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PubMed2005

Phylogeography of Barbary macaques (Macaca sylvanus) and the origin of the Gibraltar colony.

The Barbary macaque (Macaca sylvanus) is the earliest offshoot of the genus Macaca and the only extant African representative, all other species being Asiatic. Once distributed throughout North Africa, M. sylvanus is now restricted to isolated forest fragments in Algeria and Morocco. The species is threatened; the maximum total wild population size is estimated at 10,000 individuals. Relationships among surviving wild subpopulations in Algeria (96 samples) and Morocco (116 samples) were examined by using 468-bp sequences from hypervariable region I of the mitochondrial DNA control region. Twenty-four different haplotypes were identified, differing by 1-26 mutational steps (0.2-5.6%) and 1 insertion. With one exception (attributable to secondary introduction in coastal Morocco), Algerian and Moroccan haplotypes are clearly distinct. However, whereas Moroccan subpopulations show little divergence in hypervariable region I sequences and little correspondence with geographical distribution, there is a deep division between two main subpopulations in Algeria and one marked secondary division, with haplotypes generally matching geographical distribution. Accepting an origin of the genus Macaca of 5.5 million years ago, the Moroccan population and the two main Algerian subpopulations diverged approximately 1.6 million years ago. Distinction between Moroccan and Algerian haplotypes permitted analysis of the origin of the Gibraltar colony of Barbary macaques (68 samples; 30% of the population). It is generally held that the present Gibraltar population descended from a dozen individuals imported during World War II. However, the Gibraltar sample was found to include Algerian and Moroccan haplotypes separated by at least 16 mutational steps, revealing a dual origin of the founding females.

Algeria↗
PubMed2002

Integrin alpha(v)beta3 targeted therapy for Kaposi's sarcoma with an in vitro evolved antibody.

Here, we define integrin alpha(v)beta3 as a molecular target for antibody therapy for Kaposi's sarcoma (KS). We previously reported, using a new phage display strategy based on designed combinatorial V gene libraries, the humanization of mouse monoclonal antibody LM609 directed to human integrin alpha(v)beta3. In the present study, we describe the in vitro affinity maturation of humanized LM609 by using a phage display strategy for the sequential and parallel optimization of three complementarity determining regions of the antibody molecule. The evolved Fab had an affinity of 150 pM and was converted into IgG1 by use of a new mammalian expression vector. The resulting whole antibody, designated JC-7U IgG1, was found to selectively target human KS in a nude mouse model and inhibit tumor growth at a therapeutically relevant dose. Because of its high affinity and its high degree of humanization, JC-7U IgG1 is an excellent drug candidate for therapeutic applications that involve integrin alpha(v)beta3 as the molecular target. Of particular interest is therapy for KS, breast cancer, melanoma, and other cancers in which integrin alpha(v)beta3 is expressed on both angiogenic endothelial cells and tumor cells, which would allow a dual antiangiogenic and antitumor strike with a single drug.

Animals↗
PubMed2005

Methods for obtaining and analyzing whole chloroplast genome sequences.

During the past decade, there has been a rapid increase in our understanding of plastid genome organization and evolution due to the availability of many new completely sequenced genomes. There are 45 complete genomes published and ongoing projects are likely to increase this sampling to nearly 200 genomes during the next 5 years. Several groups of researchers including ours have been developing new techniques for gathering and analyzing entire plastid genome sequences and details of these developments are summarized in this chapter. The most important developments that enhance our ability to generate whole chloroplast genome sequences involve the generation of pure fractions of chloroplast genomes by whole genome amplification using rolling circle amplification, cloning genomes into Fosmid or bacterial artificial chromosome (BAC) vectors, and the development of an organellar annotation program (Dual Organellar GenoMe Annotator [DOGMA]). In addition to providing details of these methods, we provide an overview of methods for analyzing complete plastid genome sequences for repeats and gene content, as well as approaches for using gene order and sequence data for phylogeny reconstruction. This explosive increase in the number of sequenced plastid genomes and improved computational tools will provide many insights into the evolution of these genomes and much new data for assessing relationships at deep nodes in plants and other photosynthetic organisms.

Amino Acid Sequence↗
PubMed2005

Regenerative capacity and the developing immune system.

Many components of the vertebrate immune system have evolved with dual, interrelated functions of both protecting injured tissues from infection and providing for tissue maintenance and repair of injuries. The capacity for organ regeneration, prominent among invertebrates and certain phylogenically primitive vertebrates, is poorly developed in mammals. We have proposed that evolution of the mammalian immune system has produced inflammatory cellular interactions at sites of injury which have optimized tissue defense and facilitated tissue repair, but that these improvements included concomitant loss of regenerative capacity. This chapter briefly reviews work in two regenerating systems: scar-free repair of fetal mammalian skin and regeneration of amputated limbs in larval frogs. In both organs the potential to regenerate anatomically and functionally complete new structures is lost gradually during ontogeny and this loss coincides with development of an immune system producing an inflammatory response in injured tissues. Failure of organ regeneration has long been associated with scarring or fibrosis and this phenomenon is a direct result of inflammatory interactions of immune cells and fibroblasts at sites of injury. Several aspects of immunity related to repair are reviewed, including the importance of antigen-presenting cells and lymphocytes, relevant cytokines and growth factors released by these and other cells, immune functions of extracellular matrix components, and immunological functions of fibroblasts. Skin repair in various transgenic mouse models has been especially informative. Further study of immune mechanisms associated with the loss of regenerative capacity in the skin and amphibian limb will be useful for efforts to promote mammalian organ regeneration.

Animals↗
PubMed2004

The three Es of cancer immunoediting.

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

Animals↗
PubMedDate not supplied

[The growth hormone axis and insulin-like growth factors].

INTRODUCTION: Growth is regulated by the interaction of environmental signals with endogenous neuroendocrine responses to the genetic programs that determine the body plan. The insulin-like growth factors (IGFs) are integral components of multiple systems controlling both growth and metabolism. THE IGF SYSTEM: The IGF system is thouht to be more complex than other endocrine systems, as genes for six IGF-binding proteins (IGFBPs) have been identified so far. The IGFs play a critical role in both cell cycle control and apoptosis, two functions involved in regulation of tumorigenesis. Insulin-like growth factor-I (IGF-I) is essential for normal growth. Confirmation of the significance of IGF-I in human physiology was obtained by the discovery of a patient with intrauterine growth retardation and postnatal growth failure associated with a mutation in the IGF-I gene. STAGES OF EVOLUTION OF THE SOMATOMEDIN HYPOTHESIS: The original somatomedin hypothesis postulated that somatic growth was regulated by growth hormone's (GH's) stimulation of hepatic IGF-I production, with IGF-I acting in an endocrine fashion to promote growth. The dual effector theory proposed an alternative view, involving direct effects by GH on peripheral tissues not mediated by IGF-I and GH-stimulated local IGF-I production for autocrine/paracrine action. It is now clear that GH stimulates the formation of ternary IGF binding complex, which stabilizes IGF-I in the serum.

Animals↗
PubMed1997

Rational approach to limiting emergence of antimicrobial drug resistance.

Microbial resistance to the available antimicrobial agents continues to be a major problem with regard to nosocomial and community acquired pathogens. The development of resistance to commonly used antimicrobials is of particular concern when it occurs in pathogenic organisms that cause invasive disease. This has implications on morbidity and mortality of infectious diseases, and will also result in escalated costs of care due to the use of alternative antimicrobials which are often more costly. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressure of antimicrobial use and societal factors that enhance the transmission of drug resistant organisms. The emergence of antibiotic resistant bacteria has generally correlated with the rise and fall of specific antibiotic use in clinical practice. Although the discovery of a new drug temporarily confers therapeutic superiority over bacterial pathogens, the subsequent rapid evolution of resistance limits the duration of the effectiveness of specific agents against pathogens. Surveillance and the development of drug policies that encourage judicious use of antimicrobials will help to minimise the spread of resistant infections. This paper reviews how this dual strategy may be used to control antimicrobial resistance.

Bacterial Infections↗
PubMed1999

Evolution of lumbar bone mineral content during adolescence and adulthood: a longitudinal study in 395 healthy females 10-24 years of age and 206 premenopausal women.

In a longitudinal study of 395 normal 10- to 24-year-old female volunteers, 105 of whom were initially premenarcheal, lumbar bone mineral density (BMD) and content (BMC) were measured by dual-energy X-ray absorptiometry (DXA) at inclusion and after a 2-year interval. The mean age of menarche was 13.1 +/- 1.1 years (n = 395). In a multiple regression analysis the BMD and BMC relative gains were highly correlated with the height and weight relative gains and with the time since menarche (r = 0.91 and r = 0.93, respectively). The mean relative annual increments in body height, in L2-4 vertebral height, in BMD and in BMC peaked respectively at 1.5, 1.0, 0.6 and 0.7 years before menarche. The four perimenarcheal years, beginning with the first pubertal clinical signs, are essential for bone acquisition, since 46.7% of adult BMC is acquired during this period. Two years after menarche, BMC is 85% of the adult value. Seven years after menarche no further significant variation in BMC is observed. In 206 menstruating women 27-47 years old, a DXA lumbar measurement was also performed after a 4-year interval. There was a small but significant increase of 0.3%/year in BMD and 0.7%/year in BMC, contrasting with the results in the young population. This could be explained by a volumetric expansion with aging, which is supported by a small increase in L2-4 area (0.4%/year). In conclusion, this longitudinal study on the lumbar site emphasizes the importance of the pre- and perimenarcheal period, when half of lumbar adult BMC is acquired. This suggests that greater attention must be paid to this period regarding nutrition and physical activity.

Adolescent↗
PubMed2001

Fluorescence in situ hybridization study of TEL/AML1 fusion and other abnormalities involving TEL and AML1 genes. Correlation with cytogenetic findings and prognostic value in children with acute lymphocytic leukemia.

BACKGROUND AND OBJECTIVES: The TEL/AML1 fusion is the most common genetic abnormality found in childhood acute lymphoblastic leukemias (ALL). Although it is very difficult to identify by conventional cytogenetic techniques it can be readily detected using fluorescence in situ hybridization (FISH). We carried out cytogenetic and FISH studies on 42 children with ALL in order to know the frequency of this translocation in our population, the incidence of TEL and/or AML1 gene alterations, and their correlation with clinical evolution and prognosis. In addition, we performed reverse transcription polymerase chain reaction (RT-PCR) in some cases, confirming the feasibility of FISH techniques in the detection of this translocation. DESIGN AND METHODS: Bone marrow samples were obtained from 42 childhood ALL patients. The copy number of AML1 and TEL genes were studied using fluorescent in situ hybridization with a dual color DNA probe specific for the AML1 and TEL genes. RESULTS: We found a frequency of TEL/AML1 fusion of 17% in our sample. Double TEL/AML1 fusion, lack of TEL signal and extra AML1 signals were frequent additional FISH abnormalities. Duplication of a chromosomal complement, deletion of chromosome 12p arm, and polysomies of chromosome 21 are plausible explanations for these additional FISH findings. However, a relatively high proportion of our cases (9.5%) presented specific amplification of AML1. A statistically significant difference in prognosis was found between patients with and without these additional AML1 or TEL FISH alterations (p<0.02), which could be related to the presence of specific karyotypes. INTERPRETATIONS AND CONCLUSIONS: The frequency of TEL/AML1 fusion is similar to that found in other populations (17%). We found that FISH analysis of AML and TEL is related to the evolution of the disease. The absence of alterations in these genes revealed by FISH could be indicative of bad prognosis, while the presence of alterations is related to a good evolution. Our results suggest that interphase FISH analysis to search for alterations in AML and TEL genes could be extremely useful for complementing cytogenetic studies and for providing additional information about the possible outcome of the disease in patients with ALL.

Adolescent↗
PubMed1995

Effect of carbon:nitrogen ratio on kinetics of phenol biodegradation by Acinetobacter johnsonii in saturated sand.

In polluted soil or ground water, inorganic nutrients such as nitrogen may be limiting, so that Monod kinetics for carbon limitation may not describe microbial growth and contaminant biodegradation rates. To test this hypothesis we measured 14CO2 evolved by a pure culture of Acinetobacter johnsonii degrading 120 micrograms 14C-phenol per ml in saturated sand with molar carbon:nitrogen (CN) ratios ranging from 1.5 to 560. We fit kinetics models to the data using non-linear least squares regression. Phenol disappearance and population growth were also measured at CN1.5 and CN560. After a 5- to 10-hour lag period, most of the 14CO2 evolution curves at all CN ratios displayed a sigmoidal shape, suggesting that the microbial populations grew. As CN ratio increased, the initial rate of 14CO2 evolution decreased. Cell growth and phenol consumption occurred at both CN1.5 and CN560, and showed the same trends as the 14CO2 data. A kinetics model assuming population growth limited by a single substrate best fit the 14CO2 evolution data for CN1.5. At intermediate to high CN ratios, the data were best fit by a model originally formulated to describe no-growth metabolism of one substrate coupled with microbial growth on a second substrate. We suggest that this dual-substrate model describes linear growth on phenol while nitrogen is available and first-order metabolism of phenol without growth after nitrogen is depleted.

Acinetobacter↗
PubMed2005

Polydnavirus genomes reflect their dual roles as mutualists and pathogens.

Symbionts often exhibit significant reductions in genome complexity while pathogens often exhibit increased complexity through acquisition and diversification of virulence determinants. A few organisms have evolved complex life cycles in which they interact as symbionts with one host and pathogens with another. How the predicted and opposing influences of symbiosis and pathogenesis affect genome evolution in such instances, however, is unclear. The Polydnaviridae is a family of double-stranded (ds) DNA viruses associated with parasitoid wasps that parasitize other insects. Polydnaviruses (PDVs) only replicate in wasps but infect and cause severe disease in parasitized hosts. This disease is essential for survival of the parasitoid's offspring. Thus, a true mutualism exists between PDVs and wasps as viral transmission depends on parasitoid survival and parasitoid survival depends on viral infection of the wasp's host. To investigate how life cycle and ancestry affect PDVs, we compared the genomes of Campoletis sonorensis ichnovirus (CsIV) and Microplitis demolitor bracovirus (MdBV). CsIV and MdBV have no direct common ancestor, yet their encapsidated genomes share several features including segmentation, diversification of virulence genes into families, and the absence of genes required for replication. In contrast, CsIV and MdBV share few genes expressed in parasitized hosts. We conclude that the similar organizational features of PDV genomes reflect their shared life cycle but that PDVs associated with ichneumonid and braconid wasps have likely evolved different strategies to cause disease in the wasp's host and promote parasitoid survival.

Animals↗
PubMed1995

Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline, and venlafaxine.

Drug development in psychiatry has evolved from a process dependent on chance discovery to one based on rationally targeting specific mechanisms of action believed to be important in the pathophysiology underlying psychiatric syndromes. Antidepressant pharmacotherapy is the first area to have substantially benefited from this evolution. Serotonin selective reuptake inhibitors (SSRIs) were the first class of psychiatric medications developed based on such molecular targeting. Nefazodone is a new antidepressant that combines blockade of the serotonin-2 receptor with serotonin uptake inhibition. Perhaps as a result of this dual action, nefazodone caused fewer complaints of nervousness (e.g., agitation, anxiety), insomnia, and tremors and a higher incidence of confusion, dizziness, and vision disturbance than do other advanced generation antidepressants based on several different ways of assessing the relative incidence of these adverse effects. Reports of sexual dysfunction on nefazodone and bupropion treatment were lower than on treatment with other recently released antidepressants.

1-Naphthylamine↗
PubMed2004

Pleiotropic effect of disrupting a conserved sequence involved in a long-range compensatory interaction in the Drosophila Adh gene.

Recent advances in experimental analyses of the evolution of RNA secondary structures suggest a more complex scenario than that typically considered by Kimura's classical model of compensatory evolution. In this study, we examine one such case in more detail. Previous experimental analysis of long-range compensatory interactions between the two ends of Drosophila Adh mRNA failed to fit the classical model of compensatory evolution. To further investigate and verify long-range pairing in Drosophila Adh with respect to models of compensatory evolution and its potential functional role, we introduced site-directed mutations in the Drosophila melanogaster Adh gene. We explore two alternative hypotheses for why previous analysis of long-range compensatory interactions failed to fit the classical model. Specifically, we investigate whether the disruption of a conserved short-range pairing within Adh exon 2 has an effect on Adh expression or if there is a dual functional role of a conserved sequence in the 3'-UTR in both long-range pairing and the negative regulation of Adh expression. We find that a classical result was not observed due to the pleiotropic effect of changing a nucleotide involved in both long-range base pairing and the negative regulation of gene expression.

3' Untranslated Regions↗
PubMed2006

Does physiological beta cell turnover initiate autoimmune diabetes in the regional lymph nodes?

The initial immune process that triggers autoimmune beta cell destruction in type 1 diabetes is not fully understood. In early infancy there is an increased beta cell turnover. Recurrent exposure of tissue-specific antigens could lead to primary sensitization of immune cells in the draining lymph nodes of the pancreas. An initial immune injury to the beta cells can be inflicted by several cell types, primarily macrophages and T cells. Subsequently, infiltrating macrophages transfer antigens exposed by apoptotic beta cells to the draining lymph nodes, where antigen presenting cells process and amplify a secondary immune reaction. Antigen presenting cells evolve as dual players in the activation and suppression of the autoimmune reaction in the draining lymph nodes. We propose a scenario where destructive insulitis is caused by recurrent exposure of specific antigens due to the physiological turnover of beta cells. This sensitization initiates the evolution of reactive clones that remain silent in the regional lymph nodes, where they succeed to evade regulatory clonal deletion.

Animals↗
PubMed2002

Depressant effect on a C-fibre reflex in the rat, of RB101, a dual inhibitor of enkephalin-degrading enzymes.

The effect of N-[(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithiol]-1-oxopropyl]-L-phenylalanine benzyl ester (RB101), a dual inhibitor of the enkephalin-degrading enzymes, neutral endopeptidase and aminopeptidase N, was assessed in anaesthetised rats on the C-fibre reflex elicited by electrical stimulation within the sural nerve territory and recorded from the ipsilateral biceps femoris muscle. The temporal evolution of the pharmacological response was monitored by the repeated application of a constant stimulus intensity, namely three times threshold (3 T). In addition, recruitment curves were built by varying the stimulus intensity from 0 to 7 T. RB101 (7.5, 15 and 30 mg kg(-1), i.v.) induced a dose-dependent, naloxone-reversible depression of the reflex, which lasted around 60 min with the highest dose. The ED(50) was calculated as 16.9 mg kg(-1). Analyses of the recruitment curves revealed: (1) a significant increase of threshold; (2) a significant depression of the reflex in the ascending part of the curve; and (3) a lack of major depressive effects on the responses elicited by the strongest stimuli (corresponding to the plateau of the curve). The increase in the nociceptive threshold by enkephalin-degrading enzyme inhibitors, confirms previous data obtained from behavioural tests. In addition, the present study revealed an efficacy of these compounds over a wide range of stimulus intensities, albeit excluding the highest.

Aminopeptidases↗
PubMed1999

Anterior cephalic neural crest is required for forebrain viability.

The prosencephalon, or embryonic forebrain, grows within a mesenchymal matrix of local paraxial mesoderm and of neural crest cells (NCC) derived from the posterior diencephalon and mesencephalon. Part of this NCC population forms the outer wall of capillaries within the prosencephalic leptomeninges and neuroepithelium itself. The surgical removal of NCC from the anterior head of chick embryos leads to massive cell death within the forebrain neuroepithelium during an interval that precedes its vascularization by at least 36 hours. During this critical period, a mesenchymal layer made up of intermingled mesodermal cells and NCC surround the neuroepithelium. This layer is not formed after anterior cephalic NCC ablation. The neuroepithelium then undergoes massive apoptosis. Cyclopia ensues after forebrain deterioration and absence of intervening frontonasal bud derivatives. The deleterious effect of ablation of the anterior NC cannot be interpreted as a deficit in vascularization because it takes place well before the time when blood vessels start to invade the neuroepithelium. Thus the mesenchymal layer itself exerts a trophic effect on the prosencephalic neuroepithelium. In an assay to rescue the operated phenotype, we found that the rhombencephalic but not the truncal NC can successfully replace the diencephalic and mesencephalic NC. Moreover, any region of the paraxial cephalic mesoderm can replace NCC in their dual function: in their early trophic effect and in providing pericytes to the forebrain meningeal blood vessels. The assumption of these roles by the cephalic neural crest may have been instrumental in the rostral expansion of the vertebrate forebrain over the course of evolution.

Animals↗
PubMed2002

The effects of growth hormone replacement therapy on bone metabolism in adult-onset growth hormone deficiency: a 2-year open randomized controlled multicenter trial.

Adult hypopituitary patients with growth hormone deficiency (GHD) show a significant decrease in bone mass and an increased fracture rate. Replacement therapy with GH increases bone turnover. Most of the long-term data on bone mineral content (BMC) and bone mineral density (BMD) have been acquired in open, noncontrolled trials involving limited numbers of patients. To determine whether long-term GH therapy is beneficial for bone despite the increased bone turnover, 100 patients (59 men and 41 women), aged 25-65 years (mean, 49.7 years) with adult-onset GHD were randomized to treatment with GH (40 men and 28 women; mean dose, 0.18 IU/kg per week) or to a nontreated control group (19 men and 13 women) for 24 months. Despite a similar increase in parameters of bone turnover (osteocalcin [OC], procollagen type I carboxy-terminal propeptide [PICP], and pyridinolines ([PYD]) in male and female GH-treated patients compared with controls, the effects on BMC and BMD as evaluated by dual-energy X-ray absorptiometry were gender specific. A significant increase in spine BMC and BMD and total hip BMD and a decrease in BMD at the ultradistal radius over time was observed in male GH-treated patients compared with the evolution in controls (mean +/- SEM change at 24 months: +6.8 +/- 1.1% and p = 0.009, +5.1 +/- 0.8% and p = 0.005, +3.5 +/- 0.7% and p = 0.02, and -2.6 +/- 0.8% and p = 0.008, respectively). No significant treatment effects were observed in female patients. Despite the increase in the total remodeling space induced by GH treatment, prolonged GH therapy in adult-onset GHD has a positive effect on bone balance, maintaining bone mass in women, and even increasing it in men over a 2 year-period.

Absorptiometry, Photon↗
PubMed2004

Method for determination of the volume of material ejected as molten droplets during visible nanosecond ablation.

A novel method is presented for determining the volume of molten material ejected from a substrate as a result of visible pulsed-laser ablation. A 100-microm-wide pulsed-laser light sheet (tau approximately 5 ns, lambda = 532 nm) was used in conjunction with a CCD camera to provide high-speed cross-sectional images of single-pulse ablation of aluminum with a visible nanosecond laser source. Computational analysis of the two-dimensional gray-scale images was used to determine the total volume of material ejected from the substrate in the form of molten droplets. Ablation with dual-wavelength (511- and 578-nm) pulses of 30-ns duration was characterized under various fluence conditions (0-25 J cm(-2)), allowing a quantitative threshold for explosive melt ejection in aluminum to be established at approximately 10 J cm(-2). The temporal evolution of the ejected material showed that, for an incident fluence of approximately 40 J cm(-2), molten-droplet ejection commenced at approximately 400 ns and ceased after approximately 2 micros.

Journal Article↗