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PubMed2000

[Principles of construction in the fore- and hindpaw of the domestic cat (Felis catus). 2. Articulations].

According to form and range of mobility the joints of the cat's paw (articulationes manus et pedis) are adjusted to two basic functions: as far as they are used for walking in the different gaits they show components in the sagittal plane that particularly correspond to the digitigrade dog. With regard to cat-specific behaviour, i.e. climbing and catching, specific characteristics of the joints for movements in the R-plane (rotation) and A-plane (abduction/adduction) can be distinguished. For this reason highly specialized types of articulations occur in cat's paw that are unique compared to other mammals and that mostly have not been described yet. In this context, like in the skeleton (see first communication), function-adapted divergences can also be found between the joints of the forepaw and hindpaw of the cat.

Animals↗
PubMed2005

Regional brain activation during proximal stomach distention in humans: A positron emission tomography study.

BACKGROUND & AIMS: Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans. METHODS: Positron emission tomography of the brain was performed in 11 healthy volunteers during 4 conditions: (1) no distention and isobaric distention to the individual thresholds for (2) first, (3) marked, and (4) unpleasant sensation. Data were analyzed using statistical parametric mapping. RESULTS: During maximal distention relative to baseline, significant (P corrected <.05) regional brain activation occurred in the left and right gyrus postcentralis (Brodmann area [BA] 43), the left gyrus temporalis superior (BA 38), the right gyrus frontalis inferior (BA 47, orbitofrontal cortex), the right midanterior cingulate gyrus (BA 24), the right anterior insula, and the left cerebellar hemisphere. These areas showed a progressive increase in activation with increasing intensity of the distending stimulus. CONCLUSIONS: We found evidence for a neuronal network processing distention stimuli of the proximal stomach that is overall consistent with the "visceral stimulation network" described in the literature. In addition, we found activation of the orbitofrontal cortex, confirming its role as a convergence zone for processing of food-related stimuli and regulation of hunger, appetite, satiety, and food intake. We found no evidence for a functional neuroanatomic divergence in the processing of noxious and innocuous gastric stimuli.

Abdomen↗
PubMed2006

Tdrd1/Mtr-1, a tudor-related gene, is essential for male germ-cell differentiation and nuage/germinal granule formation in mice.

Embryonic patterning and germ-cell specification in mice are regulative and depend on zygotic gene activities. However, there are mouse homologues of Drosophila maternal effect genes, including vasa and tudor, that function in posterior and germ-cell determination. We report here that a targeted mutation in Tudor domain containing 1/mouse tudor repeat 1 (Tdrd1/Mtr-1), a tudor-related gene in mice, leads to male sterility because of postnatal spermatogenic defects. TDRD1/MTR-1 predominantly localizes to nuage/germinal granules, an evolutionarily conserved structure in the germ line, and its intracellular localization is downstream of mouse vasa homologue/DEAD box polypeptide 4 (Mvh/Ddx4), similar to Drosophila vasa-tudor. Tdrd1/Mtr-1 mutants lack, and Mvh/Ddx4 mutants show, strong reduction of intermitochondrial cement, a form of nuage in both male and female germ cells, whereas chromatoid bodies, another specialized form of nuage in spermatogenic cells, are observed in Tdrd1/Mtr-1 mutants. Hence, intermitochondrial cement is not a direct prerequisite for oocyte development and fertility in mice, indicating differing requirements for nuage and/or its components between male and female germ cells. The result also proposes that chromatoid bodies likely have an origin independent of or additional to intermitochondrial cement. The analogy between Mvh-Tdrd1 in mouse spermatogenic cells and vasa-tudor in Drosophila oocytes suggests that this molecular pathway retains an essential role(s) that functions in divergent species and in different stages/sexes of the germ line.

Animals↗
PubMed2001

Perforin-low memory CD8+ cells are the predominant T cells in normal humans that synthesize the beta -chemokine macrophage inflammatory protein-1beta.

The synthesis of antiviral beta-chemokines has joined cytolysis as a potential mechanism for the control of HIV-1 infection by CD8(+) T cells. Recent evidence suggests that these two effector functions can diverge in some individuals infected with HIV-1; however, little is known about the CD8(+) T cell subsets in normal individuals that synthesize antiviral beta-chemokines. In this report, we have used mutliparameter flow cytometry to characterize the T cell subsets that secrete the antiviral beta-chemokine macrophage inflammatory protein (MIP)-1beta. These studies have shown: (i) CD8(+) cells are the predominant T cell subset that synthesizes MIP-1beta; (ii) MIP-1beta and IFN-gamma are synthesized congruently in most CD8(+) T cells; however, significant numbers of these cells synthesize only one of these effector molecules; (iii) approximately 60% of the CD8(+) T cells that synthesize MIP-1beta lack perforin; (iv) MIP-1beta is synthesized with approximately equal frequency by CD28(+) and CD28(-) subpopulations of CD8(+) T cells; (v) MIP-1beta is synthesized by three distinct CD8(+) T cell subsets defined by the expression of CD45R0 and CD62L; and (vi) MIP-1beta is not synthesized in short-term cultures of naive CD8(+) T cells. These results demonstrate substantial subset heterogeneity of MIP-1beta synthesis among CD8(+) T cells and suggest that these subsets should be evaluated as correlates of protective immunity against HIV-1.

CD28 Antigens↗
PubMed2003

Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis.

In mammals, the continuous production of hematopoietic cells (HCs) is sustained by a small number of hematopoietic stem cells (HSCs) residing in the bone marrow. Early HSC activity arises in the aorta-gonad mesonephros region, within cells localized to the ventral floor of the major blood vessels, suggesting that the first HSCs may be derived from cells capable of giving rise to the hematopoietic system and to the endothelial cells of the vasculature. TIE1 (TIE) and TIE2 (TEK) are related receptor tyrosine kinases with an embryonic expression pattern in endothelial cells, their precursors, and HCs, suggestive of a role in the divergence and function of both lineages. Indeed, gene targeting approaches have shown that TIE1, TIE2, and ligands for TIE2, the angiopoietins, are essential for vascular development and maintenance. To explore possible roles for these receptors in HCs, we have examined the ability of embryonic cells lacking both TIE1 and TIE2 to contribute to developmental and adult hematopoiesis by generating chimeric animals between normal embryonic cells and cells lacking these receptors. We show here that TIE receptors are not required for differentiation and proliferation of definitive hematopoietic lineages in the embryo and fetus; surprisingly, however, these receptors are specifically required during postnatal bone marrow hematopoiesis.

Aging↗
PubMed1990

Primary structure of keratinocyte transglutaminase.

The nucleotide and deduced amino acid sequences of the coding regions of human and rat keratinocyte transglutaminases (protein-glutamine: amine gamma-glutamyltransferase; EC 2.3.2.13) have been determined. These yield proteins of approximately 90 kDa that are 92% identical, indicative of the conservation of important structural features. Alignments of amino acid sequences show substantial similarity among the keratinocyte transglutaminase, human clotting factor XIII catalytic subunit, guinea pig liver tissue transglutaminase, and the human erythrocyte band-4.2 protein. The keratinocyte enzyme is most similar to factor XIII, whereas the band-4.2 protein is most similar to the tissue transglutaminase. A salient feature of the keratinocyte transglutaminase is its 105-residue extension beyond the N terminus of the tissue transglutaminase. This extension and the unrelated activation peptide of factor XIII (a 37-residue extension) appear to be added for specialized functions after divergence of the tissue transglutaminase from their common lineage.

Amino Acid Sequence↗
PubMed1993

Variant-specific surface proteins of Giardia lamblia are zinc-binding proteins.

Giardia lamblia undergoes surface antigenic variation. The variant-specific surface proteins (VSPs) are a distinct family of cysteine-rich proteins. Characteristically, cysteine residues occur mostly as CXXC tetrapeptides. Four of the reported five VSPs contain a putative metal-binding domain that resembles other metal-binding motifs; the fifth is closely related but lacks an essential histidine. Three different native VSPs bound Zn2+. Co2+, Cu2+, and Cd2+ inhibited Zn2+ binding. Analysis of recombinant VSP fusion proteins showed that the putative binding motif bound Zn2+. Surprisingly, peptide fragments from other regions of the VSP contain numerous CXXCXnCXXC motifs that also bound Zn2+. Analysis of deduced amino acid sequences showed well-conserved CXXC spacing in three out of five VSPs, suggesting conservation of structure despite amino acid sequence divergence. The function of VSPs is unknown, but by binding Zn2+ or other metals in the intestine, VSPs may contribute to Zn2+ malnutrition or inhibition of metal-dependent intestinal enzymes, which would lead to malabsorption, a well-known consequence of giardiasis.

Amino Acid Sequence↗
PubMed1998

Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family.

p38 mitogen-activated protein (MAP) kinase activities were significantly increased in mouse hearts after chronic transverse aortic constriction, coincident with the onset of ventricular hypertrophy. Infection of cardiomyocytes with adenoviral vectors expressing upstream activators for the p38 kinases, activated mutants of MAP kinase kinase 3b(E) (MKK3bE) and MAP kinase kinase 6b(E) (MKK6bE), elicited characteristic hypertrophic responses, including an increase in cell size, enhanced sarcomeric organization, and elevated atrial natriuretic factor expression. Overexpression of the activated MKK3bE in cardiomyocytes also led to an increase in apoptosis. The hypertrophic response was enhanced by co-infection of an adenoviral vector expressing wild type p38 beta, and was suppressed by the p38 beta dominant negative mutant. In contrast, the MKK3bE-induced cell death was increased by co-infection of an adenovirus expressing wild type p38 alpha, and was suppressed by the dominant negative p38 alpha mutant. This provides the first evidence in any cell system for divergent physiological functions for different members of the p38 MAP kinase family. The direct involvement of p38 pathways in cardiac hypertrophy and apoptosis suggests a significant role for p38 signaling in the pathophysiology of heart failure.

Adenoviridae↗
PubMed1999

Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines.

Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and all-trans-retinoic acid (trans-RA) are potent regulators of growth of cancer cells. In this study, we investigated the effect of TPA and trans-RA alone or their combination on proliferation of human breast cancer ZR75-1 and T47D and lung cancer H460 and H292 cell lines. trans-RA caused various degrees of growth inhibition of these cell lines. However, TPA showed inhibition of proliferation of H460 and H292 cells and induction of ZR75-1 cell growth. Although trans-RA did not significantly regulate the growth inhibitory effect of TPA, it completely prevented its growth stimulating function. The divergent effects of TPA were associated with specific disruption of cell cycle events, an induction of G(0)/G(1) arrest in H460 and H292 cells and inhibition of G(0)/G(1) arrest with increase of S phase in ZR75-1 cells. Induction of G(0)/G(1) arrest was accompanied by induction of p21(WAF1) and ERK activity, whereas inhibition of G(0)/G(1) arrest was associated with enhanced activity of JNK and AP-1 but not ERK. trans-RA did not affect TPA-induced p21(WAF1) expression. However, it inhibited TPA-induced AP-1 activity in ZR75-1 cells and the constitutive AP-1 activity in H460 and H292 cells. Thus, trans-RA modulates TPA activity through its interaction through TPA-induced JNK/AP-1 pathway but not TPA-induced ERK/p21(WAF1) pathway.

Breast Neoplasms↗
PubMed1999

Identification and functional characterization of two highly divergent aryl hydrocarbon receptors (AHR1 and AHR2) in the teleost Fundulus heteroclitus. Evidence for a novel subfamily of ligand-binding basic helix loop helix-Per-ARNT-Sim (bHLH-PAS) factors.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor through which 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds cause altered gene expression and toxicity. The AHR belongs to an emerging multigene family of transcription factors possessing basic helix loop helix (bHLH) and Per-ARNT-Sim (PAS) domains. Most bHLH-PAS proteins occur as duplicates or "paralog groups" in mammals, but only a single mammalian AHR has been identified. Here we report the cDNA cloning of two distinct AHRs, designated FhAHR1 and FhAHR2, from a single vertebrate species, the teleost Fundulus heteroclitus (Atlantic killifish). Both Fundulus AHR proteins possess bHLH and PAS domains that are closely related to those of the mammalian AHR. FhAHR1 and FhAHR2 are highly divergent (40% overall amino acid identity; 61% identity in the N-terminal half), suggesting that they arose from a gene duplication predating the divergence of mammals and fish. Photoaffinity labeling with 2-azido-3-[(125)I]iodo-7, 8-dibromodibenzo-p-dioxin and velocity sedimentation analysis using 2,3,7,8-[1,6-(3)H]TCDD showed that both FhAHR1 and FhAHR2 exhibit specific, high-affinity binding of dioxins. Both AHRs also showed specific, TCDD- and ARNT-dependent interactions with a mammalian xenobiotic response element. The two Fundulus AHR genes displayed different tissue-specific patterns of expression; FhAHR1 transcripts were primarily expressed in brain, heart, ovary, and testis, while FhAHR2 transcripts were equally abundant in many tissues. Phylogenetic analysis demonstrated that Fundulus AHR1 is an ortholog of mammalian AHRs, while AHR2 forms in Fundulus and other fish are paralogous to Fundulus AHR1 and the mammalian AHRs and thus represent a novel vertebrate subfamily of ligand-binding AHRs.

Amino Acid Sequence↗
PubMed2001

Sturgeon orphanin, a molecular "fossil" that bridges the gap between the opioids and orphanin FQ/nociceptin.

The elucidation of the cDNA sequence for sturgeon proorphanin provides a unique window for interpreting the evolutionary history of the opioid/orphanin gene family. The molecular "fossil" status of this precursor can be seen in several ancestral sequence characteristics that point to its origin as a duplication of either a prodynorphin- or proenkephalin-like gene. The sturgeon proorphanin cDNA encodes a precursor protein of 194 residues, and the orphanin heptadecapeptide itself binds not only the opioid receptor-like 1 (ORL1) receptor but also the classical (mu, kappa, and delta) opioid receptors with near equal affinity. Allowing for this broad receptor specificity are several amino acid substitutions at key positions in the heptadecapeptide sequence, relative to its mammalian orthologs, that have been linked by amino acid scans and site-directed mutagenic studies to the exclusion of mammalian orphanin FQ/nociceptin from classic opioid ligands (i.e. F1Y and L14W). The unique receptor binding profile of sturgeon orphanin not only provides insight into the evolutionary history of the opioid and opioid-related peptides but also provides an ideal context in which to investigate the underlying mechanisms by which novel and often divergent physiological functions arise in receptor-ligand systems.

Amino Acid Sequence↗
PubMed1998

Functional redundancy of the nuclear factor kappa B inhibitors I kappa B alpha and I kappa B beta.

The transcription factor NF-kappaB is sequestered in the cytoplasm by the inhibitor proteins of the IkappaB family. Each member of the IkappaB exhibits structural and biochemical similarities as well as differences. In an effort to address the functional redundancy of two closely related IkappaB molecules, IkappaBalpha and IkappaBbeta, we generated knock-in mice by replacing the IkappaBalpha gene with the IkappaBbeta gene. The knock-in mice do not express IkappaBalpha, but express a T7-tagged IkappaBbeta under the promoter and regulatory sequence of ikba. Unlike the IkappaBalpha-deficient mice, which display severe postnatal developmental defects and die by postnatal day 8, homozygous knock-in mice survive to adulthood, are fertile, and exhibit no apparent abnormalities. Furthermore, thymocytes and embryonic fibroblasts from the knock-in animals exhibit an inducible NF-kappaB response similar to that of wild-type animals. These results indicate that IkappaBalpha and IkappaBbeta share significant similarities in their biochemical activity, and that they acquired their different functions from divergent expression patterns during evolution.

Animals↗
PubMed1996

The small GTP-binding proteins, Rac and Rho, regulate cytoskeletal organization and exocytosis in mast cells by parallel pathways.

In mast cells, activation of GTP-binding proteins induces centripetal reorganization of actin filaments. This effect is due to disassembly, relocalization, and polymerization of F-actin and is dependent on two small GTPases, Rac and Rho. Activities of Rac and Rho are also essential for the secretory function of mast cells. In response to GTP-gamma-S and/or calcium, only a proportion of permeabilized mast cells is capable of secretory response. Here, we have compared actin organization of secreting and nonsecreting cell populations. We show that the cytoskeletal and secretory responses are strongly correlated, indicating a common upstream regulator of the two functions. The secreting cell population preferentially displays both relocalization and polymerization of actin. However, when actin relocalization or polymerization is inhibited by phalloidin or cytochalasin, respectively, secretion is unaffected. Moreover, the ability of the constitutively active mutants of Rac and Rho to enhance secretion is also unaffected in the presence of cytochalasin. Therefore, Rac and Rho control these two functions by divergent, parallel signaling pathways. Cortical actin disassembly occurs in both secreting and nonsecreting populations and does not, by itself, induce exocytosis. A model for the control of exocytosis is proposed that includes at least four GTP-binding proteins and suggests the presence of both shared and divergent signaling pathways from Rac and Rho.

Actins↗
PubMed1995

A generalized least-squares estimate for the origin of sporophytic self-incompatibility.

Analysis of nucleotide sequences that regulate the expression of self-incompatibility in flowering plants affords a direct means of examining classical hypotheses for the origin and evolution of this major feature of mating systems. Departing from the classical view of monophyly of all forms of self-incompatibility, the current paradigm for the origin of self-incompatibility postulates multiple episodes of recruitment and modification of preexisting genes. In Brassica, the S locus, which regulates sporophytic self-incompatibility, shows homology to a multigene family present both in self-compatible congeners and in groups for which this form of self-incompatibility is atypical. A phylogenetic analysis of S-allele sequences together with homologous sequences that do not cosegregate with self-incompatibility permits dating the change of function that marked the origin of self-incompatibility. A generalized least-squares method is introduced that provides closed-form expressions for estimates and standard errors for function-specific divergence rates and times of divergence among sequences. This analysis suggests that the age of the sporophytic self-incompatibility system expressed in Brassica exceeds species divergence within the genus by four- to fivefold. The extraordinarily high levels of sequence diversity exhibited by S alleles appears to reflect their ancient derivation, with the alternative hypothesis of hypermutability rejected by the analysis.

Alleles↗
PubMed1992

Interaction of lactoferrin and lipopolysaccharide (LPS): effects on the antioxidant property of lactoferrin and the ability of LPS to prime human neutrophils for enhanced superoxide formation.

Lactoferrin is a 77-kDa iron-binding protein to which a wide variety of divergent biologic functions have been ascribed. It has recently been reported that lactoferrin interacts with bacterial lipopolysaccharide (LPS) in such a fashion as to affect the binding of lactoferrin to myeloid cells. Two other potential interactions of LPS and lactoferrin were explored. Lactoferrin prevents hydroxyl radical formation by binding iron, even at low pH. Lactoferrin inhibited iron-catalyzed formation of hydroxyl radical in the presence of LPS at pH 7.4 and 4.5. Low concentrations of LPS can be used to "prime" neutrophils toward enhanced function, such as formation of stimulated superoxide anion. Lactoferrin inhibited LPS priming of neutrophils if LPS contamination of the protein (provided by commercial suppliers) was first reduced. Inhibition of LPS priming was observed whether apolactoferrin or iron-saturated lactoferrin was used. Similar inhibition of LPS priming was observed when neutrophils were incubated with other serum proteins (e.g., albumin, apotransferrin, or iron-saturated transferrin). These results show that LPS should not be expected to affect the free radical biology of lactoferrin, which is a crucial physiologic function of this protein. However, lactoferrin inhibits LPS priming, and this effect requires consideration in experimental models of inflammation.

Apoproteins↗
PubMed1998

Evolutionary distances for protein-coding sequences: modeling site-specific residue frequencies.

Estimation of evolutionary distances from coding sequences must take into account protein-level selection to avoid relative underestimation of longer evolutionary distances. Current modeling of selection via site-to-site rate heterogeneity generally neglects another aspect of selection, namely position-specific amino acid frequencies. These frequencies determine the maximum dissimilarity expected for highly diverged but functionally and structurally conserved sequences, and hence are crucial for estimating long distances. We introduce a codon-level model of coding sequence evolution in which position-specific amino acid frequencies are free parameters. In our implementation, these are estimated from an alignment using methods described previously. We use simulations to demonstrate the importance and feasibility of modeling such behavior; our model produces linear distance estimates over a wide range of distances, while several alternative models underestimate long distances relative to short distances. Site-to-site differences in rates, as well as synonymous/nonsynonymous and first/second/third-codon-position differences, arise as a natural consequence of the site-to-site differences in amino acid frequencies.

Amino Acids↗
PubMed1991

Evolution of messenger RNA structure and regulation in the genus Mus: the androgen-inducible RP2 mRNAs.

The RP2 gene is one of several genes that are regulated by androgens in the mouse kidney. Previous studies have demonstrated that androgen inducibility of RP2 transcription varies among species within the genus Mus, indicating extensive evolutionary modification of the participating regulatory elements. Thus, while a five-fold induction of transcription occurs in M. domesticus, none is detectable in M. hortulanus or M. caroli. In the present paper, we have sequenced cDNAs representing the RP2 mRNAs of M. caroli and M. saxicola and have compared them with each other and with M. domesticus. Several findings from the sequence comparisons indicate that the encoded 41-kD polypeptide is physiologically functional. First, divergence within noncoding regions of the mRNAs exceeds that within coding regions. Second, the 357-codon open reading frame has been maintained among the species, with approximately 90% of the amino acid replacements being conservative. Finally, substitution rates at synonymous sites within the coding regions are from twofold to threefold greater than those at nonsynonymous sites. The genetic elements responsible for variations in RP2 inducibility among species were studied by cis/trans analyses of mice heterozygous for RP2 alleles, using a primer extension assay to measure expression of species-specific mRNAs. The results show that the absence of transcriptional induction in M. hortulanus is due to a cis-acting genetic element, while that in M. caroli is due to a trans-acting element. Thus, the androgen-resistant RP2 phenotypes of these two species derive from distinct genetic events.

Animals↗