A visual metaphor describing neural dynamics in schizophrenia

Background

In many scientific disciplines the use of a metaphor as an heuristic aid is not uncommon. A well known example in somatic medicine is the ‘defense army metaphor’ used to characterize the immune system. In fact, probably a large part of the everyday work of doctors consists of ‘translating’ scientific and clinical information (i.e. causes of disease, percentage of succes versus risk of side-effects) into information tailored to the needs and capacities of the individual patient. The ability to do so in an effective way is at least partly what makes a clinician a good communicator. Schizophrenia is a severe psychiatric disorder which affects approximately 1% of the population. Over the last two decades a large amount of molecular-biological, imaging and genetic data have been accumulated regarding the biological underpinnings of schizophrenia. However, it remains difficult to understand how the characteristic symptoms of schizophrenia such as hallucinations and delusions are related to disturbances on the molecular-biological level. In general, psychiatry seems to lack a conceptual framework with sufficient explanatory power to link the mental- and molecular-biological domains.

Methodology/Principal Findings

Here, we present an essay-like study in which we propose to use visualized concepts stemming from the theory on dynamical complex systems as a ‘visual metaphor’ to bridge the mental- and molecular-biological domains in schizophrenia. We first describe a computer model of neural information processing; we show how the information processing in this model can be visualized, using concepts from the theory on complex systems. We then describe two computer models which have been used to investigate the primary theory on schizophrenia, the neurodevelopmental model, and show how disturbed information processing in these two computer models can be presented in terms of the visual metaphor previously described. Finally, we describe the effects of dopamine neuromodulation, of which disturbances have been frequently described in schizophrenia, in terms of the same visualized metaphor.

Conclusions/Significance

The conceptual framework and metaphor described offers a heuristic tool to understand the relationship between the mental- and molecular-biological domains in an intuitive way. The concepts we present may serve to facilitate communication between researchers, clinicians and patients.     

A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial "Excitatory Amino Acid Transporters" (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a beta-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in "Myelin Oligodendrocyte Glycoprotein" (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFgamma and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a beta-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis.     

Detection of natural infection with Mycobacterium intracellulare in healthy wild-caught Chacma baboons (Papio ursinus) by ESAT-6 and CFP-10 IFN-γ ELISPOT tests following a tuberculosis outbreak

Background

The current tuberculosis vaccine is a live vaccine derived from Mycobacterium bovis and attenuated by serial in vitro passaging. All vaccine substrains in use stem from one source, strain Bacille Calmette-Guérin. However, they differ in regions of genomic deletions, antigen expression levels, immunogenicity, and protective efficacy.

Results

As a RecA phenotype increases genetic stability and may contribute restricting the ongoing evolution of the various BCG substrains while maintaining their protective efficacy, we aimed to inactivate recA by allelic replacement in BCG vaccine strains representing different phylogenetic lineages (Pasteur, Frappier, Denmark, Russia). Homologous gene replacement was achieved successfully in three out of four strains. However, only illegitimate recombination was observed in BCG substrain Russia. Sequence analyses of recA revealed that a single nucleotide insertion in the 5' part of recA led to a translational frameshift with an early stop codon making BCG Russia a natural recA mutant. At the protein level BCG Russia failed to express RecA.

Conclusion

According to phylogenetic analyses BCG Russia is an ancient vaccine strain most closely related to the parental M. bovis. We hypothesize that recA inactivation in BCG Russia occurred early and is in part responsible for its high degree of genomic stability, resulting in a substrain that has less genetic alterations than other vaccine substrains with respect to M. bovis AF2122/97 wild-type.     

A tool box for operational mosquito larval control: preliminary results and early lessons from the Urban Malaria Control Programme in Dar es Salaam, Tanzania

Background

As the population of Africa rapidly urbanizes, large populations could be protected from malaria by controlling aquatic stages of mosquitoes if cost-effective and scalable implementation systems can be designed.

Methods

A recently initiated Urban Malaria Control Programme in Dar es Salaam delegates responsibility for routine mosquito control and surveillance to modestly-paid community members, known as Community-Owned Resource Persons (CORPs). New vector surveillance, larviciding and management systems were designed and evaluated in 15 city wards to allow timely collection, interpretation and reaction to entomologic monitoring data using practical procedures that rely on minimal technology. After one year of baseline data collection, operational larviciding with Bacillus thuringiensis var. israelensis commenced in March 2006 in three selected wards.

Results

The procedures and staff management systems described greatly improved standards of larval surveillance relative to that reported at the outset of this programme. In the first year of the programme, over 65,000 potential Anopheles habitats were surveyed by 90 CORPs on a weekly basis. Reaction times to vector surveillance at observations were one day, week and month at ward, municipal and city levels, respectively. One year of community-based larviciding reduced transmission by the primary malaria vector, Anopheles gambiae s.l., by 31% (95% C.I. = 21.6–37.6%; p = 0.04).

Conclusion

This novel management, monitoring and evaluation system for implementing routine larviciding of malaria vectors in African cities has shown considerable potential for sustained, rapidly responsive, data-driven and affordable application. Nevertheless, the true programmatic value of larviciding in urban Africa can only be established through longer-term programmes which are stably financed and allow the operational teams and management infrastructures to mature by learning from experience.     

BioPEGylation of polyhydroxyalkanoates: influence on properties and satellite-stem cell cycle

The addition of poly(ethylene glycol), PEG, to bioprocessing systems producing polyhydroxyalkanoates (PHAs), has been reported as a means of their molecular weight control and can also support bioPEGylation, resulting in hybrids with amphiphillic properties. However, the study of such natural-synthetic hybrids of PHA-b-PEG is still in its infancy. In this study, we report the influence of bioPEGylation of polyhydroxyoctanoate (PHO) on its physiochemical, material, and biological properties. Consistent with previous studies, bioPEGylation with diethylene glycol (DEG) showed a significant reduction in PHA molecular weight (57%). In comparison to solvent cast films of PHO, PHO-b-DEG films possessed a noticeable X-ray diffraction peak at 9.82 degrees and increased Young's modulus of 11 Gpa (83%). Potential biocompatibility was investigated by measuring the early phase of apoptosis in myoblastic satellite-stem cells (C2C12). Comparative analysis of cell proliferation and progression in the presence of the mcl-PHA and its hybrid showed that the latter induced significant cell cycle progression: the first time a biomaterial has been shown to do so. Microtopographies of the film surfaces demonstrated that these differences were not due to changes in surface morphology; both polymers possessed average surface rugosities of 1.4 +/- 0.2 microm. However, a slight decrease in surface hydrophobicity (3.5 +/- 0.9 degrees) due to the hydrophilic DEG may have exerted an influence. The results support the further study of bioPEGylated PHAs as potential biomaterials in the field of tissue engineering.     

Genetic Variation in Toxicant-Stressed Populations: An Evaluation of the “Genetic Erosion” Hypothesis

The question whether environmental pollution affects genetic diversity in natural populations remains unanswered to date despite the fact that genetic variation is one of the three pillars of biodiversity recognized in the Rio convention of 1993. The loss of genetic diversity in populations subjected to anthropogenic stress can be designated as “genetic erosion” and may be considered as a factor of concern in risk assessment of toxic chemicals. Theoretically there are four different ways in which toxicants can affect genetic variation: (i) by increasing mutation rates, (ii) by directional selection on tolerant genotypes, (iii) by causing bottleneck events, and (iv) by altering migration. This paper reviews studies that have documented genetic change in animal populations exposed to environmental pollution. In these studies, genetic variation is measured in a variety of ways: heritability of quantitative characters, heterozygosity of allozyme loci, haplotype diversity in mitochondrial DNA, and variability in RAPD fingerprints. Studies on cadmium tolerance of Collembola living in metal-contaminated soil suggest that strong directional selection pressure may decrease genetic variability of traits immediately linked to tolerance. Allozyme studies in fish have documented a similar decrease of genetic variation in populations living in strongly acidified waters. A correlation between RAPD-PCR-based genetic similarity and site contamination has been documented in crayfish. Overall, there is significant support for the genetic erosion hypothesis, but the issue cannot be considered settled. In most studies insufficient attention is given to factors such as population size, bottlenecks and mutation, which may influence genetic variability in addition to the toxicant selection regime. At the moment, there does not seem to be a sound scientific basis for incorporating genetic diversity measurements into risk assessment, despite the variety of easily applicable molecular techniques available. It is often not known what kind of variation is measured by these techniques (neutral or selectable) and how the markers are inherited. Given the importance of the issue, as stressed by the Rio Convention, a concentrated research effort is necessary to better define the question and find a general approach to evaluate its importance in ecological risk assessment.     

Mycosin-1, a subtilisin-like serine protease of Mycobacterium tuberculosis, is cell wall-associated and expressed during infection of macrophages

Background  

Exported proteases are commonly associated with virulence in bacterial pathogens, yet there is a paucity of information regarding their role in Mycobacterium tuberculosis. There are five genes (mycP1-5) present within the genome of Mycobacterium tuberculosis H37Rv that encode a family of secreted, subtilisin-like serine proteases (the mycosins). The gene mycP1 (encoding mycosin-1) was found to be situated 3700 bp (four ORF's) from the RD1 deletion region in the genome of the attenuated vaccine strain M. bovis BCG (bacille de Calmette et Guérin) and was selected for further analyses due to the absence of expression in this organism.     

Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions

Dendritic cells (DC) are potent antigen-presenting cells capable of inducing T and B responses and immune tolerance. We have characterized some aspects of energy metabolism accompanying the differentiation process of human monocytes into DC. Compared to precursor monocytes, DC exhibited a much larger number of mitochondria and consistently (i) a higher endogenous respiratory activity and (ii) a more than sixfold increase in ATP content and an even larger increase in the activity of the mitochondrial marker enzyme citrate synthase. The presence in the culture medium of rotenone, an inhibitor of the respiratory chain Complex I, prevented the increase in mitochondrial number and ATP level, without affecting cell viability. Rotenone inhibited DC differentiation, as revealed by the observation that the expression of CD1a, which is a specific surface marker of DC differentiation, was strongly reduced. Cells cultured in the presence of rotenone displayed a lower content of growth factor-induced, mitochondrially generated, hydrogen peroxide. A similar drop in ROS was observed upon addition of catalase, which caused functional effects similar to those produced by rotenone treatment. These results suggest that ROS play a crucial role in DC differentiation and that mitochondria are an important source of ROS in this process.     

A photoswitchable ITAM peptidomimetic: synthesis and real time surface plasmon resonance (SPR) analysis of the effects of cis-trans isomerization on binding

The Syk protein plays an important role in immune receptor signaling. The Syk tandem SH2 domain (tSH2)-ITAM interaction is important for recruiting Syk to the receptor complex and for Syk kinase activation. A peptidomimetic ligand for tSH2 was synthesized in which a photoswitchable azobenzene moiety was incorporated. Such a photoswitchable moiety may regulate the distance between the two phosphotyrosine containing ITAM sequences, which bind to tSH2. Different affinities of the cis and trans isomer of the ligand were found by surface plasmon resonance (SPR). By in situ irradiation during SPR measurements the effect of the cis-trans isomerization on binding could be monitored in real time.