Mechanisms and regulation of iron trafficking across the capillary endothelial cells of the blood-brain barrier.

The transcellular trafficking of iron from the blood into the brain interstitium depends on iron uptake proteins in the apical membrane of brain microvascular capillary endothelial cells and efflux proteins at the basolateral, abluminal membrane. In this review, we discuss the three mechanisms by which these cells take-up iron from the blood and the sole mechanism by which they efflux this iron into the abluminal space. We then focus on the regulation of this efflux pathway by exocrine factors that are released from neighboring astrocytes.

A Systems Pharmacology Model of Erythropoiesis in Mice Induced by Small Molecule Inhibitor of Prolyl Hydroxylase Enzymes.

Mammalian erythropoiesis is a conserved process tightly controlled by the hypoxia-inducible factor (HIF1) pathway. In this study, a small molecule inhibitor (PHI-1) of prolyl-hydroxylase-2 (PHD2) enzyme involved in regulating HIF1α levels was orally administered to male BALB/c mice at 10 and 30 mg/kg. A systems pharmacology model was developed based on the measured PHI-1 plasma exposures, kidney HIF1α, kidney erythropoietin (EPO) mRNA, plasma EPO, reticulocyte counts, red blood cells, and hemoglobin levels.

Targeted genetic manipulations of neuronal subtypes using promoter-specific combinatorial AAVs in wild-type animals.

Techniques to genetically manipulate the activity of defined neuronal subpopulations have been useful in elucidating function, however applicability to translational research beyond transgenic mice is limited. Subtype targeted transgene expression can be achieved using specific promoters, but often currently available promoters are either too large to package into many vectors, in particular adeno-associated virus (AAV), or do not drive expression at levels sufficient to alter behavior. To permit neuron subtype specific gene expression in wildtype animals, we developed a combinatorial AAV targeting system that drives, in combination, subtype specific Cre-recombinase expression with a strong but non-specific Cre-conditional transgene.

On drawing a line through the spectrogram: how do we understand deficits of vocal pitch imitation?

In recent years there has been a remarkable increase in research focusing on deficits of pitch production in singing. A critical concern has been the identification of "poor pitch singers," which we refer to more generally as individuals having a "vocal pitch imitation deficit." The present paper includes a critical assessment of the assumption that vocal pitch imitation abilities can be treated as a dichotomy.

Intrusions of a drowsy mind: neural markers of phenomenological unpredictability.

The transition from a relaxed to a drowsy state of mind is often accompanied by hypnagogic experiences: most commonly, perceptual imagery, but also linguistic intrusions, i.e., the sudden emergence of unpredictable anomalies in the stream of inner speech.

Cognitive enhancement kept within contexts: neuroethics and informed public policy.

Neurothics has far greater responsibilities than merely noting potential human enhancements arriving from novel brain-centered biotechnologies and tracking their implications for ethics and civic life. Neuroethics must utilize the best cognitive and neuroscientific knowledge to shape incisive discussions about what could possibly count as enhancement in the first place, and what should count as genuinely "cognitive" enhancement. Where cognitive processing and the mental life is concerned, the lived context of psychological performance is paramount.

Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats.

The cannabinoid CB1 receptor system is involved in feeding behaviors and the CB1 receptor antagonist SR141716A is an effective antiobesity drug. However, SR141716A also has serious side effects, which prompted the exploration of alternative strategies to modulate this important drug target. Recently a CB1 receptor allosteric modulating site has been discovered and the allosteric modulating activity of several modulators including ORG27569 has been characterized in vitro.

Comparative organization of the claustrum: what does structure tell us about function?

The claustrum is a subcortical nucleus present in all placental mammals. Many anatomical studies have shown that its inputs are predominantly from the cerebral cortex and its outputs are back to the cortex. This connectivity thus suggests that the claustrum serves to amplify or facilitate information processing in the cerebral cortex.

Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration.

There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive.

Biomedical informatics: we are what we publish.

Introduction: This article is part of a For-Discussion-Section of Methods of Information in Medicine on "Biomedical Informatics: We are what we publish". It is introduced by an editorial and followed by a commentary paper with invited comments. In subsequent issues the discussion may continue through letters to the editor.

Contrasting Roles of IL-22 and IL-17 in Murine Genital Tract Infection by Neisseria gonorrhoeae.

Murine genital tract infection with Neisseria gonorrhoeae has previously been found to induce IL-17 which is important in both recruitment of neutrophils and prompt clearance of the infection. As IL-22 is another Th17-related cytokine that has been implicated in the immune responses in several infection models, we investigated its role in vaginal gonococcal infection of mice. Production of IL-22 was observed in response to stimulation with N.

New concepts in immunity to Neisseria gonorrhoeae: innate responses and suppression of adaptive immunity favor the pathogen, not the host.

It is well-known that gonorrhea can be acquired repeatedly with no apparent development of protective immunity arising from previous episodes of infection. Symptomatic infection is characterized by a purulent exudate, but the host response mechanisms are poorly understood. While the remarkable antigenic variability displayed by Neisseria gonorrhoeae and its capacity to inhibit complement activation allow it to evade destruction by the host's immune defenses, we propose that it also has the capacity to avoid inducing specific immune responses.

Analysis of sustainable pest control using a pesticide and a screened refuge.

We describe and analyze a 'screened refuge' technique for indefinitely sustaining control of insect pests using transgenic pesticidal crops or an applied pesticide, even when resistance is not recessive. The screen is a physical barrier that restricts pest movement. In a deterministic discrete-time model of the use of this technique, we obtain asymptotic analytical formulas for the two important equilibria of the system in terms of the refuge size and the pest fitnesses, mutation rates, and mobility out of and into the refuge.

Evaluation of the antimicrobial activity of dentifrices on human oral bacteria.

Objective: In vitro testing of antimicrobial agents is an important tool in the testing hierarchy, and may provide interesting insights into their potential clinical efficacy. Agents with demonstrable in vitro antimicrobial activity may be effective against the same microorganisms in vivo, whereas agents without demonstrable in vitro antimicrobial activity are unlikely to exhibit in vivo antimicrobial activity. In addition, these methods may also be useful in screening antimicrobial agents in product formulations because such agents with both in vitro and in vivo activity may have reduced antimicrobial effects when formulated into a dentifrice.

Immunoreactivity of ICAM-1 in human tumors, metastases and normal tissues.

Intercellular adhesion molecule-1 (ICAM-1) is implicated to play a role in cancer metastasis, and may serve as a diagnostic tool for tumor prognosis and progression as well as a target for therapeutic intervention. The aim of this study was to carry out a comprehensive survey of ICAM-1 immunoreactivity in normal, malignant and metastatic tissues. We assessed immunoreactivity of ICAM-1 in a total of 300 tissue cores from multiple tissue arrays of normal, malignant, and metastatic tissues by immunohistochemistry.

Extraction of RDC/TMD subscales from the symptom check list-90: does context alter respondent behavior?

Aims: To test whether extraction of the 2 subscales in the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) affected the subscale score reliability and whether scores from the RDC/TMD subscales are comparable to the same scales when the whole Symptom Check List-90 (SCL-90R) is administered.

Methods: The full SCL90-R and a modified version containing only the depression and somatization scales were administered in counterbalanced order to 103 subjects. As another test of context, a subset of participants completed the modified and full versions as part of a larger battery of instruments relevant to facial pain.

Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination.

This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn). The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure.

Differential and trajectory methods for time course gene expression data.

Motivation: The issue of high dimensionality in microarray data has been, and remains, a hot topic in statistical and computational analysis. Efficient gene filtering and differentiation approaches can reduce the dimensions of data, help to remove redundant genes and noises, and highlight the most relevant genes that are major players in the development of certain diseases or the effect of drug treatment. The purpose of this study is to investigate the efficiency of parametric (including Bayesian and non-Bayesian, linear and non-linear), non-parametric and semi-parametric gene filtering methods through the application of time course microarray data from multiple sclerosis patients being treated with interferon-beta-1a.