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PubMed1991

Isolation and characterization of cDNAs encoding beta A2- and beta A4-crystallins: heterologous interactions in the predicted beta A4-beta B2 heterodimer.

Except for the two acidic chains, beta A2 and beta A4, the primary structures of all bovine beta-crystallins have previously been elucidated, either by direct protein sequencing or prediction from cDNA sequencing. Both beta A2 and beta A4 were found to be synthesized in half-year-old calf lenses and are therefore likely to be present in a cDNA bovine library constructed from mRNA isolated from lenses of that age. A large number of cDNA clones was screened with all available crystallin, actin, vimentin and lens membrane protein MP26 probes and finally with a randomly primed mRNA probe. Clones positive for the latter, but negative for known lens proteins, were isolated and sequenced. beta A2, comprising 197 aa, and beta A4, comprising 209 aa, were identified. Both proteins have a conserved two-domain structure and an N-terminal extension which is variable. A three-dimensional model of the structure of beta A4 was made based on the coordinates of one subunit from the beta B2 dimer which has recently been solved using x-ray diffraction techniques. The resulting heterodimer structure, together with the compiled bovine beta-crystallin sequences, was used to indicate those regions of the sequences which distinguish acidic from basic beta-crystallins with a view to defining structural features necessary for subunit recognition in beta-crystallin aggregates. With the aid of the present data, the complete evolutionary tree of the bovine beta-crystallin family has been constructed, which confirms the early separation of the genes encoding the three acidic and the three basic beta-crystallins.

Amino Acid Sequence↗
PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗
PubMed1969

Enzymes of tryptophan biosynthesis in Serratia marcescens.

In Serratia marcescens, the tryptophan biosynthetic enzymes were formed coordinately. A number of tryptophan auxotrophs showed single biochemical lesions; several mutants showed pleiotropic effects. Sucrose density gradient centrifugation revealed an unique pattern of migration of the tryptophan biosynthetic enzymes. The repression response of the Serratia enzymes to exogenous tryptophan was fivefold more sensitive than that found in Escherichia coli. When this information is contrasted with the available information on the other Enterobacteriaceae, one is compelled to conclude that S. marcescens enjoys a rather marked evolutionary divergence from the other enteric organisms.

Enzyme Repression↗
PubMed2026

Host-driven evolution shapes the polysaccharide utilization profiles of alga-associated Flavobacteriaceae.

BACKGROUND: Marine algae represent major producers of complex polysaccharides and serve as hosts for diverse microbial communities in the phycosphere. Flavobacteriaceae are among the key bacterial taxa involved in polysaccharide degradation and carbon remineralization in this environment. However, the extent to which algal hosts drive the divergence of polysaccharide utilization profiles in these bacteria remains unclear. RESULTS: We conducted a genome-resolved analysis of 103 cultured Flavobacteriaceae strains isolated from red, green, and brown macroalgae, as well as from diatoms and dinoflagellates. We found that macroalga-associated strains generally harbored more abundant and diverse CAZyme-encoding genes than their microalga-associated counterparts. Moreover, strains associated with different algal phyla showed distinct metabolic specializations that aligned with the typical polysaccharides of their respective hosts, strongly supporting host-specific adaptation. In four widely distributed genera (Maribacter, Flagellimonas, Polaribacter, Winogradskyella), CAZyme profile dissimilarity and key glycoside hydrolase gene divergence exhibited phylogenetic congruence with algal host phylogeny (Mantel r up to 0.76 and 0.85, respectively), indicative of host-associated functional adaptation. Using Maribacter as a model, cultivation experiments and transcriptome characterization demonstrated that polysaccharide utilization efficiency is not solely linked to the organization of genes into polysaccharide utilization loci (PULs), but also associated with the expression dynamics of key transcription factors (TFs), particularly those from AraC and DeoR families, whose expression patterns were coordinated with laminarin degradation. Notably, these two TF families also exhibited host-associated divergence patterns similar to those of CAZyme-encoding genes. Furthermore, analysis of the Tara Oceans metagenomic data indicated that, within the AraC and DeoR families, a higher proportion of genes were positively correlated with chlorophyll a content compared to other TF families, reinforcing their specialized roles in alga-associated bacterial lifestyles. CONCLUSIONS: Our integrative genomic and transcriptomic analyses reveal evolutionary and regulatory adaptation of marine Flavobacteriaceae to distinct algal hosts. These findings highlight algae-derived habitats as specialized niches that shape microbial metabolic potential, and suggest that carbohydrate metabolism plays a key role in host-driven bacterial evolution across global oceans. Video Abstract.

Flavobacteriaceae↗
PubMed2006

Cognitive developmental biology: history, process and fortune's wheel.

Biological contributions to cognitive development continue to be conceived predominantly along deterministic lines, with proponents of different positions arguing about the preponderance of gene-based versus experience-based influences that organize brain circuits irreversibly during prenatal or early postnatal life, and evolutionary influences acting through selection on small numbers of genes. This article discusses evolutionary, mechanistic and probabilistic aspects of developmental processes that cognitive scientists need to better integrate. Developmental processes inseparably fuse experience-dependent and experience-independent components, have important stochastic contributions, and exhibit a greater degree of mechanistic continuity between developing and adult nervous systems than previously thought. Their balanced integration leads to new models for "critical or sensitive" period phenomena and behavioral biases. A general understanding of behavioral development - cognitive developmental biology--will require better coordination between comparative animal and human developmental research programs.

Brain↗
PubMed1999

RFLP- and RAPD-based genetic relationships of seven diploid species of Avena with the A genome.

Relatively few molecular analyses are available for diploid oat species, which constitute the majority of the wild species of Avena and, therefore, the principal natural reservoir of variability. The present work reports an RAPD-(random amplified polymorphic DNA) and RFLP-(restriction fragment length polymorphism) based study of the intra- and interspecific variability of seven diploid A-genome oat species. Both types of markers resulted in valid tools for identifying polymorphisms both within and between species. The two statistical analyses, UPGMA (unweighted pair group method, arithmetic mean) and PCoA (principal coordinate analysis), computed on the basis of genetic similarities estimated from RAPDs and RFLPs, showed that the different accessions grouped according to species, but the similarity coefficients were consistently higher in the RFLP analysis. Furthermore, slight differences were observed in the intra- and interspecific relationships found with the two types of markers. This may support the hypothesis that the polymorphisms revealed by the two types of markers may associate with regions of the genome having different evolutionary rates. The relationships among species are not identical to those deduced from previous karyotypic and morphological studies, thus suggesting a partially different evolutionary pathway in oat speciation.

Avena↗
PubMed2005

Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense-antisense transcripts.

Is sense-antisense (SA) pairing of transcripts a common mode of gene regulation in the human genome? Although >20% of human genes might form SA pairs, the extent to which they are involved in antisense regulation is unknown. Simultaneous expression of paired sense and antisense genes is an essential step and an important indicator of antisense regulation. In this article, we demonstrate that human SA pairs tend to be co-expressed and/or inversely expressed more frequently than expected by chance. Moreover, co-expressed and inversely expressed SA pairs exhibit a striking pattern of evolutionary conservation. These findings suggest that antisense regulation is a common and important mechanism of gene regulation in the human genome.

Animals↗
PubMed2003

African origin of polyomavirus JC and implications for prehistoric human migrations.

The presence of distinctive types of JC virus (JCV) in the main ethnic groups suggests a close coevolution with the human host. However, phylogenetic trees of JCV show a basal clade of European lineages (Types 1/4), whereas trees of human genes are coherent in placing the first split between African and non-African populations. This discrepancy places into question the effectiveness of JCV as a marker of human population history. The present study investigates the evolution of JCV using a large set of fully sequenced strains. Their relationships are first elucidated by principal coordinates analysis. It is suggested that Type 6 from West Africa could represent the ancestral type, while the peculiar phylogeny of Types 1/4 could reflect their direct origin from the ancestral lineage. Further credit to the African origin of JCV is provided by a neighbor-joining analysis based on slow-evolving sites. Sequence analysis of fast-evolving sites reveals that the deep emergence of Types 1/4 in the tree does not reflect a real evolutionary divergence; rather it is the implicit result of a remarkably different G + C content. The hypothesis that Types 1/4 originated directly from Type 6 is confirmed by examining the pattern of variation at a few specific fast-evolving sites. On the basis of this approach, a twofold exit of JCV from Africa is hypothesized: one in the direction of the Eurasian continent and another limited to Europe. These findings suggest that two distinct migrations of individuals played a key role in the peopling of Europe during prehistoric times.

Africa↗
PubMed2004

Tracking the evolution of porphobilinogen synthase metal dependence in vitro.

Metal ions are indispensable cofactors for chemical catalysis by a plethora of enzymes. Porphobilinogen synthases (PBGSs), which catalyse the second step of tetrapyrrole biosynthesis, are grouped according to their dependence on Zn(2+). Using site-directed mutagenesis, we embarked on transforming Zn(2+)-independent Pseudomonas aeruginosa PBGS into a Zn(2+)-dependent enzyme. Nine PBGS variants were generated by permutationally introducing three cysteine residues and a further two residues into the active site of the enzyme to match the homologous Zn(2+)-containing PBGS from Escherichia coli. Crystal structures of seven enzyme variants were solved to elucidate the nature of Zn(2+) coordination at high resolution. The three single-cysteine variants were invariably found to be enzymatically inactive and only one (D139C) was found to bind detectable amounts of Zn(2+). The double mutant A129C/D139C is enzymatically active and binds Zn(2+) in a tetrahedral coordination. Structurally and functionally it mimics mycobacterial PBGS, which bears an equivalent Zn(2+)-coordination site. The remaining two double mutants, without known natural equivalents, reveal strongly distorted tetrahedral Zn(2+)-binding sites. Variant A129C/D131C possesses weak PBGS activity while D131C/D139C is inactive. The triple mutant A129C/D131C/D139C, finally, displays an almost ideal tetrahedral Zn(2+)-binding geometry and a significant Zn(2+)-dependent enzymatic activity. Two additional amino acid exchanges further optimize the active site architecture towards the E.coli enzyme with an additional increase in activity. Our study delineates the potential evolutionary path between Zn(2+)-free and Zn(2+)-dependent PBGS enyzmes showing that the rigid backbone of PBGS enzymes is an ideal framework to create or eliminate metal dependence through a limited number of amino acid exchanges.

Amino Acid Sequence↗
PubMed2001

Crystal structure of E. coli beta-carbonic anhydrase, an enzyme with an unusual pH-dependent activity.

Carbonic anhydrases fall into three distinct evolutionary and structural classes: alpha, beta, and gamma. The beta-class carbonic anhydrases (beta-CAs) are widely distributed among higher plants, simple eukaryotes, eubacteria, and archaea. We have determined the crystal structure of ECCA, a beta-CA from Escherichia coli, to a resolution of 2.0 A. In agreement with the structure of the beta-CA from the chloroplast of the red alga Porphyridium purpureum, the active-site zinc in ECCA is tetrahedrally coordinated by the side chains of four conserved residues. These results confirm the observation of a unique pattern of zinc ligation in at least some beta-CAS: The absence of a water molecule in the inner coordination sphere is inconsistent with known mechanisms of CA activity. ECCA activity is highly pH-dependent in the physiological range, and its expression in yeast complements an oxygen-sensitive phenotype displayed by a beta-CA-deletion strain. The structural and biochemical characterizations of ECCA presented here and the comparisons with other beta-CA structures suggest that ECCA can adopt two distinct conformations displaying widely divergent catalytic rates.

Amino Acid Sequence↗
PubMed2002

Creating high-level components with a generative representation for body-brain evolution.

One of the main limitations of scalability in body-brain evolution systems is the representation chosen for encoding creatures. This paper defines a class of representations called generative representations, which are identified by their ability to reuse elements of the genotype in the translation to the phenotype. This paper presents an example of a generative representation for the concurrent evolution of the morphology and neural controller of simulated robots, and also introduces GENRE, an evolutionary system for evolving designs using this representation. Applying GENRE to the task of evolving robots for locomotion and comparing it against a non-generative (direct) representation shows that the generative representation system rapidly produces robots with significantly greater fitness. Analyzing these results shows that the generative representation system achieves better performance by capturing useful bias from the design space and by allowing viable large scale mutations in the phenotype. Generative representations thereby enable the encapsulation, coordination, and reuse of assemblies of parts.

Algorithms↗
PubMed1983

Type I and type II keratins have evolved from lower eukaryotes to form the epidermal intermediate filaments in mammalian skin.

We have traced the evolutionary origins of keratin-like sequences to the genomes of lower eukaryotes. The proteins encoded by these genes have evolved to form the intermediate filaments that comprise the backbone of vertebrate skin cells. Two related but distinct types of keratins encoded by two separate multigene subfamilies are expressed in the epidermal keratinocytes of vertebrate species from fish to human. Both at the level of protein and at the level of DNA, these two classes of keratins are coordinately conserved throughout vertebrate evolution, indicating the central role that both types of keratins must play in the assembly and structure of the 8-nm filament.

Animals↗
PubMed2006

Isolation of cDNAs for R2R3-MYB, bHLH and WDR transcriptional regulators and identification of c and ca mutations conferring white flowers in the Japanese morning glory.

The transcriptional regulators for anthocyanin biosynthesis include members of proteins containing an R2R3-MYB domain, a bHLH (basic helix-loop-helix) domain and conserved WD40 repeats (WDRs). Spacial and temporal expression of the structural genes encoding the enzymes for anthocyanin biosynthesis is thought to be determined by combinations of the R2R3-MYB, bHLH and WDR factors and their interactions. While the wild-type Japanese morning glory (Ipomoea nil) exhibits blue flowers with colored stems and dark-brown seeds, the c mutants display white flowers with red stems and colored seeds, and the ca mutants exhibit white flowers with green stems and ivory seeds. Here, we characterize the tissue-specific expression of three MYB genes, three bHLH genes and two WDR genes in I. nil. We also show that the recessive c-1 and ca alleles are frameshift mutations caused by a 2 bp deletion and 7 bp insertions in the genes for the R2R3-MYB and WDR transcriptional regulators designated as InMYB1 and InWDR1, respectively. In addition to defects in flower, stem and seed pigmentations, the ca mutants were found to show reduced trichome formation in seeds but to produce leaf and stem trichomes and root hairs normally. Except for the gene for chalcone synthase E in the ca mutant, all structural genes tested were coordinately reduced in both c-1 and ca mutant flower limbs. However, slight but significant expression of the genes for chalcone synthase D, chalcone isomerase and flavanone 3-hydroxylase in the pathway for flavonol biosynthesis was detectable in c-1 and ca mutants, whereas no such residual expression could be observed in other genes involved in the later anthocyanin biosynthesis pathway. The biological roles of the C-1 and Ca genes in I. nil epidermal traits and their evolutionary implications are also discussed.

Acyltransferases↗
PubMed2003

Eggshell and egg yolk proteins in fish: hepatic proteins for the next generation: oogenetic, population, and evolutionary implications of endocrine disruption.

The oocyte is the starting point for a new generation. Most of the machinery for DNA and protein synthesis needed for the developing embryo is made autonomously by the fertilized oocyte. However, in fish and in many other oviparous vertebrates, the major constituents of the egg, i.e. yolk and eggshell proteins, are synthesized in the liver and transported to the oocyte for uptake. Vitellogenesis, the process of yolk protein (vitellogenin) synthesis, transport, and uptake into the oocyte, and zonagenesis, the synthesis of eggshell zona radiata proteins, their transport and deposition by the maturing oocyte, are important aspects of oogenesis. The many molecular events involved in these processes require tight, coordinated regulation that is under strict endocrine control, with the female sex steroid hormone estradiol-17beta in a central role. The ability of many synthetic chemical compounds to mimic this estrogen can lead to unscheduled hepatic synthesis of vitellogenin and zona radiata proteins, with potentially detrimental effects to the adult, the egg, the developing embryo and, hence, to the recruitment to the fish population. This has led to the development of specific and sensitive assays for these proteins in fish, and the application of vitellogenin and zona radiata proteins as informative biomarkers for endocrine disrupting effects of chemicals and effluents using fish as test organisms. The genes encoding these important reproductive proteins are conserved in the animal kingdom and are products of several hundred million years of evolution.

Journal Article↗
PubMed2004

Detecting Traces of Prehistoric Human Migrations by Geographic Synthetic Maps of Polyomavirus JC.

The polyomavirus JC (JCV) is a double-stranded DNA virus that is ubiquitous in human populations and is excreted in urine by a large percentage of individuals (20-70%). The strong genetic stability, combined with a mechanism of transmission mainly within the family, makes JCV a good marker of human migrations. In this study, the coevolution of JCV with its human host is investigated by using over a thousand nucleotide sequences deposited in the EMBL database; they correspond to the IG region, which is the genomic region with the highest rate of variation. The pattern of genetic diversity in JCV is evaluated by the principal coordinates analysis and the construction of synthetic maps. The first principal coordinate supports the existence of two distinct virus lineages, both arising from the ancestral African type. The first synthetic map suggests a two-migration model of the human dispersal out of Africa, thus implying a more complex picture than that known from human genes. The second principal coordinate points out the distinctiveness of strains coming from Asian/Amerind populations. The picture yielded by the second synthetic map appears to be more consistent with that known from human genes. In fact, it provides evidence of a deep split of the Asian lineage of JCV into two main branches: one diffusing in Japan and Americas, the other in Southeast Asia. The view that JCV, with its peculiar feature of a dual early emergence from Africa, can provide new information about the evolutionary history of our ancestors is discussed.

Databases, Nucleic Acid↗
PubMed2005

Integration of posture and movement: contributions of Sherrington, Hess, and Bernstein.

Neural mechanisms that integrate posture with movement are widespread throughout the central nervous system (CNS), and they are recruited in patterns that are both task- and context-dependent. Scientists from several countries who were born in the 19th century provided essential groundwork for these modern-day concepts. Here, the focus is on three of this group with each selected for a somewhat different reason. Charles Sherrington (1857-1952) had innumerable contributions that were certainly needed in the subsequent study of posture and movement: inhibition as an active coordinative mechanism, the functional anatomy of spinal cord-muscle connectivity, and helping set the stage for modern work on the sensorimotor cortex and the corticospinal tract. Sadly, however, by not championing the work of his trainee and collaborator, Thomas Graham Brown (1882-1965), he delayed progress on two key motor control mechanisms: central programming and pattern generation. Walter Hess (1881-1973), a self-taught experimentalist, is now best known for his work on CNS coordination of autonomic (visceral) and emotional behavior. His contributions to posture and movement, however, were also far-reaching: the coordination of eye movements and integration of goal-directed and "framework" (anticipatory set) motor behavior. Nikolai Bernstein (1896-1966), the quintessence of an interdisciplinary, self-taught movement neuroscientist, made far-reaching contributions that were barely recognized by Western workers prior to the 1960s. Today, he is widely praised for showing that the CNS's hierarchy of control mechanisms for posture and movement is organized hand-in-hand with distributed and parallel processing, with all three subject to evolutionary pressures. He also made important observations, like those of several previous workers, on the goal focus of voluntary movements. The contributions of Sherrington, Hess, and Bernstein are enduring. They prompt thought on the philosophical axioms that appear to have driven their research, and the continual need for emphasis on interdisciplinary, comparative, and transnational approaches to advance movement neuroscience.

Affect↗
PubMed2002

Carbohydrate-induced differential gene expression patterns in the hyperthermophilic bacterium Thermotoga maritima.

The hyperthermophilic bacterium Thermotoga maritima MSB8 was grown on a variety of carbohydrates to determine the influence of carbon and energy source on differential gene expression. Despite the fact that T. maritima has been phylogenetically characterized as a primitive microorganism from an evolutionary perspective, results here suggest that it has versatile and discriminating mechanisms for regulating and effecting complex carbohydrate utilization. Growth of T. maritima on monosaccharides was found to be slower than growth on polysaccharides, although growth to cell densities of 10(8) to 10(9) cells/ml was observed on all carbohydrates tested. Differential expression of genes encoding carbohydrate-active proteins encoded in the T. maritima genome was followed using a targeted cDNA microarray in conjunction with mixed model statistical analysis. Coordinated regulation of genes responding to specific carbohydrates was noted. Although glucose generally repressed expression of all glycoside hydrolase genes, other sugars induced or repressed these genes to varying extents. Expression profiles of most endo-acting glycoside hydrolase genes correlated well with their reported biochemical properties, although exo-acting glycoside hydrolase genes displayed less specific expression patterns. Genes encoding selected putative ABC sugar transporters were found to respond to specific carbohydrates, and in some cases putative oligopeptide transporter genes were also found to respond to specific sugar substrates. Several genes encoding putative transcriptional regulators were expressed during growth on specific sugars, thus suggesting functional assignments. The transcriptional response of T. maritima to specific carbohydrate growth substrates indicated that sugar backbone- and linkage-specific regulatory networks are operational in this organism during the uptake and utilization of carbohydrate substrates. Furthermore, the wide ranging collection of such networks in T. maritima suggests that this organism is capable of adapting to a variety of growth environments containing carbohydrate growth substrates.

Carbohydrate Metabolism↗
PubMed1991

[Neuropsychiatric approach to a child with spinal muscular atrophy. A study of relational problems].

Various years' experience of an extensive series of children suffering from progressive chronic spinal muscular atrophy have made it possible to elaborate a neuropsychiatric approach model conducted on the basis of a viewpoint capable of integrating the clinico-medical aspect and aptitude to empathic listening aimed at establishing a therapeutic alliance with the patient. With advancing age and the course of the disease, in most cases very different difficulties and problems are encountered. These change continuously in relation to the stage reached in emotional development. Entry to school and socialisation mark a particular moment in the confrontation with peers and present the ill child with his diversity. With the emergence of adolescent problems, there is also a dramatic new impact between the body image of a wounded, deteriorated self and the evolutionary effort aimed at identifying with the peer group, the autonomisation of parental figures, the integration of a sexed image of the self. Room can be found in this framework for the child neuropsychiatrist who is able to offer himself as a point of reference and set himself up as a model for elaborating disease anxieties. From personal experience it also emerges that in children suffering from a chronic, often fatal disease there is often the need for a physician to coordinate and integrate needs of both a clinical and sociorelational nature for the purpose of allowing the family to get closer to the needs of their child and prevent him from falling prey to destructive type anxieties.

Child↗