The development of the pharyngeal region in the dog

The morphogenesis of the pharyngeal region is believed to be involved in the occurrence of so-called "Branchial Cysts", a condition affecting human and canine adolescents of comparable age, and which is characterised by the appearance of cystic lesions on the lateral aspects of the upper portion of the neck. These lesions are usually small in the human, while in the dog, due to the presence of a hair coat, they remain undiscovered until they have become large and pendulous. It is generally believed that branchial cysts arise from remnants of the branchial apparatus which are induced to proliferate by certain hormonal combinations present in the young individual. Investigators (Bhaskar and Bernier, 1959)» who recently examined a large number of human lesions deny a purely branchiogenic origin however, and postulate that epithelial remnants of bronchial or, what is more likely, parotid origin, after becoming trapped in developing lymph nodes, produce this condition, which according to their view should be renamed "Benign Lymphoepithelial Cysts".Investigations into the etiology of branchial cysts in the dog, at present being carried out at the author's home university (Ontario Veterinary College, University of Toronto), became focused on the developmental processes of the pharyngeal region in that animal, because experience with the human condition suggested a developmental defect. 2 A search of the literature available to the author revealed that the development of the canine pharyngeal region was practically unknown, only some selected aspects such as the early development of the thyroid and parathyroids having been described by Godwin (193^S 1937 a) of the Kingsbury school. It was uncovered further that the developmental anatomy of the dog as a whole had scarcely been studied, which is surprising in view of this animal's importance to the veterinary surgeon and to the research worker.The present study, then, was undertaken in an attempt to close the obvious gap in our knowledge of canine embryogenesis, and to provide those interested in the etiology of branchial cysts with what might be considered a working basis for further clinical and embryological examinations. It was found necessary to survey the entire field of pharyngeal development, from the appearance of a foregut to conditions found at full term, since confinement of the field, even though it could have been explored to much greater depth, would have proved useful neither to those interested in canine embryology nor to those studying branchial cysts. The former would find that the large gap in the knowledge of this region still persisted and the latter would not be able to select the particular anatomical region or developmental stage which may interest them for further scrutiny.The lack of previous work on canine development and subsequent absence of known standards of developmental reference made it necessary to devote much space to the description and staging of the einbryological material prior to sectioning. The hulk of the thesis however is devoted to the description of the developmental processes observed in the pharyngeal region, and minor points worthy of short discussion are dealt with here, because it was thought that due to the wide field covered in this study a separate discussion would appear rather disjointed. Major anatomical areas however have been extracted from this section and are presented at the end in the form of REGIONAL REVIEWS

Acute Dissociation and Cardiac Reactivity to Script-Driven Imagery in Trauma-Related Disorders

Background: Potential acute protective functions of dissociation include modulation of stress-induced psychophysiological arousal. This study was designed to explore whether acute dissociative reactions during a stress experiment would override the effects of reexperiencing. Methods: Psychophysiological reactions during exposure to script-driven trauma imagery were studied in relation to acute responses of reexperiencing and dissociative symptoms in 61 patients with histories of exposure to a variety of traumas. Acute symptomatic responses were assessed with the Responses to Script-Driven Imagery Scale (RSDI), and participants were divided into four groups by median splits of RSDI reexperiencing and dissociation subscale scores. Results: In a comparison of the high RSDI reexperiencing groups with low versus high acute dissociative symptoms, the high dissociators exhibited significantly lower heart rate (HR) during trauma script and a significantly smaller script-induced decrease in parasympathetic cardiac activity. HR reactivity to the trauma script was negatively correlated with acute dissociative symptom severity. Conclusions: Acute dissociative reactions are a potential moderator of response to experimental paradigms investigating psychologically traumatized populations. We therefore suggest that future research on psychophysiological stress reactions in traumatized samples should routinely assess for acute dissociative symptoms

Binding of a Gating Modifier Toxin Induces Intersubunit Cooperativity Early in the Shaker K Channel's Activation Pathway

Potassium currents from voltage-gated Shaker K channels activate with a sigmoid rise. The degree of sigmoidicity in channel opening kinetics confirms that each subunit of the homotetrameric Shaker channel undergoes more than one conformational change before the channel opens. We have examined effects of two externally applied gating modifiers that reduce the sigmoidicity of channel opening. A toxin from gastropod mucus, 6-bromo-2-mercaptotryptamine (BrMT), and divalent zinc are both found to slow the same conformational changes early in Shaker's activation pathway. Sigmoidicity measurements suggest that zinc slows a conformational change independently in each channel subunit. Analysis of activation in BrMT reveals cooperativity among subunits during these same early steps. A lack of competition with either agitoxin or tetraethylammonium indicates that BrMT binds channel subunits outside of the external pore region in an allosterically cooperative fashion. Simulations including negatively cooperative BrMT binding account for its ability to induce gating cooperativity during activation. We conclude that cooperativity among K channel subunits can be greatly altered by experimental conditions

The tarantula toxin GxTx detains K+ channel gating charges in their resting conformation.

Allosteric ligands modulate protein activity by altering the energy landscape of conformational space in ligand-protein complexes. Here we investigate how ligand binding to a K+ channel's voltage sensor allosterically modulates opening of its K+-conductive pore. The tarantula venom peptide guangxitoxin-1E (GxTx) binds to the voltage sensors of the rat voltage-gated K+ (Kv) channel Kv2.1 and acts as a partial inverse agonist. When bound to GxTx, Kv2.1 activates more slowly, deactivates more rapidly, and requires more positive voltage to reach the same K+-conductance as the unbound channel. Further, activation kinetics are more sigmoidal, indicating that multiple conformational changes coupled to opening are modulated. Single-channel current amplitudes reveal that each channel opens to full conductance when GxTx is bound. Inhibition of Kv2.1 channels by GxTx results from decreased open probability due to increased occurrence of long-lived closed states; the time constant of the final pore opening step itself is not impacted by GxTx. When intracellular potential is less than 0 mV, GxTx traps the gating charges on Kv2.1's voltage sensors in their most intracellular position. Gating charges translocate at positive voltages, however, indicating that GxTx stabilizes the most intracellular conformation of the voltage sensors (their resting conformation). Kinetic modeling suggests a modulatory mechanism: GxTx reduces the probability of voltage sensors activating, giving the pore opening step less frequent opportunities to occur. This mechanism results in K+-conductance activation kinetics that are voltage-dependent, even if pore opening (the rate-limiting step) has no inherent voltage dependence. We conclude that GxTx stabilizes voltage sensors in a resting conformation, and inhibits K+ currents by limiting opportunities for the channel pore to open, but has little, if any, direct effect on the microscopic kinetics of pore opening. The impact of GxTx on channel gating suggests that Kv2.1's pore opening step does not involve movement of its voltage sensors

Influence of a magnetic field on the viscosity of a dilute gas consisting of linear molecules.

The viscomagnetic effect for two linear molecules, N2 and CO2, has been calculated in the dilute-gas limit directly from the most accurate ab initio intermolecular potential energy surfaces presently available. The calculations were performed by means of the classical trajectory method in the temperature range from 70 K to 3000 K for N2 and 100 K to 2000 K for CO2, and agreement with the available experimental data is exceptionally good. Above room temperature, where no experimental data are available, the calculations provide the first quantitative information on the magnitude and the behavior of the viscomagnetic effect for these gases. In the presence of a magnetic field, the viscosities of nitrogen and carbon dioxide decrease by at most 0.3% and 0.7%, respectively. The results demonstrate that the viscomagnetic effect is dominated by the contribution of the jj¯ polarization at all temperatures, which shows that the alignment of the rotational axes of the molecules in the presence of a magnetic field is primarily responsible for the viscomagnetic effect

Gender agreement on adverbs in Spanish

In this article we explore the exceptional gender agreement of the Spanish adverb mucho (‘much’), when it modifies comparative adjectives inside DPs that contain a particular type of noun (as in muchafem mejor intenciónfem, ‘much better intention’). This phenomenon, which we describe in detail, raises crucial questions both about the mechanisms of agreement and about the nature of gender in a language such as Spanish. We will argue on the basis of our analysis that agreement is not semantically motivated, but blindly triggered by certain formal configurations. We will also argue that –at least in languages such as Spanish– gender information is scattered in two different positions inside the DP.Peer reviewe

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported