IMPRINTING EFFECTS OF THREE AMINO ACIDS (ALANINE,LYSINE AND GLYCINE) AND THEIR OLIGOPEPTIDES INTETRAHYMENA PYRIFORMIS. DATA FROM THE HORMONE AND HORMONE RECEPTOR EVOLUTION

Hormonal imprinting takes place at the first encounter of the hormone and receptor, and results in a changed binding capacity and reaction of the cell and its progeny generations. The imprinting effect of three amino acids and their oligopeptides is studied using fluorescent-labelled peptides. Glycine and lysine could provoke positive imprinting (increased binding in the progeny generations) for their own peptides, but alanine could not. Mostly positive imprinting was provoked by glycine and lysine peptides for their own peptides of different chain length. The optimal chain length provoking self-imprinting was four for glycine, two for lysine and three for alanine. Except in this case, alanine was neutral or provoked mostly negative imprinting. After reaching the optimal chain length, there is a decline in binding. Evolutionary conclusions are discussed.     

Respiratory burst metabolic status of macrophages in experimental leprosy.

Peritoneal macrophages from uninfected controls and Mycobacterium leprae infected Swiss albino mice were studied for their respiratory burst (RB) activity at different time intervals. The RB metabolic activity of macrophages declined significantly after 3 month infection using latex (p less than 0.001) and M. leprae (p less than 0.01) as stimuli. However, significant rise (p less than 0.001) in the oxidative metabolic activity was seen at 6 and 9 months postinfection period on stimulation with both the stimuli. The sharp rise in the oxidative metabolic status at peak period of infection in the experimental animals suggests that the macrophages are functionally normal though M. leprae is unable to trigger the respiratory burst sufficiently.     

Intense photon emission induced by fracture of γ–irradiated Dy‐, Tm‐, Sm‐ and Mn‐doped CaSO4 single crystals

When an γ‐irradiated Dy‐, Tm‐, Sm‐ or Mn‐doped CaSO₄ crystal is impulsively deformed, two peaks appear in the ML intensity versus time curve, whereby the first ML peak is found in the deformation region and the second in the post‐deformation region of the crystals. In this study, intensities I_m1 and I_m2 corresponding to first and second ML peaks, respectively, increased linearly with an impact velocity v₀ of the piston used to deform the crystals, and times t_m1 and t_m2 corresponding to the first and second ML peaks, respectively, decreased with impact velocity. Total ML intensity initially increased with impact velocity and then reached a saturation value for higher values of impact velocity. ML intensity increased with increasing γ‐doses and size of crystals. Results showed that the electric field produced as a result of charging of newly‐created surfaces caused tunneling of electrons to the valence band of the hole‐trapping centres. The free holes generated moved in the valence band and their subsequent recombination with electron trapping centres released energy, thereby resulting in excitation of luminescent centres. Copyright © 2012 John Wiley & Sons, Ltd.     

Cell Budding from Normal Appearing Epithelia: A Predictor of Colorectal Cancer Metastasis?

Background: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC.Novel findings: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or “budding” of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte''s natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker.New hypothesis: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as “seeds” to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation.     

Alterations in Cortical Sensorimotor Connectivity following Complete Cervical Spinal Cord Injury: A Prospective Resting-State fMRI Study

Functional magnetic resonance imaging (fMRI) studies have demonstrated alterations during task-induced brain activation in spinal cord injury (SCI) patients. The interruption to structural integrity of the spinal cord and the resultant disrupted flow of bidirectional communication between the brain and the spinal cord might contribute to the observed dynamic reorganization (neural plasticity). However, the effect of SCI on brain resting-state connectivity patterns remains unclear. We undertook a prospective resting-state fMRI (rs-fMRI) study to explore changes to cortical activation patterns following SCI. With institutional review board approval, rs-fMRI data was obtained in eleven patients with complete cervical SCI (>2 years post injury) and nine age-matched controls. The data was processed using the Analysis of Functional Neuroimages software. Region of interest (ROI) based analysis was performed to study changes in the sensorimotor network using pre- and post-central gyri as seed regions. Two-sampled t-test was carried out to check for significant differences between the two groups. SCI patients showed decreased functional connectivity in motor and sensory cortical regions when compared to controls. The decrease was noted in ipsilateral, contralateral, and interhemispheric regions for left and right precentral ROIs. Additionally, the left postcentral ROI demonstrated increased connectivity with the thalamus bilaterally in SCI patients. Our results suggest that cortical activation patterns in the sensorimotor network undergo dynamic reorganization following SCI. The presence of these changes in chronic spinal cord injury patients is suggestive of the inherent neural plasticity within the central nervous system.     

Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next‐generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four‐case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.     

The correlation of protein structure and evolution of a protein-coding gene: phylogenetic inference using cytochrome oxidase III

Discriminating phylogenetic signal from noise in DNA sequence data is a difficult problem in phylogenetic inference at higher systematic levels. For protein-coding genes, noise at synonymous (silent) positions can be filtered by deleting entire codon positions or types of change at a codon position. This method is not appropriate for replacement sites, because changes at each site within a codon may not be independent. This research presents a method using information from protein structure to evaluate variation in replacement sites. Analysis of the correlation of amino acid variation with protein structure identified rapidly evolving codons in the COIII gene. In a series of phylogenetic analyses attempting to recover a known set of vertebrate relationships, downweighting these labile codons produced the most accurate results. Structural correlates of variable and invariant residues identified in this study can be used to increase the accuracy of models used for phylogenetic inference. Viewing amino acid variation within a phylogenetic framework provided insight into residue changes important in the secondary and tertiary structures of the molecule, changes that were correlated between pairs of neighboring residues or between residues in neighboring helices.      

Ultrasound imaging in an experimental model of fatty liver disease and cirrhosis in rats

Background

Atypical scrapie was first identified in Norwegian sheep in 1998 and has subsequently been identified in many countries. Retrospective studies have identified cases predating the initial identification of this form of scrapie, and epidemiological studies have indicated that it does not conform to the behaviour of an infectious disease, giving rise to the hypothesis that it represents spontaneous disease. However, atypical scrapie isolates have been shown to be infectious experimentally, through intracerebral inoculation in transgenic mice and sheep. The first successful challenge of a sheep with 'field' atypical scrapie from an homologous donor sheep was reported in 2007.

Results

This study demonstrates that atypical scrapie has distinct clinical, pathological and biochemical characteristics which are maintained on transmission and sub-passage, and which are distinct from other strains of transmissible spongiform encephalopathies in the same host genotype.

Conclusions

Atypical scrapie is consistently transmissible within AHQ homozygous sheep, and the disease phenotype is preserved on sub-passage.