Evolution of methods for carrier detection in hemophilia.
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Conducting sites in excitable membranes.
Electrical activity of conducting membranes is produced by transient changes in membrane conductance to Na and K ions. These time- and voltage-dependent conductance changes are controlled by intrinsic proteins that span the membrane and provide a pathway for ion movement. Several lines of evidence indicate that the membrane conducting sites are indeed largely or entirely protein structures. Proteolytic enzymes, when applied on unmyelinated axonal membrane such as the gar olfactory nerve or on eel electroplax, completely destroyed tetrodotoxin (TTX) binding. Treatment of the internal face of the giant axon of the squid with proteases resulted in the loss of the inactivation mechanism of the increased sodium conductance. The binding site of the TTX component in membrane isolated from eel electroplax, estimated by the method of irradiation inactivation, revealed MWs in the range of 230-240 kd. Moreover, this membrane component undergoes a cycle of phosphorylation-dephosphorylation that is affected by electrical activity and various neurotropic compounds and has also been shown to be a protein by the use of proteolytic enzymes. The membrane conducting sites through which ions are flowing are generally called "channels," and the activated "channels" are thought to form "pores" through which ions diffuse according to their electrochemical potential. The channel behaves as though it exists in open or closed permeability or "gating" states. The gating is generally assumed to be solely controlled by the voltage gradient across the membrane. Hence, the denominations of "gating proteins" are often attributed to the specific protein forming the membrane conducting sites. These proteins are intrinsic membrane proteins whose conformational changes, driven by the electric field in the membrane, are responsible for the ion fluxes generating the electrical activity in excitable cells. Electrical excitation of conducting cells involves transient permeability increases to Na+, K+, and Ca+ ions. In some specific cases, Cl-ions may also be involved. These ionic permeabilities are voltage-dependent and can be modified selectively and independently by a variety of compounds, thus leading to the idea that specific entities are spatially separated in the membrane and are acting independently. However, some data of patch-clamp analysis are best interpreted if one assumes that the activation of a specific entity may control the activation of another entity, thereby suggesting a kind of cooperation among some specific ionic sites.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16.
Analyses of chromosomal rearrangements that have occurred during the evolution of the hominoids can reveal much about the mutational mechanisms underlying primate chromosome evolution. We characterized the breakpoints of the pericentric inversion of chimpanzee chromosome 18 (PTR XVI), which is homologous to human chromosome 16 (HSA 16). A conserved 23-kb inverted repeat composed of satellites, LINE and Alu elements was identified near the breakpoints and could have mediated the inversion by bringing the chromosomal arms into close proximity with each other, thereby facilitating intrachromosomal recombination. The exact positions of the breakpoints may then have been determined by local DNA sequence homologies between the inversion breakpoints, including a 22-base pair direct repeat. The similarly located pericentric inversion of gorilla (GGO) chromosome XVI, was studied by FISH and PCR analysis. The p- and q-arm breakpoints of the inversions in PTR XVI and GGO XVI were found to occur at slightly different locations, consistent with their independent origin. Further, FISH studies of the homologous chromosomal regions in macaque and orangutan revealed that the region represented by HSA BAC RP11-696P19, which spans the inversion breakpoint on HSA 16q11-12, was derived from the ancestral primate chromosome homologous to HSA 1. After the divergence of orangutan from the other great apes approximately 12 million years ago (Mya), a duplication of the corresponding region occurred followed by its interchromosomal transposition to the ancestral chromosome 16q. Thus, the most parsimonious interpretation is that the gorilla and chimpanzee homologs exhibit similar but nonidentical derived pericentric inversions, whereas HSA 16 represents the ancestral form among hominoids.
Animals↗
Finding Nemo: molecular phylogeny and evolution of the unusual life style of anemonefish.
Anemonefish are a group of 28 species of coral reef fish belonging to the family Pomacentridae, subfamily Amphiprioninae, all characterized by living in symbiosis with sea anemones of several genera. Some anemonefish are specialized to cooperate with a single or few species of sea anemone, being immune to their poisonous tentacles but sensible to those of other species of sea anemones, while other anemonefish are more generalist and able to live together with a number of different species of sea anemone hosts. Despite the common life style, anemonefish species occur in a variety of colors, body shapes and degree of dependence from the host. To understand the evolutionary mechanisms responsible for the anemonefish diversification, we studied 23 out of 28 species of anemonefish by analyzing three mitochondrial regions: the cytochrome b gene, the 16S ribosomal RNA gene and the first half of the D-loop, a non-coding, regulatory region to reconstruct their molecular phylogeny through Bayesian and maximum parsimony approaches. The evolution of specialization was studied by means of character reconstruction methods. This work includes the highest number of anemonefish so far analyzed and particularly some species that had never been studied before. The results support a monophyletic origin for the subfamily Amphiprioninae, in contrast to the current taxonomy, based on morphological characters, that divides anemonefish into two separate genera. Moreover, we formulate some hypotheses concerning the life style and origin of the ancestral anemonefish.
Animals↗
Transmembrane ion transport by polyphosphate/poly-(R)-3-hydroxybutyrate complexes.
Transmembrane ion transport, a critical process in providing energy for cell functions, is carried out by pore-forming macromolecules capable of discriminating among very similar ions and responding to changes in membrane potential. It is widely regarded that ion channels are exclusively proteins, relatively late arrivals in cell evolution. Here we discuss the formation of ion-selective, voltage-activated channels by complexes of two simple homopolymers, namely, inorganic polyphosphates (polyPs) and poly-(R)-3-hydroxybutyrates (PHBs), derived from phosphate and acetate, respectively. Each has unique molecular characteristics that facilitate ion selection, solvation, and transport. Complexes of the two polymers, isolated from bacterial plasma membranes or prepared from the synthetic polymers, form voltage-dependent, Ca2+-selective channels in planar lipid bilayers that are selective for divalent over monovalent cations, permeant to Ca2+, Sr2+, and Ba2+, and blocked by transition metal cations in a concentration-dependent manner. Recently, both polyP and PHB have been found to be components of ion-conducting proteins: namely, the human erythrocyte Ca2+-ATPase pump and the Streptomyces lividans potassium channel. The contribution of polyP and PHB to ion selection and/or transport in these proteins is yet unknown, but their presence gives rise to the hypothesis that these and other ion transporters are supramolecular structures in which proteins, polyP, and PHB cooperate in forming well-regulated and specific cation transfer systems.
Calcium-Transporting ATPases↗
Major components of a sea urchin block to polyspermy are structurally and functionally conserved.
One sperm fusing with one egg is requisite for successful fertilization; additional sperm fusions are lethal to the embryo. Because sperm usually outnumber eggs, evolution has selected for mechanisms that prevent this polyspermy by immediately modifying the egg extracellular matrix. We focus here on the contribution of cortical granule contents in the sea urchin block to polyspermy to begin to understand how well this process is conserved. We identified each of the major constituents of the fertilization envelope in two species of seaurchins, Strongylocentrotus purpuratus and Lytechinus variegatus, that diverged 30 to 50 million years ago. Our results show that the five major structural components of the fertilization envelope, derived from the egg cortical granules, are semiconserved. Most of these orthologs share sequence identity and encode multiple low-density lipoprotein receptor type A repeats or CUB domains but at least two contain radically different carboxy-terminal repeats. Using a new association assay, we also show that these major structural components are functionally conserved during fertilization envelope construction. Thus, it seems that this population of female reproductive proteins has retained functional motifs while gaining significant sequence diversity-two opposing paths that may reflect cooperativity among the proteins that compose the fertilization envelope.
Animals↗
Evolution kinetics and phase transitions of complex adaptive systems.
Motivated by the fact that a population of competing agents never set up a true stationary distribution, we propose a theory of evolution kinetics for complex adaptive systems. The formula derived for the survival probability is used to describe different phases in the population evolution when the prize-to-fine ratio as well as time changes. A kinetic phase diagram is obtained to show the phase boundaries for the self-segregating region, the intermediate region, and the clustering region. The kinetic evolutionary equations of strategy distribution are also established and used to give the root-mean-square separation of strategy distribution. It is revealed that the rootstock of the phase transitions is ascribed to the cooperation and competition among agents with different gene values for a limited resource.
Adaptation, Physiological↗
[Reluctant partner: Canada's relationship with the Pan American Health Organization (PAHO)].
Despite a strong commitment to multilateralism and international health cooperation in the post World War II era, Canada refrained form joining the Pan American Health Organization - PAHO until 1971. Drawing on letters and memos sent between Canadian diplomats and government representatives, this paper explores official Canadian accounts of the factors that delayed Canada's membership in PAHO. These factors include the initial lack of official relations between Canada and Latin America, US hegemony in the region, and budgetary constraints. Canada's cautious position regarding PAHO is also placed within the context of Canada's overall foreign policy to the region, emphasizing the parallels between Canada's reluctant association with PAHO and the evolution of Canada's engagement with the region as a whole.
Canada↗
Origin of multicellular organisms as an inevitable consequence of dynamical systems.
The origin of multicellular organisms is studied by considering a cell system that satisfies minimal conditions, that is, a system of interacting cells with intracellular biochemical dynamics, and potentiality in reproduction. Three basic features in multicellular organisms-cellular diversification, robust developmental process, and emergence of germ-line cells-are found to be general properties of such a system. Irrespective of the details of the model, such features appear when there are complex oscillatory dynamics of intracellular chemical concentrations. Cells differentiate from totipotent stem cells into other cell types due to instability in the intracellular dynamics with cell-cell interactions, as explained by our isologous diversification theory (Furusawa and Kaneko, 1998a; Kaneko and Yomo, 1997). This developmental process is shown to be stable with respect to perturbations, such as molecular fluctuations and removal of some cells. By further imposing an adequate cell-type-dependent adhesion force, some cells are released, from which the next generation cell colony is formed, and a multicellular organism life-cycle emerges without any finely tuned mechanisms. This recursive production of multicellular units is stabilized if released cells are few in number, implying the separation of germ cell lines. Furthermore, such an organism with a variety of cellular states and robust development is found to maintain a larger growth speed as an ensemble by achieving a cooperative use of resources, compared to simple cells without differentiation. Our results suggest that the emergence of multicellular organisms is not a "difficult problem" in evolution, but rather is a natural consequence of a cell colony that can grow continuously.
Algorithms↗
Identifying the protein folding nucleus using molecular dynamics.
Molecular dynamics simulations of folding in an off-lattice protein model reveal a nucleation scenario, in which a few well-defined contacts are formed with high probability in the transition state ensemble of conformations. Their appearance determines folding cooperativity and drives the model protein into its folded conformation. Amino acid residues participating in those contacts may serve as "accelerator pedals" used by molecular evolution to control protein folding rate.
Binding Sites↗
Tryptophan phosphorescence study of enzyme flexibility and unfolding in laboratory-evolved thermostable esterases.
Directed evolution of p-nitrobenzyl esterase (pNB E) has yielded eight generations of increasingly thermostable variants. The most stable esterase, 8G8, has 13 amino acid substitutions, a melting temperature 17 degrees C higher than the wild-type enzyme, and increased hydrolytic activity toward p-nitrophenyl acetate (pNPA), the substrate used for evolution, at all temperatures. Room-temperature activities of the evolved thermostable variants range from 3.5 times greater to 4.0 times less than wild type. The relationships between enzyme stability, catalytic activity, and flexibility for the esterases were investigated using tryptophan phosphorescence. We observed no correlation between catalytic activity and enzyme flexibility in the vicinity of the tryptophan (Trp) residues. Increases in stability, however, are often accompanied by decreases in flexibility, as measured by Trp phosphorescence. Phosphorescence data also suggest that the N- and C-terminal regions of pNB E unfold independently. The N-terminal region appears more thermolabile, yet most of the thermostabilizing mutations are located in the C-terminal region. Mutational studies show that the effects of the N-terminal mutations depend on one or more mutations in the C-terminal region. Thus, the pNB E mutants are stabilized by long-range, cooperative interactions between distant parts of the enzyme.
Directed Molecular Evolution↗
Detecting recent positive selection in the human genome from haplotype structure.
The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.
Africa↗
Geometric framework for phase synchronization in coupled noisy nonlinear systems.
A geometric approach is introduced for understanding the phenomenon of phase synchronization in coupled nonlinear systems in the presence of additive noise. We show that the emergence of cooperative behavior through a change of stability via a Hopf bifurcation entails the spontaneous appearance of a gauge structure in the system, arising from the evolution of the slow dynamics, but induced by the fast variables. The conditions for the oscillators to be synchronised in phase are obtained. The role of weak noise appears to be to drive the system towards a more synchronized behavior. Our analysis provides a framework to explain recent experimental observations on noise-induced phase synchronization in coupled nonlinear systems.
Journal Article↗
Genetic models in pathogenesis.
To decipher the complexity of host-pathogen interactions the widest possible range of model hosts and of analytical methods is required. As some virulence mechanisms and certain host responses have been conserved throughout evolution, even simple organisms can be used as model hosts to help our understanding of infectious diseases. The availability of molecular genetic tools and a cooperative community of researchers are pivotal to the emergence of model systems. In this review, we first summarize the genetic screens that can be used to identify pathogen virulence factors, then we present a comparative overview of existing or emerging genetically tractable host models.
Animals↗
Virtual cooperativity in myoglobin oxygen saturation curve in skeletal muscle in vivo.
BACKGROUND: Myoglobin (Mb) is the simplest monomeric hemoprotein and its physicochemical properties including reversible oxygen (O2)binding in aqueous solution are well known. Unexpectedly, however, its physiological role in intact muscle has not yet been established in spite of the fact that the role of the more complex tetrameric hemoprotein, hemoglobin (Hb), in red cells is well established. Here, I report my new findings on an overlooked property of skeletal Mb. METHODS: I directly observed the oxygenation of Mb in perfused rat skeletal muscle under various states of tissue respiration. A computer-controlled rapid scanning spectrophotometer was used to measure the oxygenation of Mb in the transmission mode. The light beam was focused on the thigh (quadriceps) through a 5-mm-diameter light guide. The transmitted light was conducted to the spectrophotometer through another 5-mm-diameter light guide. Visible difference spectra in the range of 500-650 nm were recorded when O2 uptake in the hindlimb muscle reached a constant value after every stepwise change in the O2 concentration of the buffer. RESULTS: The O2 dissociation curve (ODC) of Mb, when the effluent buffer O2 pressure was used as the abscissa, was of a sigmoid shape under normal and increased respiratory conditions whereas it was of rectangular hyperbolic shape under a suppressed respiratory condition. The dissociation curve was shifted toward the right and became more sigmoid with an increase in tissue respiration activity. These observations indicate that an increase in O2 demand in tissues makes the O2 saturation of Mb more sensitive to O2 pressure change in the capillaries and enhances the Mb-mediated O2 transfer from Hb to cytochrome oxidase (Cyt. aa3), especially under heavy O2 demands. CONCLUSION: The virtual cooperativity and O2 demand-dependent shifts of the ODC may provide a basis for explaining why Mb has been preserved as monomer during molecular evolution.
Journal Article↗
Computational study of experience-dependent plasticity in adult rat cortical barrel-column.
We model experience-dependent plasticity in the adult rat S1 cortical representation of the whiskers (the barrel cortex) which has been produced by trimming all whiskers on one side of the snout except two. This manipulation alters the pattern of afferent sensory activity while avoiding any direct nerve damage. Our simplified model circuitry represents multiple cortical layers and inhibitory neurons within each layer of a barrel-column. Utilizing a computational model we show that the evolution of the response bias in the barrel-column towards spared whiskers is consistent with synaptic modifications that follow the rules of the Bienenstock, Cooper and Munro (BCM) theory. The BCM theory postulates that a neuron possesses a dynamic synaptic modification threshold, thetaM, which dictates whether the neuron's activity at any given instant will lead to strengthening or weakening of the synapses impinging on it. However, the major prediction of our model is the explanation of the delay in response potentiation in the layer-IV neurons through a masking effect produced by the thresholded monotonically increasing inhibition expressed by either the logarithmic function, h(x) = mu log(1 + x), or by the power function, h(x) = mu x(0.8-0.9), where mu is a constant. Furthermore, simulated removal of the supragranular layers (layers II/III) reduces plasticity of neurons in the remaining layers (IV-VI) and points to the role of noise in synaptic plasticity.
Animals↗
Adamantiades-Behçet disease: an enigmatic process with oral manifestations.
Adamantiades-Behçet disease (ABD) is a chronic multisystemic vasculitis that is able to affect any human organ or system. Recurrent oral ulcers are a very important clinical sign. ABD is a worldwide pathology, which prevalence varies according to the population and geographic location. Although ABD has been known for ages, its aetiology remains an enigma. Genetic, immunological and microbiological factors have been associated. A wide spectrum of clinical manifestations (oral, genital, cutaneous, ocular, neurological, vascular and gastrointestinal) and an unpredictable evolution with repeated periods of exacerbation and remission are the most representative aspects of this pathology. The complex treatment of ABD requires a deep multidisciplinary cooperation; therefore, there is an extensive development of new therapeutic agents that have improved the prognosis of ABD. In this review were analysed the main etiological, clinical and therapeutic aspects of the disease.
Behcet Syndrome↗
Juvenile myelomonocytic leukemia: analyses of treatment results in the EORTC Children's Leukemia Cooperative Group (CLCG).
Forty-six children with juvenile myelomonocytic leukemia (JMML) diagnosed between 1978 and 1993 in 12 centers were retrospectively studied. There is no evidence that any conventional treatment influences the long-term evolution of JMML. Among 28 patients treated without bone marrow transplantation (BMT), 26 died (median survival: 17 months), two are alive, one in complete remission (CR) after intensive chemotherapy. Allogenic BMT is the best treatment: 18 patients underwent BMT, 11 are in CR (at 9, 15, 22, 25, 41, 45, 49, 53, 66, 90 and 108 months). Conditioning regimens using chemotherapy alone may cure some patients (3/6) occasionally despite autologous reconstitution (1/3); if relapse occurs, a second BMT may be curative (2/3). Among the 12 patients conditioned immediately with TBI, six are in CR, one is in relapse, five died (one of them in durable autologus CR from Schwannoma). It is our opinion that splenectomy is of therapeutic value and seems not to have influenced the incidence of infections complications. We found no argument in favor of intensive chemotherapy before conditioning. Results with HLA-matched unrelated donors are satisfactory. One patient relapsed at 4 months after an unrelated BMT and entered a new CR after discontinuation of cyclosporine.
Antineoplastic Combined Chemotherapy Protocols↗