Recent developments in membrane-protein structural genomics

Recent work has identified the topology of almost all the inner membrane proteins in Escherichia coli, and advances in nuclear magnetic resonance spectroscopy now allow the determination of α-helical membrane protein structures at high resolution. Together these developments will help overcome the current limitations of high-throughput determination of membrane protein structures.     

The Perils of Adapting to Dose Errors in Radiation Therapy

We consider adaptive robust methods for lung cancer that are also dose-reactive, wherein the treatment is modified after each treatment session to account for the dose delivered in prior treatment sessions. Such methods are of interest because they potentially allow for errors in the delivered dose to be corrected as the treatment progresses, thereby ensuring that the tumor receives a sufficient dose at the end of the treatment. We show through a computational study with real lung cancer patient data that while dose reaction is beneficial with respect to the final dose distribution, it may lead to exaggerated daily underdose and overdose relative to non-reactive methods that grows as the treatment progresses. However, by combining dose reaction with a mechanism for updating an estimate of the uncertainty, the magnitude of this growth can be mitigated substantially. The key finding of this paper is that reacting to dose errors – an adaptation strategy that is both simple and intuitively appealing – may backfire and lead to treatments that are clinically unacceptable.     

Tyrosine availability prevents tyramine-induced tachyphylaxis in the isolated rat heart

Isolated rat hearts perfused with Chenoweth-Koelle solution exhibit tachyphylaxis to tyramine. This tachyphylaxis was prevented if tyrosine was included in the perfusion solution. Other amino acids, including glycine, serine, phenylalanine, valine, tryptophan, glutamate, aspartate, arginine, lysine and -tyrosine, failed to prevent the tyramine-induced tachyphylaxis. Hearts from reserpinized animals showed increased chronotropy after tyramine only when tyrosine was present in the medium. This response could be blocked by , m-hydroxybenzyl-hydrazine and d,l-propanolol, indicating that it was mediated by the synthesis and release of catecholamines. These experiments suggest that sympathetic nerves in the isolated rat heart exhibit a requirement for tyrosine when catecholamine release is enhanced.     

Nerves on tr[ac]k to support pancreatic cancer metabolism

Nerve-cancer interactions modulate pancreatic cancer growth through direct effects on cancer cells and the microenviron-ment.New evidence now shows that nerves ...     

Representations of specific acoustic patterns in the auditory cortex and hippocampus

Previous behavioural studies have shown that repeated presentation of a randomly chosen acoustic pattern leads to the unsupervised learning of some of its specific acoustic features. The objective of our study was to determine the neural substrate for the representation of freshly learnt acoustic patterns. Subjects first performed a behavioural task that resulted in the incidental learning of three different noise-like acoustic patterns. During subsequent high-resolution functional magnetic resonance imaging scanning, subjects were then exposed again to these three learnt patterns and to others that had not been learned. Multi-voxel pattern analysis was used to test if the learnt acoustic patterns could be ‘decoded’ from the patterns of activity in the auditory cortex and medial temporal lobe. We found that activity in planum temporale and the hippocampus reliably distinguished between the learnt acoustic patterns. Our results demonstrate that these structures are involved in the neural representation of specific acoustic patterns after they have been learnt.     

Behavioral cues associated with oviposition by Trioza eugeniae

Trioza eugeniae oviposited significantly more eggs on Syzygium paniculatum leaves free of eggs compared to leaves with pre-existing eggs in a choice experiment, suggesting that females modify oviposition based on cues associated with the presence of eggs. In separate experiments, females avoided ovipositing on parts of leaves where eggs were present, but readily oviposited on areas of the same leaf without eggs. Epideictic pheromones are apparently not used by this species because females readily oviposited on areas of a leaf from which eggs had previously been removed. Females laid 57% of all their eggs along the margins of normal leaves, but also oviposited on artificial margins produced by cutting the leaves. The preference for natural margins over artificial margins was eliminated when the entire margin was coated with an antitranspirant compound to mask the damaged edge. These studies show that ovipositing psyllids respond both to the presence of eggs and to the suitability of the substrate.     

Increased Frequency and Compromised Function of T Regulatory Cells in Systemic Sclerosis (SSc) Is Related to a Diminished CD69 and TGFβ Expression

Background

Regulatory T cells (Tregs) are essential in the control of tolerance. Evidence implicates Tregs in human autoimmune conditions. Here we investigated their role in systemic sclerosis (SSc).

Methods/Principal Findings

Patients were subdivided as having limited cutaneous SSc (lcSSc, n = 20) or diffuse cutaneous SSc (dcSSc, n = 48). Further subdivision was made between early dcSSc (n = 24) and late dcSSc (n = 24) based upon the duration of disease. 26 controls were studied for comparison. CD3+ cells were isolated using FACS and subsequently studied for the expression of CD4, CD8, CD25, FoxP3, CD127, CD62L, GITR, CD69 using flow cytometry. T cell suppression assays were performed using sorted CD4CD25^highCD127^- and CD4CD25^lowCD127^high and CD3⁺ cells. Suppressive function was correlated with CD69 surface expression and TGFβ secretion/expression. The frequency of CD4⁺CD25⁺ and CD25^highFoxP3^highCD127^neg T cells was highly increased in all SSc subgroups. Although the expression of CD25 and GITR was comparable between groups, expression of CD62L and CD69 was dramatically lower in SSc patients, which correlated with a diminished suppressive function. Co-incubation of Tregs from healthy donors with plasma from SSc patients fully abrogated suppressive activity. Activation of Tregs from healthy donors or SSc patients with PHA significantly up regulated CD69 expression that could be inhibited by SSc plasma.

Conclusions/Significance

These results indicate that soluble factors in SSc plasma inhibit Treg function specifically that is associated with altered Treg CD69 and TGFβ expression. These data suggest that a defective Treg function may underlie the immune dysfunction in systemic sclerosis.