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Biomedical subjects

C Adami

Publications and source records attributed to C Adami.

At least 19 recordsLinked to original sources
PubMed2001

Interaction between directional epistasis and average mutational effects.

We investigate the relationship between the average fitness decay due to single mutations and the strength of epistatic interactions in genetic sequences. We observe that epistatic interactions between mutations are correlated to the average fitness decay, both in RNA secondary structure prediction as well as in digital organisms replicating in silico. This correlation implies that, during adaptation, epistasis and average mutational effect cannot be optimized independently. In experiments with RNA sequences evolving on a neutral network, the selective pressure to decrease the mutational load then leads to a reduction in the amount of sequences with strong antagonistic interactions between deleterious mutations in the population.

Epistasis, Genetic↗
PubMed2001

Evolution of digital organisms at high mutation rates leads to survival of the flattest.

Darwinian evolution favours genotypes with high replication rates, a process called 'survival of the fittest'. However, knowing the replication rate of each individual genotype may not suffice to predict the eventual survivor, even in an asexual population. According to quasi-species theory, selection favours the cloud of genotypes, interconnected by mutation, whose average replication rate is highest. Here we confirm this prediction using digital organisms that self-replicate, mutate and evolve. Forty pairs of populations were derived from 40 different ancestors in identical selective environments, except that one of each pair experienced a 4-fold higher mutation rate. In 12 cases, the dominant genotype that evolved at the lower mutation rate achieved a replication rate >1.5-fold faster than its counterpart. We allowed each of these disparate pairs to compete across a range of mutation rates. In each case, as mutation rate was increased, the outcome of competition switched to favour the genotype with the lower replication rate. These genotypes, although they occupied lower fitness peaks, were located in flatter regions of the fitness surface and were therefore more robust with respect to mutations.

Biological Evolution↗
PubMed2001

A comparison between dynamic pelvic magnetic resonance imaging and videoproctography in patients with constipation.

PURPOSE: This study attempts to compare the diagnostic efficacy of dynamic pelvic magnetic resonance imaging with that of videoproctography for the presence of rectocele, sigmoidocele, and intussusception as well as the measurement of anorectal angle and perineal descent in constipated patients. METHODS: Patients volunteering for the study and fulfilling the criteria for videoproctography to evaluate constipation were also scheduled for dynamic pelvic magnetic resonance imaging. Patients undergoing videoproctography were placed in the left lateral decubitus position, after which 50 ml of liquid barium paste was introduced into the rectum. After this, approximately 100 ml of thick barium paste similar to stool in consistency was injected into the rectum, and the patient was instructed to defecate while video images were taken. For dynamic pelvic magnetic resonance imaging, air, to be used as contrast, was allowed to accumulate in the rectum via examination with the patient in the prone position. A capsule was taped to the perineal skin immediately posterior to the anal orifice for marking. Sagittal and axial T1 images were obtained through the pelvis at 8-mm intervals with dynamic breathhold sagittal images of the anorectal region obtained at rest and during strain and squeeze maneuvers. Total acquisition time per maneuver was approximately 19 seconds. The tests were performed by different examiners blinded to the result of the other evaluation. The investigations were independently interpreted, findings compared, and patients questioned regarding their impression of dynamic pelvic magnetic resonance imaging and videoproctography. RESULTS: From June 1996 to April 1997, 22 patients (15 females) with a mean age of 68 (range, 21-85) years underwent both videoproctography and dynamic pelvic magnetic resonance imaging. Dynamic pelvic magnetic resonance imaging was only able to detect 1 of 12 (8.3 percent) anterior rectoceles and one of two (50 percent) posterior rectoceles identified by videoproctography. It failed to recognize any of the rectoanal intussusception (zero of four) but did show 9 of 12 (75 percent) sigmoidoceles. Significant discrepancy of measurement of the anorectal angle and perineal descent exists between the two studies, and dynamic pelvic magnetic resonance imaging was not able to detect any (0 of 11) of the patients with increased fixed perineal descent and only half (one of two) of the patients with increased dynamic perineal descent noted on videoproctography. All 22 patients preferred dynamic pelvic magnetic resonance imaging over videoproctography because of greater comfort. CONCLUSION: Occasionally, the increased cost of new technology can be justified by the enhanced diagnostic yield. The ability to avoid unnecessary surgery or, conversely, to continue to search for otherwise occult pathology that can be surgically corrected justifies routine application of these new tools. However, this study has shown that, despite a cost of approximately ten times more for dynamic pelvic magnetic resonance imaging than for videoproctography, no clinical changes were made. Thus, on the basis of this study, we cannot endorse the routine application of dynamic pelvic magnetic resonance imaging for the evaluation of constipated patients. In certain selected individuals, it may play a role, but further study is necessary to clarify its exact role.

Adult↗
PubMed2001

S100B expression in and effects on microglia.

We evaluated the intracellular and extracellular biological role of S100B protein with respect to microglia. S100B, which belongs to the multigenic family of Ca2+-binding proteins, is abundant in astrocytes where it is found diffusely in the cytoplasm and is associated with membranes and cytoskeleton constituents. S100B protein is also secreted by astrocytes and acts on these cells to stimulate nitric oxide secretion in an autocrine manner. However, little is known about the relationship between S100B and microglia. To address this issue, we used primary microglia from newborn rat cortex and the BV-2 microglial cell line, a well-established cell model for the study of microglial properties. S100B expression was assessed by immunofluorescence in primary microglia and by RT-PCR, Western blotting, and immunofluorescence in BV-2 cells. S100B was found in microglia in the form of a filamentous network as well as diffusely in the cytoplasm and associated with intracellular membranes. S100B relocated around phagosomes during BV-2 phagocytosis of opsonized Cryptococcus neoformans. Furthermore, interferon-gamma (IFN-gamma) treatment caused cell shape changes and redistribution of S100B, and downregulation of S100B mRNA expression in BV-2 cells. Treatment of BV-2 cells with nanomolar to micromolar amounts of S100B resulted in increased IFN-gamma-induced expression of inducible nitric oxide synthase mRNA as well as nitric oxide secretion. Taken together, these data suggest a possible role for S100B in the accomplishment/regulation of microglial cell functions.

Animals↗
PubMed2000

Evolution of biological complexity.

To make a case for or against a trend in the evolution of complexity in biological evolution, complexity needs to be both rigorously defined and measurable. A recent information-theoretic (but intuitively evident) definition identifies genomic complexity with the amount of information a sequence stores about its environment. We investigate the evolution of genomic complexity in populations of digital organisms and monitor in detail the evolutionary transitions that increase complexity. We show that, because natural selection forces genomes to behave as a natural "Maxwell Demon," within a fixed environment, genomic complexity is forced to increase.

Biological Evolution↗
PubMed2000

A pilot assessment of whether external coil MRI is useful to assess evacuatory disorders.

This study assessed the value of common surface coil magnetic resonance imaging (MRI) in patients with evacuatory disorders including fecal incontinence and constipation. These findings were then compared with those from other standard physiological examinations and/or surgical findings. From July 1996 to June 1997, 14 consecutive patients underwent surface coil MRI for evaluation of either fecal incontinence (n=5) or constipation (n=9). In patients with incontinence we compared the findings from endoanal ultrasound (EAUS), anal MRI, and surgery regarding morphopathological findings of the internal and external anal sphincter components. In constipated patients the findings of videoprography and dynamic pelvic MRI were compared regarding the presence of rectocele, rectoanal intussusception, and sigmoidocele as well as the measurements of anorectal angle and perineal descent. The five incontinent patients were all women, with a median age of 67 years (range 43-77). EAUS revealed an anterior sphincter defect in two patients, a posterior defect in one, and normal anal sphincter images in two. Surgical findings confirmed an anterior external anal sphincter scar in two patients, an internal anal sphincter defect in one, and an anatomically normal anal sphincter in two. In one patient, although anal MRI showed posterior external anal sphincter defect, EAUS and surgery revealed normal external anal sphincter appearance. The accuracy rate between EAUS and anal MRI was only 20%, that between surgery and anal MRI 40%, and that between surgery and EAUS 80%. Thus EAUS was more accurate than anal MRI in incontinent patients. The nine constipated patients were all women, with a mean age of 59 years (range 40-78). Videoproctography revealed an anterior rectocele in six patients, rectoanal intussusception in three, and sigmoidocele in five; no abnormalities were identified in two patients. On dynamic pelvic MRI anterior rectocele was seen in three patients and sigmoidocele in two, and five studies were interpreted as normal. One of the patients underwent sigmoidectomy for sigmoidocele, and five patients were treated by biofeedback. Thus the accuracy rate of dynamic pelvic MRI against videoproctography was 60% for anterior rectocele, 40% for sigmoidocele, and zero for rectoanal intussusception. In conclusion, neither MRI for the evaluation of patients with fecal incontinence nor for the evaluation of patients with constipation added any significant information that would warrant its continued use in these patient groups. Perhaps the more widespread availability of an endoanal coil will alter this conclusion; however, at the present time we cannot routinely endorse the expense, time, or inconvenience of these MRI investigations in patients with these diagnoses. Larger prospective comparative studies are required prior to endorsing the technique.

Adult↗
PubMed2000

Open problems in artificial life.

This article lists fourteen open problems in artificial life, each of which is a grand challenge requiring a major advance on a fundamental issue for its solution. Each problem is briefly explained, and, where deemed helpful, some promising paths to its solution are indicated.

Artificial Intelligence↗
PubMed2000

A developmental model for the evolution of artificial neural networks.

We present a model of decentralized growth and development for artificial neural networks (ANNs), inspired by developmental biology and the physiology of nervous systems. In this model, each individual artificial neuron is an autonomous unit whose behavior is determined only by the genetic information it harbors and local concentrations of substrates. The chemicals and substrates, in turn, are modeled by a simple artificial chemistry. While the system is designed to allow for the evolution of complex networks, we demonstrate the power of the artificial chemistry by analyzing engineered (handwritten) genomes that lead to the growth of simple networks with behaviors known from physiology. To evolve more complex structures, a Java-based, platform-independent, asynchronous, distributed genetic algorithm (GA) has been implemented that allows users to participate in evolutionary experiments via the World Wide Web.

Algorithms↗
PubMed1999

A simple explanation for taxon abundance patterns.

For taxonomic levels higher than species, the abundance distributions of the number of subtaxa per taxon tend to approximate power laws but often show strong deviations from such laws. Previously, these deviations were attributed to finite-time effects in a continuous-time branching process at the generic level. Instead, we describe herein a simple discrete branching process that generates the observed distributions and find that the distribution's deviation from power law form is not caused by disequilibration, but rather that it is time independent and determined by the evolutionary properties of the taxa of interest. Our model predicts-with no free parameters-the rank-frequency distribution of the number of families in fossil marine animal orders obtained from the fossil record. We find that near power law distributions are statistically almost inevitable for taxa higher than species. The branching model also sheds light on species-abundance patterns, as well as on links between evolutionary processes, self-organized criticality, and fractals.

Animals↗
PubMed1999

Genome complexity, robustness and genetic interactions in digital organisms.

Digital organisms are computer programs that self-replicate, mutate and adapt by natural selection. They offer an opportunity to test generalizations about living systems that may extend beyond the organic life that biologists usually study. Here we have generated two classes of digital organism: simple programs selected solely for rapid replication, and complex programs selected to perform mathematical operations that accelerate replication through a set of defined 'metabolic' rewards. To examine the differences in their genetic architecture, we introduced millions of single and multiple mutations into each organism and measured the effects on the organism's fitness. The complex organisms are more robust than the simple ones with respect to the average effects of single mutations. Interactions among mutations are common and usually yield higher fitness than predicted from the component mutations assuming multiplicative effects; such interactions are especially important in the complex organisms. Frequent interactions among mutations have also been seen in bacteria, fungi and fruitflies. Our findings support the view that interactions are a general feature of genetic systems.

Biological Evolution↗
PubMed1999

Tetanus toxin impairs accessory and secretory functions in interferon-gamma-treated murine macrophages.

Tetanus neurotoxin (TT), a product of microbial origin, acts as a zinc endopeptidase on vesicle-associated membrane proteins (VAMP). We have demonstrated that TT displays inhibitory effects on secretory and accessory functions in the murine macrophage (Mphi) cell line GG2EE. Nitric oxide (NO) secretion was decreased when interferon (IFN)-gamma-pretreated GG2EE Mphis were coincubated with a fungal costimulus (SMP200) and TT. When heat-inactivated TT was used this effect was not evident. The TT-mediated phenomenon was dose-dependent and specific since, under the same experimental conditions, it did not affect interleukin-6 or tumor necrosis factor-alpha secretion. Furthermore, IFN-gamma-induced major histocompatibility complex class II molecule expression and GG2EE accessory function, assessed by SMP200-stimulated lymphoproliferation, were also inhibited by TT. Such inhibition was incomplete, in line with our previous results showing that TT partially cleaves VAMP proteins in murine Mφ.

Animals↗
PubMed1998

A determinant for central nervous system persistence localized in the capsid of Theiler's murine encephalomyelitis virus by using recombinant viruses.

The demyelinating process in Theiler's murine encephalomyelitis virus (TMEV) infection in mice requires virus persistence in the central nervous system. Using recombinant TMEV assembled between the virulent GDVII and less virulent BeAn virus cDNAs, we now provide additional evidence supporting the localization of a persistence determinant to the leader P1 (capsid) sequences. Further, recombinant viruses in which BeAn sequences progressively replaced those of GDVII within the capsid starting at the leader NH2 terminus suggest that a conformational determinant requiring homologous sequences in both the VP2 puff and VP1 loop regions, which are in close contact on the virion surface, might underlie persistence.

Animals↗
PubMed1995

Evolution of mouse hepatitis virus (MHV) during chronic infection: quasispecies nature of the persisting MHV RNA.

Coronavirus infection of mice has been used extensively as a model for the study of acute encephalitis and chronic demyelination. To examine the evolution of coronavirus RNA during chronic demyelinating infection, we isolated RNA from intracerebrally inoculated mice at 4, 6, 8, 13, 20, and 42 days postinfection and used reverse transcription-polymerase chain reaction amplification methods (RT-PCR) to detect viral sequences. RNA sequences from two viral structural genes, the spike gene and the nucleocapsid gene, were detected throughout the chronic infection. In contrast, infectious virus was not detectable from brain homongenates beyond 13 days postinfection. These results indicate that coronavirus RNA persists in the brain at times when infectious virus is not detected. To determine if genetic changes were occurring during viral replication in the host, we cloned and sequenced the RT-PCR products from the spike and nucleocapsid regions and analyzed the sequences for mutations. Sequencing of the cloned products revealed that a variety of mutant forms of viral RNA persisted in the CNS, including point mutants, deletion mutants, and termination mutants. The mutations accumulated during persistent infection in both the spike and the nucleocapsid sequences, with greater than 65% of the mutations encoding amino acid changes. These results show that a diverse population or quasispecies consisting of mutant and deletion variant viral RNAs (which may not be capable of producing infectious virus particles) persists in the central nervous system of mice during chronic demyelinating infection. The implications of these results for the role of persistent viral genetic information in the pathogenesis of chronic demyelination are discussed.

Amino Acid Sequence↗
PubMed1995

Mutations associated with viral sequences isolated from mice persistently infected with MHV-JHM.

Mouse hepatitis virus JHM (JHMV or MHV-4) induces subacute and chronic demyelination in rodents and has been studied as a model human demyelinating diseases, such a multiple sclerosis. However, despite intensive investigation, the state of JHMV during chronic disease is poorly understood. Using reverse transcription-polymerase chain reaction amplification (RT-PCR) to "rescue" viral RNA, we have found that JHMV-specific sequences persist for at least 787 days after intracerebral inoculation of experimental mice. Analysis of persisting viral RNA reveals that it is extensively mutated, and we hypothesize that the mutations observed reflect adaptation of the viral quasispecies to low-level intracellular replication during chronic disease.

Animals↗
PubMed1994

Comparative studies on functional and secretory properties of macrophage cell lines derived from different anatomical sites.

In the present study, we compared four macrophage (M phi) cell lines from different anatomical origins for functional and secretory activities against the two morphogenetic forms of the fungus Candida albicans. We show that all the cell lines actively phagocytize the yeast and exert antimicrobial activity against both forms of Candida, although M phi of microglial origin are the most effective. When assessed for secretory properties, microglial M phi exhibit a peculiar pattern with respect to other M phi populations under either basal or stimulated conditions. In particular, only microglial M phi fail to respond to the hyphal form of the fungus (H-Candida), which instead acts as a potent tumor necrosis factor inducer in the other M phi cell lines. When exposed to H-Candida, microglial M phi are indistinguishable from other M phi in their ability to modulate specific surface adhesion molecules. In addition to strengthening the knowledge on functional heterogeneity among M phi, our data provide evidence on the peculiar behavior of microglial M phi. To what extent M phi heterogeneity may be related to tissue homeostasis is discussed.

Animals↗
PubMed1993

In vivo immortalization of murine peritoneal macrophages: a new rapid and efficient method for obtaining macrophage cell lines.

Although several murine macrophage (m phi) cell lines from different sites have previously been obtained by in vitro infection with the J2 murine retrovirus, which carries the v-raf and v-myc oncogenes, it was not possible to immortalize thioglycolate-elicited peritoneal macrophages (Pm phi s) by this in vitro procedure. A technique utilizing in vivo injection of the J2 virus has been developed to overcome this problem. The J2 virus immortalized Pm phi s in a very efficient manner in vivo because no exogenous growth factors were required for the in vitro proliferation of these cells and numerous continuous cloned cell lines were readily established. In contrast, Pm phi s obtained from uninfected mice or Pm phi s infected in vitro with the J2 virus did not proliferate. The in vivo immortalized cells had many of the morphological and functional characteristics of m phi s. Analysis of two of the clones, PMJ2-PC and PMJ2-R, demonstrated intracellular expression of the product of the v-raf gene, presence of m phi-associated cell surface antigens, interleukin-6 secretion induced by lipopolysaccharide, and biological response modifier-induced cytotoxic activity against tumor cells. In addition, one of the clones, PMJ2-PC, constitutively expressed major histocompatibility complex (MHC) class II antigens, and in the other clone, PMJ2-R, MHC class II antigens expression was induced by recombinant murine interferon-gamma. This method of utilizing the J2 virus in vivo represents a novel technique for obtaining hematopoietic cell lines from cells that are difficult to immortalize in vitro.

Animals↗