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PubMed2002

Essential genes are more evolutionarily conserved than are nonessential genes in bacteria.

The "knockout-rate" prediction holds that essential genes should be more evolutionarily conserved than are nonessential genes. This is because negative (purifying) selection acting on essential genes is expected to be more stringent than that for nonessential genes, which are more functionally dispensable and/or redundant. However, a recent survey of evolutionary distances between Saccharomyces cerevisiae and Caenorhabditis elegans proteins did not reveal any difference between the rates of evolution for essential and nonessential genes. An analysis of mouse and rat orthologous genes also found that essential and nonessential genes evolved at similar rates when genes thought to evolve under directional selection were excluded from the analysis. In the present study, we combine genomic sequence data with experimental knockout data to compare the rates of evolution and the levels of selection for essential versus nonessential bacterial genes. In contrast to the results obtained for eukaryotic genes, essential bacterial genes appear to be more conserved than are nonessential genes over both relatively short (microevolutionary) and longer (macroevolutionary) time scales.

Conserved Sequence↗
PubMed1982

Effect of diet on glucose tolerance and insulin response in chemically diabetic rats.

The long term effect of dietary carbohydrate content on the course of noninsulin-dependent diabetes has been assessed in rats with experimental chemical diabetes (CD) obtained as spontaneous evolution of neonatal streptozotocin acute diabetes. Glucose tolerance and insulin secretion were serially tested before and during high carbohydrate diet (2 and 6 mo) or high lipid diet (1 mo) in control and in CD males. In none of the control or CD groups, did the high sucrose diet significantly affect the weight gain as compared to that obtained upon the standard diet. The high sucrose diet increased the insulin response to glucose and slightly improved the glucose tolerance in the normal rats. In CD rats, it increased the insulin secretion and the insulinogenic index; glucose tolerance was unaffected. In control rats receiving the high lipid diet, the weight gain was significantly increased as compared to that obtained upon the standard diet. Their plasma insulin levels were increased both in basal and glucose stimulated states while glucose tolerance remained unchanged. In the CD rats receiving the high lipid diet, weight gain was significantly increased as compared to that obtained upon the standard diet. But in these CD rats, the insulin secretion was not significantly enhanced by the high fat diet and the glucose tolerance deteriorated. These findings indicated a beneficial long-term effect of high carbohydrate diet in the CD rats as far as their insulin response to glucose was concerned. By contrast high lipid diet may be regarded as an aggravating factor of glucose handling in chemical diabetes. The results are discussed with regard to; (1) the increased insulin production and/or release on the high sucrose diet, and (2) the decreased insulin sensitivity on the high lipid diet.

Animals↗
PubMed2004

Genome sequence of the Brown Norway rat yields insights into mammalian evolution.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Animals↗
PubMed1998

On the holistic approach in cellular and cancer biology: nonlinearity, complexity, and quasi-determinism of the dynamic cellular network.

A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype-two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross-interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controlled in dispersed rather than centralized manner), and quasi-determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self-organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context.

Genotype↗
PubMed2001

Leishmania infantum-specific IgG, IgG1 and IgG2 antibody responses in healthy and ill dogs from endemic areas. Evolution in the course of infection and after treatment.

The expression of IgG, IgG1 and IgG2 specific antibodies for Leishmania infantum was studied in five groups of dogs in Catalonia (Spain): I, 99 asymptomatic dogs (infected and uninfected) from a highly endemic area for leishmaniosis; II, 139 untreated dogs with clinically patent leishmaniosis; III, 11 naturally infected asymptomatic dogs monitored for up to 5 years since they were found seropositive to Leishmania antigen and without treatment; IV, 25 naturally infected dogs with clinically patent leishmaniosis and treated with either meglumine antimoniate and allopurinol or allopurinol alone and V, six experimentally infected dogs, treated with meglumine antimoniate and controlled for 5 years. The levels (ELISA units) of IgG, IgG1 and IgG2 in asymptomatic dogs (group I) were very variable (24+/-33, 32+/-31 and 26+/-31, respectively), and, as expected, lower than in ill dogs (group II) (168+/-34, 84+/-71 and 172+/-31, respectively). In both groups, the correlation between IgG and IgG2 levels (r=0.95, P<0.001 in group I and r=0.63, P<0.001 in group II) was higher than between IgG and IgG1 levels (r=0.01, P>0.05 in group I and r=0.31, P<0.001 in group II). In group III, IgG and IgG2 expression increased during infection, while IgG1 expression remained the same. In dogs of group IV, IgG levels after 1 year of treatment decreased more in responsive (mean values, 163+/-42 before treatment (b.t.) and 100+/-36 after treatment (a.t.)) than in unresponsive dogs (158+/-29 b.t. and 124+/-51 a.t.), especially for IgG1 (94+/-89 b.t. and 20+/-21 a.t. in responsive dogs and 35+/-25 b.t. and 22+/-13 a.t. in unresponsive dogs) rather than for IgG2 (156+/-16 b.t. and 114+/-45 a.t. in responsive and 151+/-11 b.t. and 125+/-36 a.t. in unresponsive dogs). Similar results were observed in the evolution of experimentally infected animals after consecutive and specific treatments. Overall results show the great variation in Leishmania-specific IgG1 expression in asymptomatic and symptomatic dogs, their lack of correlation with that of IgG2 and chemotherapy is more effective in dogs with initially high expression of IgG1.

Allopurinol↗
PubMed2003

[Origin of SARS from accelerated evolution of a virus by combined pollution].

The SARS virus origin which obviously differs from the theory of out-space origin and the theory of wildlife origin was theoretically discussed based on principles of pollution-evolution ecology, pathogenesis and infectant characteristics of SARS, and some relevant experimental evidence. It emphasizes on the fact that increasingly combined pollution in China provides a substantial basis for virus evolution. Gene recombination and fusion of more than one virus in ecosystems should take charge with the origin of a SARS virus. In particular, a common cold or influenza virus can acceleratedly changed into a superpower common cold or influenza virus through genetic mutation and gene recombination by increasingly combined pollution. This work can be useful for human beings to overcome SARS in theory.

Animals↗
PubMed2005

Molecular evolution of the human chromosome 15 pericentromeric region.

We present a detailed molecular evolutionary analysis of 1.2 Mb from the pericentromeric region of human 15q11. Sequence analysis indicates the region has been subject to extensive interchromosomal and intrachromosomal duplications during primate evolution. Comparative FISH analyses among non-human primates show remarkable quantitative and qualitative differences in the organization and duplication history of this region - including lineage-specific deletions and duplication expansions. Phylogenetic and comparative analyses reveal that the region is composed of at least 24 distinct segmental duplications or duplicons that have populated the pericentromeric regions of the human genome over the last 40 million years of human evolution. The value of combining both cytogenetic and experimental data in understanding the complex forces which have shaped these regions is discussed.

Animals↗
PubMed2002

Thermodynamics of hydrogen bond patterns in supramolecular assemblies of water molecules.

The PACHA (Partial Atomic Charges and Hardnesses Analysis) formalism is applied to various supramolecular assemblies of water molecules. After a detailed study of all available crystal structures for ice polymorphs, we shown that the hydrogen bond strength is roughly constant below 1 GPa and considerably weakened above that value. New hydrogen bond patterns are proposed for ice IV, V, and VI after (EB) (electrostatic balance) minimization. For other polymorphs, there is an almost perfect coincidence between experimental and predicted hydrogen bond patterns. The evolution of hydrogen bond energy as a function of molecular geometry in water clusters with up to 280 water molecules and in large supramolecular compounds is quantitatively described. Intermolecular hydrogen bonds are found to lie between -9 and -32 kJ mol-1, the stronger interaction occurs within the spherical fully disordered water droplet buried at the heart of Müller's superfullerene keplerate. The weakest one occurs in a chiral molecular snub cube built from six calix[4]resorcinarene and eight water molecules. Intramolecular hydrogen bonds are found in the range -10-100 kJ mol-1 and can thus be considerably stronger than intermolecular bonds. Finally, through the investigation of a clathrate type I compound, it was possible to obtain a deep insight of the host-guest interactions and self-assembly rules of water cages in these materials.

Crystallization↗
PubMed2004

Metastable and stable states of xanthan polyelectrolyte complexes studied by atomic force microscopy.

The compaction of the semiflexible polysaccharide xanthan with selected multi- and polyvalent cations was studied. Polyelectrolyte complexes prepared at concentrations of 1-2 microg/ml were observed by tapping mode atomic force microscopy. High-molecular-weight xanthan compacted with chitosan yields a blend of mainly toroidal and metastable structures and a small fraction of rod-like species. Polyelectrolyte complexes of xanthan with polyethylenimine and trivalent chromium yielded similar structures or alternatively less well packed species. Racquet-type morphologies were identified as kinetically trapped states occurring on the folding path toward the energetically stable state of the toroids. Thermal annealing yielded a shift of the distribution of xanthan-chitosan morphologies toward this stable state. Ensembles of toroidal and rod-like morphologies of the xanthan-chitosan structures, collected using an asphericity index, were analyzed. The mean height of the toroids increased upon heating, with a selective increase in the height range above 2 nm. It is suggested that the observed metastable structures are formed from the high-molecular-weight fraction of xanthan and that these are driven toward the toroidal state, being a low-energy state, following annealing. Considered a model system for condensation of semiflexible polymers, the compaction of xanthan by chitosan captures the system at various stages in the folding toward a low-energy state and thus allows experimental analyses of these intermediates and their evolution.

Chitin↗
PubMed1995

A mechanochemical model for adult dermal wound contraction and the permanence of the contracted tissue displacement profile.

The healing of adult mammalian skin wounds involves a complex sequence of spatially and temporally coordinated processes. Wound contraction, by reducing the size of the injury, is an intrinsic component of full-thickness excisional dermal wound healing. The underlying biomechanics of wound contraction, however, are not fully understood, and little is known about the pathogenesis of severe medical conditions known as fibrocontractive diseases. The aim of this work is to investigate a deterministic mathematical model in order to obtain insight into the mechanistic relationships between wound contraction and associated normal and pathological healing processes. The model describes the essential roles of fibroblast and myofibroblast cells, a chemical growth factor and the extracellular matrix which includes type I collagen. The model results are qualitatively consistent with the biology of fibroplasia and wound contraction. It is shown that a contracted state evolves during a (long) transient phase of healing known as "proliferation", while collagen kinetics are fundamental to the considerably longer "remodelling" phase. Some quantitative results, notably on the evolution of wound contraction, compare favourably with experimental data. Application of the model to adult human dermal wound healing in vivo, with a greater understanding of the underlying biological mechanisms involved, may suggest strategies for controlling contraction and fibrocontractive diseases.

Adult↗
PubMed2000

A glycine site antagonist ZD9379 reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion.

Spreading depressions (SDs) occur in experimental focal ischemia and contribute to lesion evolution. N-methyl-D-aspartate (NMDA) antagonists inhibit SDs and reduce infarct size. The glycine site on the NMDA receptor complex offers a therapeutic target for acute focal ischemia, potentially devoid of many side effects associated with competitive and non-competitive NMDA antagonists. We evaluated the effect of the glycine antagonist, ZD9379, on SDs and brain infarction. Male Sprague-Dawley rats (n = 18) weighing 290 to 340 g undergoing permanent middle cerebral artery occlusion (MCAO) were randomly and blindly assigned to receive drug or placebo: Group 1 (pre-MCAO treatment group, n = 5) a 5 mg/kg bolus of ZD9379 over 5 minutes followed by 5 mg/kg/hour drug infusion for 4 hours beginning 30 minutes before MCAO; Group 2 (post-MCAO treatment group, n = 7) a 5 mg/kg bolus of ZD9379 30 minutes after MCAO followed by 5 mg/kg/hour drug infusion for 4 hours; and Group 3 (control group, n = 6) vehicle for 5 hours beginning 30 minutes before MCAO. SDs were monitored electrophysiologically for 4.5 hours following MCAO by continuous recording of cortical direct current (DC) potentials and electrocorticogram (ECoG). Infarct volume was measured 24 hours after MCAO by 2,3,5 triphenyltetrazolium chloride (TTC) staining. Corrected infarct volume was 90 +/- 72 mm3 (mean +/- standard deviation) in Group 1, 105 +/- 46 mm3 in Group 2, and 226 +/- 41 mm3 in Group 3 (P < .001). The corresponding numbers of SDs in the 3 groups were 8.2 +/- 5.8, 8.1 +/- 2.5, and 16.0 +/- 5.1, respectively (P < .01). When all animals (n = 18) were analyzed, infarct volumes and the number of SDs were significantly correlated (r = .68, P = .002). This study demonstrated that ZD9379 initiated before or after MCAO significantly reduced the number of SDs and infarct volume in a permanent focal ischemia model, implying that ZD9379 is neuroprotective and its neuroprotective effect may be related to inhibiting ischemia-related SDs.

Animals↗
PubMed2005

Immunosenescence, suppression and tumour progression.

There are good arguments for suggesting that two seminal papers published 50 years ago can be taken as the beginning of modern tumour immunology. These papers by R. Baldwin, "Immunity to transplanted tumour: the effect of tumour extracts on the growth of homologous tumours in rats" and "Immunity to methylcholanthrene-induced tumours in inbred rats following atrophy and regression of the implanted tumours" (Br J Cancer 9:646-51 and 652-657, 1955) showed that once tumours are established, they and their products can be recognised by the adaptive immune system and rejected. However, the tumour normally co-evolves with immunity, like a parasite, rather than being suddenly introduced as in these, and many other, experimental models. Dynamics of this co-evolution are illustrated by findings that inflammation enhances tumorigenicity, yet is important to enable T cells to respond properly to tumour antigen and exert anti-tumour effects. The important thing is to maintain the balance between effective anti-tumour immunity and tumour escape and/or stimulatory mechanisms. Tumours almost always co-exist with immune defence systems over extended periods and interact chronically with T cells. The effect of this is potentially similar to other situations of chronic antigenic stress, particularly lifelong persistent virus infection, most strikingly, CMV infection. The questions briefly explored in this symposium paper are what happens when T lymphocyte clones are chronically stimulated by antigen which is not or cannot be eliminated? What are the similarities and differences between chronic antigenic stimulation by tumour antigen versus CMV antigen? What can we learn in one system which may illuminate the other?

Aged↗
PubMed1996

Oscillatory patterns of electrical activity in mouse pancreatic islets of Langerhans recorded in vivo.

Pancreatic beta-cells secrete insulin as a function of blood glucose concentration. One of the key steps in stimulus-secretion coupling is the depolarisation of the membrane and the appearance of bursts of calcium action potentials. Recently, the characteristics and glucose dependence of the oscillations in electrical activity in vivo have been described. The experiments described here were designed to determine the temporal evolution of such electrical activity when no experimental changes in the glycaemia are imposed. The absolute duration of the active and silent phases has been analysed and compared with the values obtained in vitro. We have found that in vivo, at glycaemia ranging from 6.0 to 7.5 mM, the electrical activity of the islets of Langerhans is permanently oscillatory, the mean duration of the depolarisation phase being 28 s. In general, the oscillatory pattern remains very constant for relatively long (up to 60 min) periods of time. In some experiments, slow or transitory changes in the degree of beta-cell activation could be observed, as well as the existence, in a very few cases, of oscillatory non-periodic patterns. Key words beta-cells middle dot Pancreas middle dot Electrophysiology middle dot Oscillations

Animals↗
PubMed2006

Evolutionary genetics of Carpodacus mexicanus, a recently colonized host of a bacterial pathogen, Mycoplasma gallisepticum.

We present molecular data documenting how introduction to the eastern United States and an epizootic involving a bacterial pathogen has affected the genetic diversity of house finches, a cardueline songbird. Population bottlenecks during introduction can cause loss of genetic variation and may negatively affect a population's ability to adapt to novel stressors such as disease. Although a genome-wide survey using Amplified Fragment Length Polymorphism (AFLP) markers suggests little loss of genetic diversity in introduced populations, an epizootic of bacterial Mycoplasma has nonetheless caused dramatic declines in the eastern US population. Sequence analysis of a candidate gene for pathogen resistance in the Major Histocompatibity Complex (MHC) in pre- and post-epizootic population samples reveals allele frequency shifts since introduction of the pathogen, but similar shifts are also observed in control populations not exposed to the bacteria, and in a neutral non-coding locus. Expression studies using a novel subtractive hybridization approach indicate decreased expression of the class II MHC locus upon exposure to Mycoplasma, a pattern also seen in MHC class I loci in mice infected with cytomegalovirus and consistent with manipulation of the finch immune system by Mycoplasma. These results will be further expanded using experimental studies as well as examination of evolution of the pathogen genome itself.

Adaptation, Physiological↗
PubMed1982

Pattern of recovery of oral and written expression and comprehension in aphasic patients.

Three hundred and eighty-eight aphasic patients (250 rehabilitated and 138 non-rehabilitated) were subjected to a study whose aim was to analyze the relationship between recovery in 4 specific language skills: oral and written expression and comprehension. By means of Cohen's K coefficient of agreement we sought to ascertain whether recovery of one out of these language skills significantly affected recovery of the remaining 3 language modalities. In rehabilitated patients recovery of oral ad written comprehension and expression always turned out to be linked; in non-rehabilitated patients oral comprehension recovery was not associated with recovery of oral expression, reading and writing. Regarding the evolution of aphasia type, none of the experimental subjects changed from a fluent to a non-fluent form of aphasia.

Agraphia↗
PubMed1996

Changes in eye blink responses following hypoglossal-facial anastomosis in the cat: evidence of adult mammal motoneuron unadaptability to new motor tasks.

Hypoglossal-facial anastomosis is used in humans to restore the activity of the mimic musculature following irrecoverable facial nerve lesions. As eyelid movement kinetics is very well known, we have used this experimental model in cats to follow the evolution of blink responses and the adaptability of hypoglossal motor pools to new motor tasks. Although the electromyographic activity of the orbicularis oculi muscle in response to corneal air puffs, flashes of light or electrical stimulation of the supraorbital nerve was not recovered in the seven months following this crossed anastomosis, reflex blinks were got back by the increased activity of the retractor bulbi and extraocular recti muscles. The lid of the anastomosed side oscillated in perfect synchronization with tongue movements during licking, while it was severely affected in its motor function during optokinetic stimulation because of the spontaneous appearance of tongue-related hypoglossal activity. Present results suggest that adult mammal motoneurons are unable to readapt their motor programs to the kinetic needs of new motor targets and that most of the functional recovery observed in the cat was achieved by the compensatory hyperactivity of motor systems not directly affected by the surgery.

Adaptation, Physiological↗
PubMed2004

Multistep laryngeal carcinogenesis helps our understanding of the field cancerisation phenomenon: a review.

In this paper, we try to briefly review the most recent knowledge on head and neck cancer, and especially multistep laryngeal carcinogenesis, and to simply explain how this has modified our understanding of field cancerisation phenomenon. Experimental studies, made possible by the recent evolution of microdissection systems, have demonstrated that the "spatial progression"of the histopathological phenotype in the surroundings of malignant or premalignant head and neck lesions correlates with molecular progression. Such a "spatial progression" can be hypothesised to reflect temporal progression. The field cancerisation process has been divided into three phases, each with its own histological and molecular characteristics. Each of these phases may have clinical implications: detection and monitoring of fields may help cancer prevention (molecular epidemiology), early detection of recurrence (or, more exactly, of second field tumours (SFTs)) (molecular diagnostics) and prognostic prediction after treatment. This model appears plausible, especially in explaining the development of multiple primary tumours (MPTs) in adjacent head and neck mucosal regions, with peculiar clinical and prognostic implications: These tumours can be defined as multiple field tumours (SFTs). However, the model, in our opinion, does not convincingly explain the development of second primary tumours (SPTs) at more distant sites, such as the lung, colon and prostate.

Disease Progression↗