The objective of this study is to define the development of all components in the chick embryonic trigeminal primary sensory-motor complex, from their first appearance through the formation of ...central and peripheral axonal projections up to stage 34 (8 days of incubation). This was accomplished by two labeling procedures: application of the monoclonal antibody HNK-1, which binds to the precursors of all these components except the placode-derived neurons, and application of HRP to axons cut immediately distal to the trigeminal ganglion. Single immunopositive motor neuron precursors are present at stage 12. These accumulate in the transient medial motor column, whose neurons initiate axon outgrowth by stage 13-14, concomitant with the onset of translocation of their somata to form the definitive trigeminal lateral motor column (LMC). Initially these translocating somata accumulate on the medial margin of the LMC. Beginning on incubation day 5, axons growing from newly formed motor neurons pass beside the lateral margin of the LMC, and the nuclei of these cells subsequently follow this pathway. These events follow a rostral-to-caudal sequence, and this phase of motor nucleus formation is complete by day 8. The lateral translocation of some caudally located nuclei is arrested beginning on day 5. This cessation, which proceeds rostrally, demarcates neurons that form the dorsal motor nucleus of the trigeminal complex. Sensory neurite formation is initiated in ophthalmic placode-derived cells at stage 14.5, one stage later by maxillomandibular neurons, and from mesencephalic V cells at stage 15. Neural crest cells do not initiate axon formation until at least day 4 to 5. Following application of HRP distal to the condensing ganglion at stage 16, labeled ophthalmic nerve projections appear in contact with the wall of the hindbrain centrally and overlying the optic vesicle peripherally. Fibers forming the descending tract elongate rapidly, reaching the level of the VIIth nerve root (200 microns caudal to the trigeminal root) by stage 18 and the cervical cord by stage 22. Labeled terminal arborizations of descending trigeminal afferents are first visible at stage 22 and are evident along the entire descending and proximal ascending tracts by stage 27. Later-developing descending axons grow in close association with existing trigeminal fibers, though a few growth cones are consistently evident superficial to the other fibers. No projections different from those reported in adult birds are seen, nor are there any contralateral afferent projections.
Clustering analysis of tumor cell cytotoxicity profiles for the National Cancer Institute (NCI)'s open compound repository has been used to catalog over 1100 metal or metalloid containing compounds ...with potential anticancer activity. The molecular features and corresponding reactivity of these compounds have been analyzed in terms of properties of their metals, their associated organic components (ligands) and their capacity to inhibit tumor cell growth. Cytotoxic responses are influenced by both the identity of the metal and the properties of its coordination ligand, with clear associations between structural similarities and cytotoxicity. Assignments of mechanisms of action (MOAs) for these compounds could be segregated into four broad response classes according to preference for binding to biological sulfhydryl groups, chelation, generation of reactive oxygen species (ROS), and production of lipophilic ions. Correlations between specific cytotoxic responses and differential gene expression profiles within the NCI's tumor cell panel serve as a validation for candidate biological targets and putative MOA classes. In addition, specific sensitivity toward subsets of metal containing agents has been found for certain tumor cell panels. Taken together, our results expand the knowledge base available for evaluating, designing and developing new metal-based anticancer drugs that may provide the basis for target-specific therapeutics.
Studies into the genetic origins of tumor cell chemoactivity pose significant challenges to bioinformatic mining efforts. Connections between measures of gene expression and chemoactivity have the ...potential to identify clinical biomarkers of compound response, cellular pathways important to efficacy and potential toxicities; all vital to anticancer drug development. An investigation has been conducted that jointly explores tumor-cell constitutive NCI60 gene expression profiles and small-molecule NCI60 growth inhibition chemoactivity profiles, viewed from novel applications of self-organizing maps (SOMs) and pathway-centric analyses of gene expressions, to identify subsets of over- and under-expressed pathway genes that discriminate chemo-sensitive and chemo-insensitive tumor cell types. Linear Discriminant Analysis (LDA) is used to quantify the accuracy of discriminating genes to predict tumor cell chemoactivity. LDA results find 15% higher prediction accuracies, using ∼30% fewer genes, for pathway-derived discriminating genes when compared to genes derived using conventional gene expression-chemoactivity correlations. The proposed pathway-centric data mining procedure was used to derive discriminating genes for ten well-known compounds. Discriminating genes were further evaluated using gene set enrichment analysis (GSEA) to reveal a cellular genetic landscape, comprised of small numbers of key over and under expressed on- and off-target pathway genes, as important for a compound's tumor cell chemoactivity. Literature-based validations are provided as support for chemo-important pathways derived from this procedure. Qualitatively similar results are found when using gene expression measurements derived from different microarray platforms. The data used in this analysis is available at http://pubchem.ncbi.nlm.nih.gov/andhttp://www.ncbi.nlm.nih.gov/projects/geo (GPL96, GSE32474).
Wheat germ agglutinin conjugated to tetramethylrhodamine isothiocyanate-dextran (WGA–TRITC) was studied as a novel tracer of primary projection neurons of pharyngeal (PhN) and superior laryngeal ...(SLN) branches of the vagus nerve. The SLN and PhN were dissected from rat cervical tissues and the proximal end of the nerves were bathed in tracer for 60–90 min. The animals were sacrificed 42–72 h later. The tissue was fixed, sliced, mounted on slides and viewed under epifluorescence. The clarity of the fluorescent label in projection neurons was confounded in some regions of the brainstem by autofluorescence. A computer image analysis method was developed to quantify fluorescence intensity for definitive identification of labeled neurons. Brainstem neurons labeled by afferent projections of the SLN and PhN were localized to the nucleus tractus solitarius. Efferents were identified in the nucleus ambiguus. WGA–TRITC labeled cells were observed in the ipsilateral brainstem at intensities significantly different from the fluorescence observed in controls (
P<0.01). The distribution and density of labeling is in agreement with results of previous investigations, suggesting that WGA–TRITC is a useful alternative for tracing SLN and PhN projections to brainstem nuclei.
To compare efficacy of casein phosphopeptide (CPP)-amorphous calcium phosphate (ACP) fluoride varnish and light-curable resin modified glass ionomer fluoride varnish (FV) in preventing white spot ...lesions and evaluating acid etching prior to CPP-ACPFV application on its efficacy.
Molars and premolars were transected and halves divided into four groups (n = 18/group): (1) resin-modified glass ionomer FV: etched and Clinpro-XT varnish (3M ESPE, Pymble, New South Wales, Australia) application; (2) CPP-ACPFV: MI varnish (GC America, Alsip, IL) application; (3) Etch+CPP-ACPFV: etched and MI varnish application; (4) Control: etched and no surface treatment. To simulate 12 weeks in an intraoral environment, samples were subjected to thermocycling, brushing, and pH cycling. Enamel surface microhardness was evaluated at baseline and after the simulated 12 weeks. Representative samples were also assessed using scanning electron microscopy (SEM).
At baseline there was no significant difference in microhardness among groups. After the simulated 12 weeks, all groups showed significant within-group differences (P < .001). Control showed the highest percentage loss of surface microhardness (89%), followed by CPP-ACPFV (58%), RMGIFV (51%), and Etch+CPP-ACPFV (24%). The control group had a significant decrease in microhardness compared to all experimental groups (P < .001). No difference was found between the RMGIFV and CPP-ACPFV varnish groups. The Etch+CPP-ACPFV group had significantly less decrease in microhardness compared to the RMGIFV (P < .001) and CPP-ACPFV groups (P < .001). With SEM, control samples showed signs of enamel surface damage, while experimental groups showed spherical particles on a relatively intact surface.
RMGIFV and CPP-ACPFV are effective in reducing enamel demineralization. Acid etching the enamel surface prior to CPP-ACPFV varnish application increased its efficacy.
Background The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the ...maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. Methods Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents ( n =30) and emerging adults ( n = 20). Results ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. Conclusions These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.
Introduction Closure and long-term retention of anterior open bites are significant concerns for orthodontists and their patients. In this study, we investigated the efficacy of orofacial ...myofunctional therapy (OMT) for maintaining closure of open bites in conjunction with orthodontic treatment. Methods The sample included 76 subjects with dental anterior open bites referred for OMT before, during, or after relapse of orthodontic treatment. The experimental cohort consisted of 27 subjects who received OMT and orthodontic treatment or retreatment. The control cohort comprised 49 subjects who had a history of orthodontic treatment with open-bite relapse. Overbite was evaluated by an OMT professional or orthodontist 2 months to 23 years after removal of the fixed appliances. Measurements were compared with t tests. Results Overbite relapse means were 0.5 mm (range, 0.0-4.0 mm) in the experimental group and 3.4 mm (range, 1.0-7.0 mm) in the control group, a difference that was clinically and statistically significant ( P <0.0001). Conclusions This study demonstrated that OMT in conjunction with orthodontic treatment was highly effective in maintaining closure of anterior open bites compared with orthodontic treatment alone.
A bicycle built for tubulin: The total synthesis of (+)-chamaecypanone C has been achieved by using a tandem retro-Diels-Alder/Diels-Alder cascade reaction (see scheme). Initial biological studies ...demonstrate that (+)-chamaecypanone C is an inhibitor of tubulin assembly and binds at the colchicine site.
An extract from Phyllanthus engleri was identified in a bioinformatic analysis of NCI 60-cell natural product extract screening data that selectively inhibited the growth of renal cancer cell lines. ...Bioassay-guided fractionation yielded two new guaiane sesquiterpenes, englerins A (1) and B (2). Englerin A showed 1000-fold selectivity against six of eight renal cancer cell lines with GI(50) values ranging from 1-87 nM. The structures of 1 and 2 and their relative stereochemistry were established by spectroscopic methods.
Cancer stem cells (CSC) are thought to be responsible for tumor maintenance and heterogeneity. Bona fide CSC purified from tumor biopsies are limited in supply and this hampers study of CSC biology. ...Furthermore, purified stem-like CSC subpopulations from existing tumor lines are unstable in culture. Finding a means to overcome these technical challenges would be a useful goal. In a first effort towards this, we examined whether a chemical probe that promotes survival of murine embryonic stem cells without added exogenous factors can alter functional characteristics in extant tumor lines in a fashion consistent with a CSC phenotype.
The seven tumor lines of the NCI60 colon subpanel were exposed to SC-1 (pluripotin), a dual kinase and GTPase inhibitor that promotes self-renewal, and then examined for tumorigenicity under limiting dilution conditions and clonogenic activity in soft agar. A statistically significant increase in tumor formation following SC-1 treatment was observed (p<0.04). Cloning efficiencies and expression of putative CSC surface antigens (CD133 and CD44) were also increased. SC-1 treatment led to sphere formation in some colon tumor lines. Finally, SC-1 inhibited in vitro kinase activity of RSK2, and another RSK2 inhibitor increased colony formation implicating a role for this kinase in eliciting a CSC phenotype.
These findings validate a proof of concept study exposure of extant tumor lines to a small molecule may provide a tractable in vitro model for understanding CSC biology.
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