New Delhi
The Women's World Boxing Championships begin in Delhi today.
This tenth edition of the tournament is set to be the biggest ever as more than 300 boxers from 72 countries will be taking part.
The highlight of 10th edition will be that new countries—Scotland, Malta, Bangladesh, Cayman Islands, DR Congo, Mozambique, Sierra Leone and Somalia—are making their debut.
MC Mary Kom will be aiming for a historic sixth gold at the event, which is being hosted by India for the first time since 2006.
This time, the 10-member Indian team, led by Mary Kom, is a mix of seasoned and young boxers.
Science & Defence
14. ISRO successfully launches GSLV Mark III D2 carrying GSAT 29 satellie
India successfully launched its latest communication satellite GSAT-29 with its heaviest rocket Geosynchronous Satellite Launch Vehicle-Mark III (GSLV-Mk III) on 14th
India space agency ISRO's Geosynchronous Satellite Launch Vehicle Mark III (GSLV Mk-III-D2) - on its second developmental flight - lifted off from Sriharikota, India's rocket port in Andhra Pradesh on the coast of the Bay of Bengal.
India's heaviest rocket referred to as "Baahubali".
This is the 67th launch from Sriharikota and the GSAT-29 is the 33rd communications satellite made by India.
It carries Ka/Ku-band high throughput communication transponders, which are intended to cater to the communication requirements of users, including those in remote areas.
GSAT-29 is a multiband, multi-beam communication satellite, intended to serve as a testbed for several new and critical technologies. The mission life of the satellite is over ten years.
The advanced communications satellite weighs 3,423 kg and will help provide internet connectivity, especially in the remote areas of Jammu and Kashmir and north-eastern
The satellite also carries a unique laser-based optical communication that ISRO is testing for the first time.
The GSLV Mk- III weighs 641 tons, which is equal to the weight of five fully loaded passenger planes. At 43 meters tall, it is higher than a 13-story building.
Although it is the heaviest among India's operational launch vehicles, it is also the shortest.
The GSLV Mk-III will be used to launch India's Chandrayaan-2 early next year and Gaganyaan before 2022.
Current-Affairs-Daily-Basis, NOV18-Current-Affairs


A large part of any site is the bingo software it uses. There are a number of top software providers out there and regular online bingo players will recognise quite a few of them.
Online bingo has significantly increased in popularity over the past few years. Part of the reason for this is the high quality experience they provide.
The software used by a bingo site is often one of the first things people look out for. It determines what kind of experience you're going to have and how easy the site is going to be to navigate through.
The actual layout and design of the site isn't something software developers are overly worried about. Their job is simply to create the programming used for the site.
Some bingo sites make use of more than one type of software. For example, they may enlist the help of one software provider for the instant games design, and another for bingo chat games. There is also security software used on most sites. So as you can see, software relates to more than just game design.
There are a few big names you are likely to come across when investigating bingo software, including Cozy Games, Dragonfish, and Playtech.
Cozy Games was set up in 2005 and is now one of the leading names in the industry. The company offers five different bingo games, 12 scratchcards, eight casino games and 70 different slot games. It is based in Malta and has an exceptional amount of players. In 2011, records showed the company had a huge 2,848,103 online players.
Dragonfish is another industry leader, boasting more than 60 different bingo sites on its popular network. As well as giving sites the chance to become part of its network, the company also provides its software on a standalone basis. It is actually a division of 888 and along with online bingo, it also offers instant games, casino, sports betting and poker. The provider is particularly well known for its large pooled bingo games; offering huge life changing jackpots.
Playtech is a popular provider, creating games to work across all platforms. It offers mobile gaming, along with a great choice of live casino and standard casino games, slots, bingo, binary options and sports betting.
While the majority of sites offer popular branded bingo software, there are a few that create their own which is 'proprietary software'.
If you're looking for a truly unique experience then seeking out standalone sites is a good idea. However, one thing you need to keep in mind is that you cannot guarantee the quality of standalone software. At least when you choose a site with software powered from a well-known provider, you know you're going to enjoy a top quality gaming experience.
Overall it is definitely worth looking into which software a company uses before you decide to sign up. To make a more informed decision about which site is best, it's also a good idea to research more about the actual software companies.


text:
from gevent.event import AsyncResult, Event
from gevent.hub import get_hub, getcurrent, Waiter

from couchbase.async.bucket import AsyncBucket
from couchbase.async.view import AsyncViewBase
from couchbase.async.n1ql import AsyncN1QLRequest
from couchbase.views.iterator import AlreadyQueriedError
try:
    from gcouchbase.iops_gevent0x import IOPS
except ImportError:
    from gcouchbase.iops_gevent10 import IOPS

class GRowsHandler(object):
    def __init__(self):
        """
        Subclass of :class:`~.AsyncViewBase`
        This doesn't expose an API different from the normal
        synchronous view API. It's just implemented differently
        """

        # We use __double_underscore to mangle names. This is because
        # the views class has quite a bit of data attached to it.
        self.__waiter = Waiter()
        self.__raw_rows = []
        self.__done_called = False
        self.start()
        self.raw.rows_per_call = 100000

    def _callback(self, *args):
        # This method overridden from the parent. Rather than do the processing
        # on demand, we must defer it for later. This is done by copying the
        # rows to a list. In the typical case we shouldn't accumulate all
        # the rows in the buffer (since .switch() will typically have something
        # waiting for us). However if the view is destroyed prematurely,
        # or if the user is not actively iterating over us, or if something
        # else happens (such as more rows arriving during a get request with
        # include_docs), we simply accumulate the rows here.
        self.__raw_rows.append(self.raw.rows)
        if self.raw.done:
            self._clear()
        self.__waiter.switch()

    def _errback(self, mres, *args):
        self._clear()
        self.__waiter.throw(*args)

    def __iter__(self):
        if not self._do_iter:
            raise AlreadyQueriedError.pyexc("Already queried")

        while self._do_iter and not self.__done_called:
            self.__waiter.get()

            rowset_list = self.__raw_rows
            self.__raw_rows = []
            for rowset in rowset_list:
                for row in self._process_payload(rowset):
                    yield row

        self._do_iter = False

class GView(GRowsHandler, AsyncViewBase):
    def __init__(self, *args, **kwargs):
        AsyncViewBase.__init__(self, *args, **kwargs)
        GRowsHandler.__init__(self)

class GN1QLRequest(GRowsHandler, AsyncN1QLRequest):
    def __init__(self, *args, **kwargs):
        AsyncN1QLRequest.__init__(self, *args, **kwargs)
        GRowsHandler.__init__(self)

class Bucket(AsyncBucket):
    def __init__(self, *args, **kwargs):
        """
        This class is a 'GEvent'-optimized subclass of libcouchbase
        which utilizes the underlying IOPS structures and the gevent
        event primitives to efficiently utilize couroutine switching.
        """
        super(Bucket, self).__init__(IOPS(), *args, **kwargs)

    def _do_ctor_connect(self):
        if self.connected:
            return

        self._connect()
        self._evconn = AsyncResult()
        self._conncb = self._on_connected
        self._evconn.get()
        self._evconn = None

    def _on_connected(self, err):
        if err:
            self._evconn.set_exception(err)
        else:
            self._evconn.set(None)

    def _waitwrap(self, cbasync):
        cur_thread = getcurrent()
        cbasync.callback = cur_thread.switch
        cbasync.errback = lambda r, x, y, z: cur_thread.throw(x, y, z)

        return get_hub().switch()

    def _meth_factory(meth, name):
        def ret(self, *args, **kwargs):
            return self._waitwrap(meth(self, *args, **kwargs))
        return ret

    def _http_request(self, **kwargs):
        res = super(Bucket, self)._http_request(**kwargs)

        w = Waiter()
        res.callback = lambda x: w.switch(x)
        res.errback = lambda x, c, o, b: w.throw(c, o, b)
        return w.get()

    def query(self, *args, **kwargs):
        kwargs['itercls'] = GView
        return super(Bucket, self).query(*args, **kwargs)

    def n1ql_query(self, query, *args, **kwargs):
        kwargs['itercls'] = GN1QLRequest
        return super(Bucket, self).n1ql_query(query, *args, **kwargs)

    def _get_close_future(self):
        ev = Event()
        def _dtor_cb(*args):
            ev.set()
        self._dtorcb = _dtor_cb
        return ev

    locals().update(AsyncBucket._gen_memd_wrappers(_meth_factory))

redpajama_set_name: RedPajamaGithub


text:
Hands and eyes-on with the high-def Oculus Rift prototype
By Logan Decker published 14 June 13
The Oculus Rift is a lightweight, boxy, head-mounted display that covers your eyes and blows your mind. Once properly adjusted so that its interior screens are aligned with each of your eyes (stabilized by a single elastic strap that runs behind your head), the image snaps into focus and you're plunged into a virtual environment, free to look around in any direction independent of your mouse movements. You can keep firing at anything ahead of you in your path while, say, you look behind yourself over your shoulder for enemies creeping up behind you, or quickly glance upward to admire the nice ornamental work on the ceiling.
The Rift is the latest in a long line of virtual-reality gadgets dating back to the 1990s that have promised to deliver deeper immersion in our games, but most of them began as fledgling curiosities hawked around the outer perimeter of the E3 show floor and ended up gathering dust in warehouses and junk drawers. The Oculus Rift, on the other hand, is picking up endorsements from PC gaming royalty, including John Carmack, Gabe Newell, and Chris Roberts. The peripheral is dazzling gamers with prototypes demoed at PAX East and GDC, as well as throughout the week here in Los Angeles at E3.
But today's demonstration—my third hands-on experience with the set—was the most exhilarating of them all thanks to a prototype unit that boosts the resolution from 1280x800 (in the model available to developers and Oculus VR's Kickstarter backers) to 1920x1200, which is the resolution Oculus VR CEO Brandan Iribe told me is intended for the consumer version. "If not better," he hinted with a smile as he tucked my head into the Rift. I began scooting around the vaulted carvern of the Unreal Engine "Elemental" demo, firing luminous missiles and tracking them with my eyes as they ricocheted off the floor and walls. At one point I watched one carom off a rock towards my feet, and Iribe had to grab me before I inadvertently slammed my head against the glass table I'd forgotten was in front of me.
Obviously a shard of bloody glass sticking conspicuously out of my forehead is not the kind of press Oculus is looking for, but that gives you a sense of how mesmerizing the Rift can be. And the key to its immersion—the word can't be avoided—is the lack of any sense of lag between the movement of my head and the display. That's also why the Rift is such a pleasure despite the relatively low resolution per display. That said, I can imagine that it's possible that after some use, the somewhat grotty-looking textures that were evident in my demo might frustrate PC gamers in particular. Until the resolution is raised even higher, some judicious use of filters and stylized graphics might be necessary for the first generation of games developed for the Rift.
In addition to the Elemental demo (as well as a touching snowfall tribute to the late Oculus co-founder Andrew Scott Reisse), Iribe demonstrated a new app developed for the Rift that drops you into a customizable virtual theater. It's got plenty of seats, a huge screen, even a projector flickering in the back—everything but the jerk using his phone in the middle of the movie. I watched the Man of Steel trailer as Iribe described the ways in which—let's call it Oculus Happy Cinema—might be used: you can sit anywhere you like, watch anything you've got, and even watch the movie with friends who also have Rifts (who could, Iribe added, also be individually muted). It might seem odd at first to use an app that creates a virtual theater instead of simply watching movies in full-screen mode, but if you think about it, that'd be like watching an IMAX movie a few feet away from the screen.
The Man of Steel trailer, and Russel Crowe's furrowed brows in particular, reminded me that in order to work properly the Rift must maintain its position perfectly; a sudden jerk of the head can cause the image to blur until the headset is readjusted. And while the Rift can track your head orientation in any direction, it can't yet sense horizontal or lateral movements, such as raising your head with your spine straight to peek over cover. There may not be much that can be done about the former—at least, not until 400,000 years or so until our eyes evolve to view focal points independently—but Iribe tells me that a solution for the latter is something Oculus is working on.
But horizontal tracking and higher resolutions are essentially refinements to a breakthrough in virtual reality technology that found a way to solve the lag problem, which for gamers means solving the vomit problem. And Oculus VR, as well as the developers who are experimenting with and developing bespoke games for the Rift, have at least another year to refine the hardware and software (no shipping date has been announced for the consumer version, though odds are good on 2014). They're both off to a fantastic start, and PC Gamer will be tapping into those experiments along the way.
For the latest from E3, check out our complete coverage .


fix NFSv2 copyrights, clarify licencing.
Email to the original author bounces. Anyone else heard from Andreas Huber lately?
Known addresses for him are: hubera AT forwiss DOT uni-passau DOT de I'm sure I tried this one and it didn't work, but can't find the mail.
I'll mail the first two and see.
The other one seems not to be the one we want either.
I am looking for the original author of the NFS_client add-on for BeOS. If you are the author, the Haiku developers have updated and added your code to their operating system for NFS support and are have been attempting to contact you to see if you are willing to license the code under the MIT license.


text:
An IESG charter
RFC - Informational (February 2004; No errata)
Updated by RFC 5742, RFC 3932
Was draft-iesg-charter
Steven Bellovin
<fred@cisco.com>
Network Working Group                                      H. Alvestrand
Request for Comments: 3710                                 Cisco Systems
Category: Informational                                    February 2004
This memo provides information for the Internet community.  It does
not specify an Internet standard of any kind.  Distribution of this
memo is unlimited.
Copyright (C) The Internet Society (2004).  All Rights Reserved.
This memo provides a charter for the Internet Engineering Steering
Group (IESG), a management function of the Internet Engineering Task
Force (IETF).  It is meant to document the charter of the IESG as it
is presently understood.
1.1.  The Role of the IESG
The Internet Engineering Steering Group (IESG) is the group
responsible for the direct operation of the IETF and for ensuring the
quality of work produced by the IETF.
The IESG charters and terminates working groups, selects their
chairs, monitors their progress and coordinates efforts between them.
The IESG performs technical review and approval of working group
documents and candidates for the IETF standards track, and reviews
other candidates for publication in the RFC series.  It also
administers IETF logistics, including operation of the Internet-Draft
document series and the IETF meeting event.
Alvestrand                   Informational                      [Page 1]
RFC 3710                    An IESG Charter                February 2004
1.2.  Historic Note
The role of the IESG in the IETF management structure has been
largely constant since 1993, after the significant changes introduced
by the "POISED" process, and documented in RFC 1602 [5].  (The
previous process was documented in RFC 1310 [4]; RFC 1602 has later
been updated by RFC 1871 [7] and obsoleted by RFC 2026 [1].)
Some of the functions were also defined in RFC 1603 [6], Working
Group Guidelines, which was later obsoleted by RFC 2418 [2].
As the community has grown, and the IESG has gathered experience, the
ways in which the IESG has approached its tasks have varied
considerably, but the tasks have remained relatively constant.
This document describes the tasks assigned to the IESG.  It does not
attempt to describe in detail the procedures the IESG uses to
accomplish these tasks; that is done elsewhere - consult the IESG's
Web pages on the IETF Website for more information [9].
At this time (spring 2003), the structure of the IETF is undergoing
reevaluation, and the result is likely to include changes to the
IESG's role.  Therefore, this document was written as a
"documentation of existing practice" rather than as IETF consensus on
what the IESG should do.
This document is published as an Informational RFC, detailing the
current operations of the IESG.  It does not claim to represent
consensus of the IETF that this is the right set of instructions to
the IESG.
2.  The Composition of the IESG
The IESG has the following members:
o  The IETF Chair, who also functions as the General Area Director
when this area is active
o  The Area Directors (ADs) for the IETF Areas
o  The Internet Architecture Board (IAB) Chair and the IETF Executive
Director, as ex-officio members of the IESG.
The IETF Chair and the Area Directors are selected by the IETF NomCom
according to the procedures of BCP 10 [3] (Nomcom procedures).
The IETF Executive Director is the person charged with running the
IETF Secretariat.
The IESG also has liaisons, who are members of the IESG mailing list
and may attend all IESG meetings.  The Liaison positions exist to
facilitate the work of the IETF by expediting communication with
other entities involved in the IETF process; which positions to have
are decided by the IESG.
The liaisons are selected as appropriate by the bodies they
represent.  At the time of this writing, the liaisons present
represent the following bodies:
The RFC Editor
The IANA
The IAB
In addition, members of the IETF Secretariat are subscribed to the
mailing list and present in the IESG meetings as needed in order to
serve as a support function.
IESG decisions are made by the IETF Chair and the Area Directors.
All IESG members can participate in the IESG's discussions.
3.  Procedural Issues
While the IESG is generally free to set its own procedures, some
parts of its procedures are properly part of its charter.  These are
given here.
3.1.  Decision Making
The IESG attempts to reach all decisions unanimously.  If unanimity
cannot be achieved, the chair may conduct informal polls to determine


Before you go on your next off-road adventure, you need to hear about Whiteline's synthetic elastomer sway bar bushings for your Jeep. These small little bushings can make your suspension set up better than when you first rolled off the dealership lot and onto the trails. Whiteline's synthetic elastomer sway bar bushings have been specifically designed for the TJ and JK, and will effectively give your sway bar the performance of a larger sway bar. Whiteline's sway bar bushings will keep the wheel weight balanced and the chassis evened out giving your Jeep better traction and stability. And with your sway bar held firmly in place by these bushings, your rock crawler can perform how it was intended to.


50 apartments in a luxurious residential project which was built through cooperation by the developers Weisman Construction Company Ltd. and Oren Hasela Construction and Investments Ltd. in the neighborhood H/300 in Holon.
Accompanying lawyers: Adv. Tal Kenneth and Adv. Idit Goral.
Lending bank: Bank Leumi le-Israel Ltd.


text:
Nel 1949, la selezione dei New Zealand Māori, squadra di rugby a 15 si reca in tour in Australia. Tre i test contro la nazionale australiana, con una vittoria, un pareggio e una sconfitta.

Da segnalare che la netta vittoria contro i "Wallabies" nel primo match, provocò l'esonero dell'allenatore australiano Johhny Wallace e la sua sostituzione con Bill Mclean, storico capitano del tour del 1947-48 in Europa. Era la prima volta che la nazionale Australiana veniva affidata ad un coach del Queensland e non del Nuovo Galles del Sud.

Risultati

Note

 1949
Maori

redpajama_set_name: RedPajamaWikipedia


"The Beginning of the Rest of Our Lives"
Something was wrong. Kayla had been basically ignoring me for a week. She would barely talk to me or even look at me. I was really starting to get scared. I didn't even know what I did.
Just then she walked passed me without even glancing up. She had Mary on her hip and she was heading towards the kitchen. Without thinking I just followed behind her silently. She was fixing Mary a bottle.
"Hi," she said back without looking up at me.
"What's wrong with you," I asked her.
"Nothing," she said back quietly.
"Something is. You haven't talked to me in a week," I said frustrated.
"I've just been quiet," she said with a shrug as she started feeding the baby.
"That's bull crap," I said.
"It's not," was all she said.
"Did I do something wrong," I begged as I walked over to her. When I reached out to touch her she jerked back.
"No," she said as she walked away.
"Kayla you're scaring me," I told her quietly.
"I'm fine. I'm just moody," she said as she sat down.
"This is not just moodiness. Something is wrong," I told her.
"It's not," she said without looking up at me. Without thinking I punched the wall as hard as I could. I left a big hole in it and Kayla jumped.
"Fine," I said as I walked out of the room. She never made a move to stop me.
"What happened," my mother asked as she ran up to me.
"I just put my hand through the wall," I said as I looked down at my throbbing hand.
"Because Kayla won't look at me or even talk to me," I said sadly.
"She's just still hurt," she said with a sigh.
"You know about this," I asked her wide eyed.
"What did I do," I begged of her.
"You offered marriage because of the baby," she said.


text:
Dr. Blake Bextine Program Manager Biological Technologies Office
Dr. Blake Bextine joined DARPA as a program manager in March 2016, and has served twice as acting deputy director of the Biological Technologies office. He is interested in novel approaches to addressing issues facing agricultural biotechnology and food security, including nucleic acid-based anti-pathogen/anti-pest strategies and insect and plant transformation strategies for rapid trait selection.
Additionally, Bextine has focused on the climate conscious approaches to infrastructure development and waste elimination utilizing cutting-edge synthetic biology platforms.
Bextine came to DARPA from the University of Texas at Tyler where he was a Professor of biology and Assistant Vice President for Research and Technology Transfer. Prior to his arrival at UT Tyler, Bextine was a post-doctoral fellow in the Department of Entomology at the University of California, Riverside.
He received his Doctor of Philosophy degree from Oklahoma State University, Master of Science in entomology from Texas Tech University, and Bachelor of Arts in biology from the University of Northern Iowa.
Bextine is a recipient of the University of Texas System Regents' Outstanding Teaching Award and has also won the UT Tyler President's Scholarly Achievement Award, White Fellowship for Teaching Excellence Award, and multiple UT Tyler Researcher of the Year Awards. He received the 2014 USDA Partnership Award along with other members of the Zebra Chip Research group. In 2014, he appeared on the Discovery Channel Television Show "Tethered."
Engineered Living Materials (ELM)


text:
Caroline Heycock és una sintactista escocesa i professora de lingüística a la Universitat d'Edimburg.

El 1991 es va doctorar a la Universitat de Pennsilvània  amb una tesi titulada Layers of predication: The non-lexical syntax of clauses.

És coneguda per la seva feina en l'àmbit de la sintaxi teòrica, amb especial referència a l'anglès, el feroès i les altres llengües germàniques, i al japonès. Els temes sobre els quals ha realitzat investigacions notables inclouen fenòmens de reconstrucció, equatives i altres construccions copulars, en particular oracions pseudoclivellades, la sintaxi i la semàntica de la conjunció nominal i el desgast sintàctic en la llengua materna dels aprenents avançats d'una segona llengua. El 2019 va ser coautora d'un treball que examinava la possible posició de les contraccions en l'anglès escocès (no confondre amb l'scots), centrant-se en l'ús d'unes "expressions de descoberta locativa" ("locative discovery expressions") en què els parlants poden pronunciar tant "there it's there" com "there its".

Ha estat editora en cap del Journal of Linguistics, publicat per la Cambridge University Press per a l'Associació Lingüística de Gran Bretanya i actualment forma part del seu consell editorial. És membre de l'equip del projecte Scots Syntax Atlas.

El juliol de 2019, Heycock va ser escollida membre (fellow) de l'Acadèmia Britànica .

Publicacions seleccionades
 Caroline Heycock. 1995. "Asymmetries in reconstruction," Linguistic inquiry. 547–570.
 Caroline Heycock, Anthony Kroch. 1999. "Pseudocleft connectedness: Implications for the LF interface level,"
 Linguistic inquiry, 30(3), 365–397.
 Ianthi Tsimpli, Antonella Sorace, Caroline Heycock, Francesca Filiaci. 2004. "First language attrition and syntactic subjects: A study of Greek and Italian near-native speakers of English,"
 International Journal of Bilingualism 8 (3), 257–277.
 Caroline Heycock. 2006. "Embedded root phenomena," 2006. The Blackwell companion to syntax.
 Gary Thoms, David Adger, Caroline Heycock, Jennifer Smith. 2019. "Syntactic variation and auxiliary contraction: The surprising case of Scots," Language. 95 (3), 421–455.

Referències

Enllaços externs
 YouTube: Generative Syntax with Prof Caroline Heycock
Alumnes de la Universitat de Pennsilvània
Lingüistes
Professors de la Universitat d'Edimburg
Lingüística
Sintaxi


text:
from __future__ import unicode_literals

from django.db import migrations, models

class Migration(migrations.Migration):

    dependencies = [
        ('myresume', '0026_contact'),
    ]

    operations = [
        migrations.AddField(
            model_name='person',
            name='available',
            field=models.BooleanField(default=True),
        ),
    ]


text:
Sound Advice by Denise Roco
People Asia – (October-November 2010)
It Started With An April Shower / The Gentle Isolation
Simple. Warm. Unique. Happy. These are four words chosen by the band that encapsulated what is essentially, Gentle Isolation. From indie label Lilystars Records, comes the much awaited EP It Started with an April Shower from this Bulacan-based quartet. Vocalist Ness Urian narrates that the early roots of the band was New Wave and Brit rock from the 80's and 90's. "We used to be a New Wave cover band with a male vocalist who then was my brother, Christopher. But he got too busy to join practice so other boys cajoled me to take his place." The boys namely, Joseph Rovero (guitars), Monch Cristobal (bass) and Bachie Rudica (drums) subdued their instrumentation to adjust to the new female lead that was and still is a naturally shy but charming girl. This fine-tuning eventually became twee. As sure as "Let's Go Slow" is making waves on the airwaves, "Faraway" (the oldest track from the album composed in 2005) is certain to make a tsunami.


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