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PubMed1999

Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a congenital muscular disease characterized by severe hypotonia and generalized muscle weakness, leading in most cases to early postnatal death. The gene responsible for the disease, MTM1, encodes a dual specificity phosphatase, named myotubularin, which is highly conserved throughout evolution. To date, 139 MTM1 mutations in independent patients have been reported, corresponding to 93 different mutations. In this report we describe the identification of 21 mutations (14 novel) in XLMTM patients. Seventeen mutations are associated with a severe phenotype in males, with death occurring mainly before the first year of life. However, four mutations-three missense (R241C, I225T, and novel mutation P179S) and one single-amino acid deletion (G294del)-were found in patients with a much milder phenotype. These patients, while having a severe hypotonia at birth, are still alive at the age of 4, 7, 13, and 15 years, respectively, and display mild to moderate muscle weakness.

Adolescent↗
PubMed2000

Suppression of diagonal peaks in three-dimensional protein NMR TROSY-type HCCH correlation experiments.

A novel method for suppression of (13)C-(13)C diagonal peaks without sensitivity loss in three-dimensional HCCH TROSY-type NMR correlation experiments involving aromatic side chains in proteins (Pervushin et al., J. Am. Chem. Soc. 120, 6394-6400 (1998)) is presented. The key element is a spin-state-selective filter in the (13)C-(13)C mixing sequence with the dual effect of selecting the TROSY resonance in the preceding evolution period and interchanging TROSY and anti-TROSY resonances. The cross peaks are invariant to this filter but diagonal peak coherence gets concentrated on the anti-TROSY transition so that it can be eliminated by a (13)C --> (1)H TROSY transfer element. The new method is demonstrated using a (13)C,(15)N-labeled protein sample, RAP 18-112 (N-terminal domain of alpha(2)-macroglobulin receptor associated protein), at 750 MHz.

Carbon Isotopes↗
PubMed1982

A histological and histochemical study of developing teeth in Polypterus (Pisces, Actinopterygii).

The tooth cap matrix contained proteins of ectodermal and mesodermal origin which extended the data already available on teleost teeth and showed that a combined origin for the tooth cap should be regarded as a primitive feature of actinopterygian fish. Furthermore, the dual nature of the Polypterus tooth cap matrix suggested that evolution of tetrapod enamel did not occur within the actinopterygians. The collar tissue was an unmodified dentine, in contrast to its enameloid nature in many other actinopterygian teeth. The presence of a range of developmental states from unmodified dentine to hypermineralized enameloid within Polypterus teeth themselves and also in other parts of the dermal skeleton, as well as the combined origin of the tooth cap, demonstrates that the enamel/enameloid/dentine system forms a continuum of tissues that have diverged from one another by changes in the relative timing of developmental events and matrix production.

Animals↗
PubMed2006

Metabolic complementarity and genomics of the dual bacterial symbiosis of sharpshooters.

Mutualistic intracellular symbiosis between bacteria and insects is a widespread phenomenon that has contributed to the global success of insects. The symbionts, by provisioning nutrients lacking from diets, allow various insects to occupy or dominate ecological niches that might otherwise be unavailable. One such insect is the glassy-winged sharpshooter (Homalodisca coagulata), which feeds on xylem fluid, a diet exceptionally poor in organic nutrients. Phylogenetic studies based on rRNA have shown two types of bacterial symbionts to be coevolving with sharpshooters: the gamma-proteobacterium Baumannia cicadellinicola and the Bacteroidetes species Sulcia muelleri. We report here the sequencing and analysis of the 686,192-base pair genome of B. cicadellinicola and approximately 150 kilobase pairs of the small genome of S. muelleri, both isolated from H. coagulata. Our study, which to our knowledge is the first genomic analysis of an obligate symbiosis involving multiple partners, suggests striking complementarity in the biosynthetic capabilities of the two symbionts: B. cicadellinicola devotes a substantial portion of its genome to the biosynthesis of vitamins and cofactors required by animals and lacks most amino acid biosynthetic pathways, whereas S. muelleri apparently produces most or all of the essential amino acids needed by its host. This finding, along with other results of our genome analysis, suggests the existence of metabolic codependency among the two unrelated endosymbionts and their insect host. This dual symbiosis provides a model case for studying correlated genome evolution and genome reduction involving multiple organisms in an intimate, obligate mutualistic relationship. In addition, our analysis provides insight for the first time into the differences in symbionts between insects (e.g., aphids) that feed on phloem versus those like H. coagulata that feed on xylem. Finally, the genomes of these two symbionts provide potential targets for controlling plant pathogens such as Xylella fastidiosa, a major agroeconomic problem, for which H. coagulata and other sharpshooters serve as vectors of transmission.

Amino Acids↗
PubMed1981

[Primary acute and subacute meningomyeloradiculopathies: study of the cerebrospinal fluid].

Forty four patients with primary acute and subacute meningomyeloradiculopathies were studied in respect to the evolutive aspects of the cerebrospinal fluid (CSF) cell-protein dual in several periods of the disease. The tendency of CSF hypercytosis to normal values of cell count occurred in most cases (96%) at the end of the period in which the study was performed (60 days). The CSF protein levels had a similar but slower behavior pattern when compared with hypercytosis. The comparative analysis of clinical improvement of two groups of patients (treated and not treated with ACTH or corticosteroids) showed a statistically significant difference between on the two groups favouring the former. This fact enhances the possibility that an auto-immune process plays an important role in cases of primary meningomyeloradiculopathies.

Acute Disease↗
PubMedDate not supplied

Evolution of the human foot: evidence from Plio-Pleistocene hominids.

The human foot serves a dual role during locomotion. It functions at times as a mobile structure and at times as a rigid lever. The human foot shows the hallmarks of an arboreal heritage wherein the foot was primarily a grasping organ. Over the course of the human career the human foot has evolved an elaborate plantar aponeurosis, strong plantar ligaments, longitudinal arches, an enlarged musculus flexor accessorius, an adducted (non-opposable) hallux, a remodeled calcaneocuboid joint, a long tarsus, and shortened toes (II to V). Comparisons of the chimpanzee and human foot allow us to reconstruct the pathway of foot evolution. Fossil foot bones of Homo habilis, dated at 1.76 million years, are remarkably like those of modern humans. Foot bones from Hadar, dated at around 3.5 million years, are remarkably chimpanzee-like, with only incipient human traits. The surprising chimpanzee-like qualities of the Hadar fossils strongly support the use of living apes as models of ancestral pongidhominid morphotypes.

Adaptation, Biological↗
PubMed2026

The DELAYED ABAXIAL TRICHOMES Helitron has dual functions in vegetative and pollen development in Arabidopsis thaliana.

Transposons drive genetic diversity and evolution by altering the genomic landscape over time. Here, we describe DELAYED ABAXIAL TRICHOMES (DAB), a Helitron/RC transposable element in Arabidopsis thaliana that has a role in vegetative phase change and gametogenesis. A genome-wide association study (GWAS) for the timing of abaxial trichome development (an adult leaf trait) in A. thaliana revealed a conserved haplotype of polymorphisms within DAB that delays abaxial trichome production. CRISPR-Cas9-induced deletions of DAB are gametophytic pollen-lethal, indicating that this locus is also required for pollen production. DAB produces 24-nucleotide siRNAs with sequence complementarity to genes involved in embryogenesis, gametogenesis, and seed development. DAB also impacts the expression of ARGONAUTE genes, genes involved in RNA-directed DNA methylation (RdDM), as well as genes in several key genetic pathways. This global effect on gene expression suggests that DAB may have functions beyond those identified in this study.

Arabidopsis↗
PubMed2025

The evolution of the plastid genomes in the holoparasitic Balanophoraceae.

The independent transition to a heterotrophic lifestyle in plants drove remarkably convergent evolutionary trajectories, characterized by morphological modifications and reductions in their plastomes. The characteristics of the minimum plastome required for survival, if they exist, remain a topic of debate. The holoparasitic family Balanophoraceae was initially presumed to have entirely lost their plastids, however, recent reports revealed the presence of reduced and aberrant plastids with odd genomes. Among the outstanding features of these genomes are the highest nucleotide composition bias across the tree of life and the only two genetic code changes ever recorded among plants. In this study, we assembled the plastomes from five genera, four of which had never been studied. Major common features include extremely high AT content, the lack of a typical quadripartite structure and extensive size reduction due to gene elimination and genome compaction. The family exhibits multiple gene and intron losses, and a broad range of scenarios regarding the evolution of the plastid trnE, a gene considered essential because of its dual function in tetrapyrrole biosynthesis and translation within the plastid. In addition, phylogenetic analyses suggest that the genus Scybalium is not monophyletic. An evolutionary model for the plastomes of the Balanophoraceae is proposed.

Genome, Plastid↗
PubMed1990

Vitellogenesis in reptiles as a model for mammalian sex-differentiated hepatic protein synthesis.

The stimulation of yolk protein synthesis by estrogen is a characteristic of female non-mammalian vertebrates; in mammals, or their reptilian ancestors, however, vitellogenesis has been suppressed as a corollary of the evolution of viviparity. It is our hypothesis that progesterone has a dual role in this phylogenetic trend: a) to inhibit myometrial contraction and thus set the stage for internal development of embryos and associated placentation and b) to inhibit yolk protein synthesis in a coordinate manner as placentation became an efficient direct supply of nutrients to the fetus. Despite the absence of vitellogenesis per se in eutherian mammals, significant sex-differentiated hepatic protein-lipid synthetic functions remain, which are under complex hormonal control. We have presented evidence that in the reptiles, the central vertebrate group from which the ancestors of modern mammals evolved, the control of yolk protein synthesis is also complex, involving both pituitary hormones (GH, PRL, and LH) and ovarian steroids (estradiol, testosterone, and progesterone). Adequate evidence exists to suggest that mammalian hepatic lipoprotein synthesis and its regulatory elements are phylogenetically derived from their reptilian ancestors and may be better understood in this context. This is of particular relevance to cardiovascular disease in which there is a clear sex bias yet for which no coordinated research program exists which takes into account the relevant phylogenetic history. We believe that reptilian, and possibly avian, models could be used to great advantage to probe the endocrine components of cardiovascular disease.

Animals↗
PubMed1990

Vertebrate vitellogenesis: molecular model for multihormonal control of gene regulation.

The stimulation of yolk protein synthesis by estrogen is a characteristic of female non-mammalian vertebrates; in mammals, however, vitellogenesis has been suppressed as a corollary of the evolution of viviparity. It is our hypothesis that progesterone has a dual role in this phylogenetic trend; a) to inhibit myometrial contraction and thus set the stage for internal development of embryos and associated placentation, b) to inhibit yolk protein synthesis as placentation became an efficient direct supply of nutrients to the fetus. We have presented evidence that in the reptiles, the central vertebrate group from which the ancestors of modern mammals evolved, the control of yolk protein synthesis is complex, involving both pituitary and ovarian steroids (estradiol, testosterone and progesterone). This system provides an excellent model for the multihormonal contents of gene regulation involving both + and - controls.

Animals↗
PubMed1996

The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution.

Mammalian Clk/Sty is the prototype for a family of dual specificity kinases (termed LAMMER kinases) that have been conserved in evolution, but whose physiological substrates are unknown. In a yeast two-hybrid screen, the Clk/Sty kinase specifically interacted with RNA binding proteins, particularly members of the serine/arginine-rich (SR) family of splicing factors. Clk/Sty itself has an serine/arginine-rich non-catalytic N-terminal region which is important for its association with SR splicing factors. In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Tryptic phosphopeptide mapping demonstrated that the sites on ASF/SF2 phosphorylated in vitro overlap with those phosphorylated in vivo. Immunofluorescence studies showed that a catalytically inactive form of Clk/Sty co-localized with SR proteins in nuclear speckles. Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors.

Amino Acid Sequence↗
PubMed2004

Dual role of oxidized LDL on the NF-kappaB signaling pathway.

Atherosclerosis is a slowly evolutive age-linked disease of large arteries, characterized by a local lipid deposition associated with a chronic inflammatory response, leading potentially to acute plaque rupture, thrombosis and ischemic heart disease. Atherogenesis is a complex sequence of events associating first expression of adhesion molecules, recruitment of mononuclear cells to the endothelium, local activation of leukocytes and inflammation, lipid accumulation and foam cell formation. Low density lipoproteins (LDLs) become atherogenic after undergoing oxidation by vascular cells, that transform them into highly bioreactive oxidized LDL (oxidized LDLs). Oxidized LDLs are involved in foam cell formation, and trigger proatherogenic events such as overexpression of adhesion molecules, chemoattractant agents growth factors and cytokines involved in the inflammatory process, cell proliferation and apoptosis. Moreover, this toxic effect of oxidized LDLs plays probably a role in plaque erosion/rupture and subsequent atherothrombosis. Several biological effects of oxidized LDLs are mediated through changes in the activity of transcription factors and subsequently in gene expression. Oxidized LDLs exert a biphasic effect on the redox-sensitive transcription factor NF-kappaB, which can be activated thereby up-regulating proinflammatory gene expression, such as adhesion molecules, tissue factor, scavenger receptor LOX-1. On the other hand, higher concentrations of oxidized LDLs may inhibit NF-kappaB activation triggered by inflammatory agents such as LPS, and may thereby exert an immunosuppressive effect. This review is an attempt to clarify the mechanism by which oxidized LDLs may up- or down-regulate NF-kappaB, the role of NF-kappaB activation (or inhibition), and the consequences of the oxidized LDLs-mediated NF-kappaB dysregulation and their potential involvement in atherosclerosis.

Animals↗
PubMed2000

[Clinical factors associated with bone mass loss previous cardiac transplantation].

BACKGROUND: A high prevalence of osteoporosis has been described in patients before and after cardiac transplantation. But clinical factors involved in previous bone loss in this condition are not well known. The purpose has been to study bone mineral density (BMD) in patients subject to cardiac transplantation, analyzing clinical and biochemical factors related to bone mass in these patients. PATIENTS AND METHODS: We have studied lumbar and hip BMD in 51 patients candidates to cardiac transplantation, evaluating the functional grade of the cardiopathy, time of evolution of the disease, and antropometric and biochemical markers of bone turnover. BMD was measured using a dual X ray densitometer. RESULTS: A significant decrease in bone mass at lumbar and hip sites was found in patients with regard to normal population. A high prevalence of osteoporosis was found (27.4%). Time of evolution of the disease prior to transplantation was found to be the most important predictive variable in bone loss at trabecular bone (lumbar spine). No modifications were found in blood routine parameters, mineral studies and in serum intact PTH. Resorption bone markers were increased and formation markers were normal, suggesting a elevated turnover osteoporosis. Patients with osteoporosis had less BMI that patients without, indicating a protective effect of body mass. Patients with osteoporosis also had a greater time of evolution of the disease. CONCLUSIONS: There is a decreased bone mass in lumbar spine and hip and a higher prevalence of osteoporosis in patients with cardiac failure before cardiac transplantation. Time of waiting for cardiac transplantation has been an important factor found in the development of metabolic bone disease in these patients.

Adult↗
PubMed2006

Evolution of the mammary gland from the innate immune system?

The mammary gland is a skin gland unique to the class Mammalia. Despite a growing molecular and histological understanding of the development and physiology of the mammary gland, its functional and morphological origins have remained speculative. Numerous theories on the origin of the mammary gland and lactation exist. The purpose of the mammary gland is to provide the newborn with copious amounts of milk, a unique body fluid that has a dual role of nutrition and immunological protection. Interestingly, antimicrobial enzymes, such as xanthine oxidoreductase or lysozyme, are directly involved in the evolution of the nutritional aspect of milk. We outline that xanthine oxidoreductase evolved a dual role in the mammary gland and hence provide new evidence supporting the hypothesis that the nutritional function of the milk evolved subsequent to its protective function. Therefore, we postulate that the mammary gland evolved from the innate immune system. In addition, we suggest that lactation partly evolved as an inflammatory response to tissue damage and infection, and discuss the observation that the two signaling pathways, NF-kB and Jak/Stat, play central roles in inflammation as well as in lactation.

Animals↗
PubMed2002

Characterization of homoisocitrate dehydrogenase involved in lysine biosynthesis of an extremely thermophilic bacterium, Thermus thermophilus HB27, and evolutionary implication of beta-decarboxylating dehydrogenase.

Although the presence of an enzyme that catalyzes beta-decarboxylating dehydrogenation of homoisocitrate to synthesize 2-oxoadipate has been postulated in the lysine biosynthesis pathway through alpha-aminoadipate (AAA), the enzyme has not yet been analyzed at all, because no gene encoding the enzyme has been identified until recently. A gene encoding a protein with a significant amino acid sequence identity to both isocitrate dehydrogenase and 3-isopropylmalate dehydrogenase was cloned from Thermus thermophilus HB27. The gene product produced in recombinant Escherichia coli cells demonstrated homoisocitrate dehydrogenase (HICDH) activity. A knockout mutant of the gene showed an AAA-auxotrophic phenotype, indicating that the gene product is involved in lysine biosynthesis through AAA. We therefore named this gene hicdh. HICDH, the gene product, did not catalyze the conversion of 3-isopropylmalate to 2-oxoisocaproate, a leucine biosynthetic reaction, but it did recognize isocitrate, a related compound in the tricarboxylic acid cycle, as well as homoisocitrate as a substrate. It is of interest that HICDH catalyzes the reaction with isocitrate about 20 times more efficiently than the reaction with the putative native substrate, homoisocitrate. The broad specificity and possible dual function suggest that this enzyme represents a key link in the evolution of the pathways utilizing citrate derivatives. Site-directed mutagenesis study reveals that replacement of Arg(85) with Val in HICDH causes complete loss of activity with isocitrate but significant activity with 3-isopropylmalate and retains activity with homoisocitrate. These results indicate that Arg(85) is a key residue for both substrate specificity and evolution of beta-decarboxylating dehydrogenases.

Alcohol Oxidoreductases↗
PubMed2000

Tol1, a fission yeast phosphomonoesterase, is an in vivo target of lithium, and its deletion leads to sulfite auxotrophy.

Lithium is the drug of choice for the treatment of bipolar affective disorder. The identification of an in vivo target of lithium in fission yeast as a model organism may help in the understanding of lithium therapy. For this purpose, we have isolated genes whose overexpression improved cell growth under high LiCl concentrations. Overexpression of tol1(+), one of the isolated genes, increased the tolerance of wild-type yeast cells for LiCl but not for NaCl. tol1(+) encodes a member of the lithium-sensitive phosphomonoesterase protein family, and it exerts dual enzymatic activities, 3'(2'),5'-bisphosphate nucleotidase and inositol polyphosphate 1-phosphatase. tol1(+) gene-disrupted cells required high concentrations of sulfite in the medium for growth. Consistently, sulfite repressed the sulfate assimilation pathway in fission yeast. However, tol1(+) gene-disrupted cells could not fully recover from their growth defect and abnormal morphology even when the medium was supplemented with sulfite, suggesting the possible implication of inositol polyphosphate 1-phosphatase activity for cell growth and morphology. Given the remarkable functional conservation of the lithium-sensitive dual-specificity phosphomonoesterase between fission yeast and higher-eukaryotic cells during evolution, it may represent a likely in vivo target of lithium action across many species.

Amino Acid Sequence↗