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MRI of peripheral nerve degeneration and regeneration: correlation with electrophysiology and histology.

Acute axonal nerve lesions cause a hyperintense signal on T2-weighted (T2-w) magnetic resonance imaging (MRI) at the nerve lesion site and distal to it. The aim of this experimental study was to investigate the spatiotemporal evolution and resolution of MR nerve signal changes following denervation and reinnervation, and to relate these findings to electrophysiology and histology. The proximal sciatic nerve of adult rats was ligated by a tight suture that was removed 1 week later to induce complete axotomy and nerve regeneration upon release. Serial electromyography (EMG) and motor nerve conduction studies were performed parallel to MRI at multiple points of time. Moreover, sciatic nerves were taken for quantitative histological evaluation. Nerve hyperintensity on T2-w MRI was present distal to the lesion at thigh level 24 h after denervation preceding the occurrence of spontaneous activity on EMG by 24 h. After 48 h, the entire sciatic nerve and its branches showed an increased signal down to the level of the lower leg. The increased nerve signal regressed with a proximo-distal gradient beginning from week 2 after onset of nerve regeneration in the thigh. On EMG, the first reinnervation potentials were detected at that time at the respective level. Compound muscle action potential (CMAP) in the foot muscle fully recovered 12 weeks after onset of nerve regeneration, that is, 2 weeks after resolution of the hyperintensity along the entire nerve on MRI. Histology revealed axonal degeneration in the acute phase and later nerve oedema parallel to the increased nerve signal on MRI. MR signal alterations occur as early as 24 h after an axonal nerve lesion and correlate with nerve fiber degeneration and later with nerve oedema on histology. MR findings in denervation and reinnervation parallel the electrophysiological changes. Thus, MRI is a promising diagnostic tool for the early detection of acute axonal nerve lesions and monitoring of nerve regeneration.

Animals↗

Psychiatric research ethics: an overview of evolving guidelines and current ethical dilemmas in the study of mental illness.

The field of psychiatry has an opportunity to construct a more refined, perhaps more enduring understanding of the ethical basis of mental illness research. The aim of this paper is to help advance this understanding by 1) tracing the evolution of the emerging ethic for biomedical experimentation, including recent recommendations of the President's National Bioethics Advisory Commission, and 2) reviewing data and concepts related to compelling ethical questions now faced in the study of mental disorders. Empirical findings on informed consent, the ethical safeguards of institutional review and surrogate decision making, and the relationship between scientific and ethical imperatives are outlined. Psychiatric researchers will increasingly be called upon to justify their scientific approaches and to seek ways of safeguarding the well-being of people with mental illness who participate in experiments. Most importantly, psychiatric investigators will need to demonstrate their appreciation and respect for ethical dimensions of investigation with special populations. Further empirical study and greater sophistication with respect to the distinct ethical issues in psychiatric research are needed. Although such measures present many challenges, they should not interfere with progress in neuropsychiatric science so long as researchers in our field seek to guide the process of reflection and implementation.

Bioethics↗

Isolation of a highly active PSII-LHCII supercomplex from thylakoid membranes by a direct method.

We have developed a simple and novel method to isolate a highly pure and active photosystem (PS) II complex, directly from thylakoid membranes. This complex is a discrete particle and contains all the proteins of the oxygen evolving complex and a set of chlorophyll alb binding proteins. The intactness of both the donor side and the acceptor side has resulted in a very high oxygen evolution activity and therefore offers a superior experimental system to that of PSII enriched membrane fragments in which there is heterogeneity in activities and biochemical composition.

Cell Membrane↗

Advances in surface plasmon resonance biosensor analysis.

The number and diversity of surface plasmon resonance (SPR) biosensor applications continue to increase. Evolutions in instrument and sensor chip technology, experimental methodology, and data analysis are making it possible to examine a wider variety of biomolecular interactions in greater mechanistic detail. SPR biosensors are poised to make a significant impact in basic research and pharmaceutical discovery.

Animals↗

Silica nanoparticle formation in the TPAOH-TEOS-H2O system: a population balance model.

A model describing the kinetics of silica nanoparticle formation in the TPAOH-TEOS-H(2)O system is presented. These nanoparticles are an important intermediate in the clear-solution synthesis of silicalite-1, so understanding the mechanisms by which they are formed and stabilized is a key step in determining the crystallization behavior of pure-silica zeolites. The model presented here is based on the mass-conserving form of the Becker-Döring population balance equations, describing growth and fragmentation by addition or removal of monomeric units, and modified to account for rapid equilibration of small silicate species and electrostatic and/or template stabilization of nanoparticles. The model predictions compare favorably with the experimental results. It is found that nanoparticle evolution exhibits distinct time regimes consisting of TEOS hydrolysis, condensation, nanoparticle formation, Ostwald ripening, and a self-sharpening mechanism in particle size distribution toward equilibrium due to stabilization during which no apparent changes in average particle size and pH are observed. Finally, the model provides an alternative, to a recent hypothesis, kinetics point of view to explain the enhanced stability of nanoparticles over extended periods of time.

Journal Article↗

Squid major lens polypeptides are homologous to glutathione S-transferases subunits.

The eye lenses of cephalopods and vertebrates evolved relatively recently and by independent routes. They provide a good experimental model for the study of convergent evolution at the protein level. One proposal is that pre-existing proteins were recruited as structural eye lens proteins during evolution. This has been confirmed for the vertebrate eye lens structural proteins, or crystallins, which have been intensively studied. Despite the limited information about cephalopod eye lenses, it has been suggested that glutathione S-transferases (GSTs) are a possible evolutionary ancestor of the squid major lens proteins. Recently, the N-terminal sequence of the squid major lens protein was shown to be 55% homologous with that of the Ya subunit of the rat GST. Here, we demonstrate that the squid major lens polypeptides are encoded by a gene family of at least three members. We characterize two cDNAs corresponding to these genes and show they probably either are GST subunits themselves, or share an evolutionary ancestor with them.

Animals↗

Clonal expansion of p53 mutant cells is associated with brain tumour progression.

Tumour progression is a fundamental feature of the biology of cancer. Cancers do not arise de novo in their final form, but begin as small, indolent growths, which gradually acquire characteristics associated with malignancy. In the brain, for example, low-grade tumours (astrocytomas) evolve into faster growing, more dysplastic and invasive high-grade tumours (glioblastomas). To define the genetic events underlying brain tumour progression, we analysed the p53 gene in ten primary brain tumour pairs. Seven pairs consisted of tumours that were high grade both at presentation and recurrence (group A) and three pairs consisted of low-grade tumours that had progressed to higher grade tumours (group B). In group A pairs, four of the recurrent tumours contained a p53 gene mutation; in three of them, the same mutation was found in the primary tumour. In group B pairs, progression to high grade was associated with a p53 gene mutation. A subpopulation of cells were present in the low-grade tumours that contained the same p53 gene mutation predominant in the cells of the recurrent tumours that had progressed to glioblastoma. Thus, the histological progression of brain tumours was associated with a clonal expansion of cells that had previously acquired a mutation in the p53 gene, endowing them with a selective growth advantage. These experimental observations strongly support Nowell's clonal evolution model of tumour progression.

Amino Acid Sequence↗

The genetic theory of adaptation: a brief history.

Theoretical studies of adaptation have exploded over the past decade. This work has been inspired by recent, surprising findings in the experimental study of adaptation. For example, morphological evolution sometimes involves a modest number of genetic changes, with some individual changes having a large effect on the phenotype or fitness. Here I survey the history of adaptation theory, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation. I also discuss the challenges that face contemporary theories of adaptation.

Adaptation, Biological↗

Study of the densification mechanisms of Al-Fe-Cr-Ti alloys during high-velocity compaction based on 3D MPFEM.

Aluminum alloy materials are widely used in aerospace and related fields, among which Al-Fe-Cr-Ti alloys have attracted increasing attention owing to their low density and excellent comprehensive properties. However, the densification mechanisms of alloy powders during high-velocity compaction (HVC) remain insufficiently understood. In this study, a three-dimensional multi-particle finite element method (3D MPFEM) model was developed to simulate the HVC process of Al-Fe-Cr-Ti alloy powders and to evaluate the effects of friction coefficient μ, impact energy per unit mass Em, hammer mass M, and compaction velocity v on powder densification. The results show that increasing μ from 0.25 to 0.65 reduced kinetic-energy transfer and stress transmission, decreasing the relative density ρ of the green from 0.7076 to 0.6797. In contrast, increasing Em from 55.58 to 144.67 J/g markedly improved densification, with the maximum relative density reaching 0.8881. Displacement-field analysis further revealed that appropriate combinations of M and v promote particle rearrangement and plastic deformation. Experimental validation confirmed that the simulated density evolution agreed well with the measured trend, although the predicted values were slightly lower. These findings indicate that 3D MPFEM can reasonably describe the macroscopic densification trend and provide qualitative particle-scale insights into deformation and energy-transfer behavior during HVC.

3D MPFEM↗

Review neuroimaging in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic degenerative disorder of unknown etiology affecting the motor system. Conventional and non-conventional neuroimaging techniques can provide essential help both to increase the confidence in ALS diagnosis and to assess the disease evolution. Signal abnormalities at the level of the motor cortex and the corticospinal tract on conventional T2-weighted magnetic resonance (MR) images are a potentially useful marker of ALS pathology. However, the prognostic value of these conventional MR abnormalities is still hampered by their low pathological specificity. Non-conventional MR techniques with a higher pathological specificity, such as MR spectroscopy, magnetization transfer imaging and diffusion-weighted imaging, seem to have some potential not only for ALS diagnosis, but also for monitoring disease evolution either naturally or when modified by experimental treatments.

Amyotrophic Lateral Sclerosis↗

Asymmetric autocatalysis and its implications for the origin of homochirality.

An autocatalytic reaction in which the reaction product serves as a catalyst to produce more of itself and to suppress production of its enantiomer serves as a mechanistic model for the evolution of homochirality. The Soai reaction provided experimental confirmation of this concept, nearly 50 years after it was first proposed. This Perspective offers a rationalization of the Soai autocatalytic reaction; accounting for enantiomeric excess and rate observations, that is both simple as well as gratifying in its implications for the chemical origin of life.

Journal Article↗

Studies on the pathogenicity of group A Streptococci. I. Its relation to surface phagocytosis.

Four strains of Group A streptococci, possessing different degrees of virulence for both mice and rats, were tested for susceptibility to phagocytosis on glass slides, in glass roller tubes, and on the surfaces of freshly excised tissues and moistened filter paper. All of the tests were performed in the absence of serum to exclude the possible presence of opsonins. Only under conditions which allowed surface phagocytosis to take place was there a correlation between virulence and susceptibility to phagocytosis. A similar relationship between virulence and surface phagocytosis was also demonstrable in vivo during the early stages of experimental streptococcal peritonitis. Systematic study of the evolution of the peritonitis revealed that its outcome was determined by the phagocytic reaction which occurred in the first few hours of the infection.

Animals↗

Molecular Genetics Information System (MOLGENIS): alternatives in developing local experimental genomics databases.

MOTIVATION: Genomic research laboratories need adequate infrastructure to support management of their data production and research workflow. But what makes infrastructure adequate? A lack of appropriate criteria makes any decision on buying or developing a system difficult. Here, we report on the decision process for the case of a molecular genetics group establishing a microarray laboratory. RESULTS: Five typical requirements for experimental genomics database systems were identified: (i) evolution ability to keep up with the fast developing genomics field; (ii) a suitable data model to deal with local diversity; (iii) suitable storage of data files in the system; (iv) easy exchange with other software; and (v) low maintenance costs. The computer scientists and the researchers of the local microarray laboratory considered alternative solutions for these five requirements and chose the following options: (i) use of automatic code generation; (ii) a customized data model based on standards; (iii) storage of datasets as black boxes instead of decomposing them in database tables; (iv) loosely linking to other programs for improved flexibility; and (v) a low-maintenance web-based user interface. Our team evaluated existing microarray databases and then decided to build a new system, Molecular Genetics Information System (MOLGENIS), implemented using code generation in a period of three months. This case can provide valuable insights and lessons to both software developers and a user community embarking on large-scale genomic projects. AVAILABILITY: http://www.molgenis.nl

Computational Biology↗

A shift to parasitism in the jellyfish symbiont Symbiodinium microadriaticum.

One of the outstanding and poorly understood examples of cooperation between species is found in corals, hydras and jellyfish that form symbioses with algae. These mutualistic algae are mostly acquired infectiously from the seawater and, according to models of virulence evolution, should be selected to parasitize their hosts. We altered algal transmission between jellyfish hosts in the laboratory to examine the potential for virulence evolution in this widespread symbiosis. In one experimental treatment, vertical transmission of algae (parent to offspring) selected for symbiont cooperation, because symbiont fitness was tied to host reproduction. In the other treatment, horizontal transmission (infectious spread) decoupled symbiont fitness from the host, potentially allowing parasitic symbionts to spread. Fitness estimates revealed a striking shift to parasitism in the horizontal treatment. The horizontally transmitted algae proliferated faster within hosts and had higher dispersal rates from hosts compared to the vertical treatment, while reducing host reproduction and growth. However, a trade-off was detected between harm caused to hosts and symbiont fitness. Virulence trade-offs have been modelled for pathogens and may be critical in stabilising 'infectious' symbioses. Our results demonstrate the dynamic nature of this symbiosis and illustrate the potential ease with which beneficial symbionts can evolve into parasites.

Animals↗

The cryptic ushA gene (ushA(c)) in natural isolates of Salmonella enterica (serotype Typhimurium) has been inactivated by a single missense mutation.

Two mutational mechanisms, both supported by experimental studies, have been proposed for the evolution of new or improved enzyme specificities in bacteria. One mechanism involves point mutation(s) in a gene conferring novel substrate specificity with partial or complete loss of the original (wild-type) activity of the encoded product. The second mechanism involves gene duplication followed by silencing (inactivation) of one of these duplicates. Some of these 'silent genes' may still be transcribed and translated but produce greatly reduced levels of functional protein; gene silencing, in this context, is distinct from the more common associations with bacterial partitioning sequences, and with genes which are no longer transcribed or translated. Whereas most Salmonella enterica strains are ushA(+), encoding an active 5'-nucleotidase (UDP-sugar hydrolase), some natural isolates, including most genetically related strains of serotype Typhimurium, have an ushA allele (designated ushA(c)) which produces a protein with, comparatively, very low 5'-nucleotidase activity. Previous sequence analysis of cloned ushA(c) and ushA(+) genes from serotype Typhimurium strain LT2 and Escherichia coli, respectively, did not reveal any changes which might account for the significantly different 5'-nucleotidase activities. The mechanism responsible for this reduced activity of UshA(c) has hitherto not been known. Sequence analysis of Salmonella ushA(+) and ushA(c) alleles indicated that the relative inactivity of UshA(c) may be due to one, or more, of four amino acid substitutions. One of these changes (S139Y) is in a sequence motif that is conserved in 5'-nucleotidases across a range of diverse prokaryotic and eukaryotic species. Site-directed mutagenesis confirmed that a Tyr substitution of Ser-139 in Salmonella UshA(+) was solely responsible for loss of 5'-nucleotidase activity. It is concluded that the corresponding single missense mutation is the cause of the UshA(c) phenotype. This is the first reported instance of gene inactivation in natural isolates of bacteria via a missense mutation. These results support a model of evolution of new enzymes involving a 'silent gene' which produces an inactive, or relatively inactive, product, and are also consistent with the evolution of a novel, but unknown, enzyme specificity by a single amino acid change.

Amino Acid Sequence↗

Fractal pharmacokinetics of the drug mibefradil in the liver.

We explore the ramifications of the fractal geometry of the key organ for drug elimination, the liver, on pharmacokinetic data analysis. A formalism is developed for the use of a combination of well-stirred Euclidean and fractal compartments in the body. Perturbation analysis is carried out to obtain analytical solutions for the drug concentration time evolution. These results are then fitted to experimental data collected from clinically instrumented dogs [see, A. Skerjanec et al., J. Pharm. Sci. 85, 189 (1995)] using the drug mibefradil. The thus obtained spectral fractal dimension has a range of values that is consistent with the value found in independently performed ultrasound experiments on the liver.

Animals↗

Dynamical plasma response during driven magnetic reconnection.

Direct measurements of a collisionless current channel during driven magnetic reconnection are obtained for the first time on the Versatile Toroidal Facility. The size of the diffusion region is found to scale with the electron drift orbit width, independent of the ion mass and plasma density. Based on experimental observations, analytic expressions governing the dynamical evolution of the current profile and the formation of the electrostatic potential that develops in response to the externally imposed reconnection drive are established. This time response is closely linked to the presence of ion polarization currents.

Journal Article↗

Evolution of terrace-width distributions on vicinal surfaces: Fokker-Planck derivation of the generalized Wigner surmise.

We use a Fokker-Planck equation to justify the generalization of the Wigner surmise for the energy-level spacing in quantum systems to the simple expression for the equilibrium terrace-width distribution of steps--with arbitrary-strength repulsions--on a vicinal surface, taking advantage of analogies to one-dimensional models of interacting, spinless fermions. This approach leads to an analytic description of the evolution toward equilibrium of steps from several experimentally relevant initial distributions: step bunches, perfect cleaved crystals, and prequench equilibrated distributions at different temperatures.

Journal Article↗