PPAR-gamma fun(gi) with prostaglandin

In our recent publication, we show for the first time that the fungal pathogen Cryptococcus neoformans is able to manipulate host cells by producing eicosanoids that mimic those found in the host. Using complementary in vivo zebrafish and in vitro macrophage cell culture models of Cryptococcus infection, we found that these eicosanoids manipulate host innate immune cells by activating the host receptor PPAR-gamma which is an important regulator of macrophage inflammatory phenotypes. We initially identified PGE2 as the eicosanoid species responsible for this effect; however, we later found that a derivative of PGE2—15-keto-PGE2—was ultimately responsible and that this eicosanoid acted as a partial agonist to PPAR-gamma. In this commentary, we will discuss some of the concepts and conclusions in our original publication and expand on their implications and future directions

Identification and characterisation of RP2 interacting proteins.

Retinitis pigmentosa (RP) is a genetically and clinically heterogenous retinal degenerative disease, which is characterised by night blindness and constriction of visual fields in the early stages which progress to blindness. X-linked RP (XLRP) is the most severe form of the disease and 2 causative genes have been identified, RP2 and RPGR. RP2 encodes a ubiquitously expressed 350 amino acid protein with a tubulin folding cofactor C (TBCC) homology domain and a C-terminal NDK homology domain. Despite the ubiquitous expression of the RP2 protein, the disease pathogenesis in patients carrying RP2 gene mutations appears to be restricted to retina. The function of RP2 in retina, or other tissues, has yet to be determined. This study aims to increase the understanding of the pathobiology of RP2 by unravelling novel molecular pathways of RP2 function. The approach taken to elucidate the cellular roles of RP2 in retina was to identify potential interacting partner proteins from a retina library using a yeast-two-hybrid approach. The Sos Recruitment System (SRS) was exploited, as RP2 had previously been shown to be predominantly localised on the plasma membrane. Several candidate protein partners for RP2 were identified. ADP-ribosylation like factor 3 (Arl3) was the most common cDNA identified in the yeast-two-hybrid screen. The interaction between RP2 and Arl3 was further defined using site directed mutagenesis to model pathogenic mutations in RP2 and a series of deletion mutants. RP2 preferentially interacted with the active GTP-bound form of Arl3 via the RP2 TBCC-homology domain. An altered cellular localisation and behaviour of RP2 was observed when co-transfected with GTP-bound Ari3. Both Arl3 and RP2 exhibit partial relocalisation to the Golgi and increased intracellular transport of RP2-GFP. Arl2 is structurally very similar to Arl3, and was also identified as a potential interactor of RP2, however the physiological significance of the RP2-Ari2 interaction is unclear. Interestingly, TBCC did not bind Arl2 or Arl3 confirming that RP2 and TBCC have different cellular functions. Four other novel potential interactors were also identified from the yeast two-hybrid screen including another small GTPase, and their interaction mapped to the C-terminus of RP2. The cellular localisation and function of these novel interactors suggest RP2 may have multiple cellular functions

Real time thermal propagtors for massive gauge bosons

We derive Feynman rules for gauge theories exhibiting spontaneous symmetry breaking using the real-time formalism of finite temperature field theory. We also derive the thermal propagators where only the physical degrees of freedom are given thermal boundary conditions. We analyse the abelian Higgs model and find that these new propagators simplify the calculation of the thermal contribution to the self energy.Comment: 7 pages, late

On an Asymptotic Series of Ramanujan

An asymptotic series in Ramanujan's second notebook (Entry 10, Chapter 3) is concerned with the behavior of the expected value of $\phi(X)$ for large $\lambda$ where $X$ is a Poisson random variable with mean $\lambda$ and $\phi$ is a function satisfying certain growth conditions. We generalize this by studying the asymptotics of the expected value of $\phi(X)$ when the distribution of $X$ belongs to a suitable family indexed by a convolution parameter. Examples include the problem of inverse moments for distribution families such as the binomial or the negative binomial.Comment: To appear, Ramanujan

Linear Amplifier Breakdown and Concentration Properties of a Gaussian Field Given that its L2\bm{L^2}-Norm is Large

In the context of linear amplification for systems driven by the square of a Gaussian noise, we investigate the realizations of a Gaussian field in the limit where its $L^2$-norm is large. Concentration onto the eigenspace associated with the largest eigenvalue of the covariance of the field is proved. When the covariance is trace class, the concentration is in probability for the $L^2$-norm. A stronger concentration, in mean for the sup-norm, is proved for a smaller class of Gaussian fields, and an example of a field belonging to that class is given. A possible connection with Bose-Einstein condensation is briefly discussed.Comment: REVTeX file, 11 pages, 1 added paragraph in the introduction, 2 added references, minor modifications in the text and abstract, submitted to J. Stat. Phy

Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Venom costs and optimization in scorpions

Scorpions use venoms as weapons to improve prey capture and predator defense, and these benefits must be balanced against costs associated with its use. Venom costs involve direct energetic costs associated with the production and storage of toxins, and indirect fitness costs arising from reduced venom availability. In order to reduce these costs, scorpions optimize their venom use via evolutionary responses, phenotypic plasticity, and behavioral mechanisms. Over long timescales, evolutionary adaptation to environments with different selection pressures appears to have contributed to interspecific variation in venomcomposition and stingermorphology. Furthermore, plastic responses may allow scorpions to modify and optimize their venom composition as pressures change. Optimal venomuse can vary when facing each prey itemand potential predator encountered, and therefore scorpions display a range of behaviors to optimize their venom use to the particular situation. These behaviors include varying sting rates, employing dry stings, and further altering the volume and composition of venom injected. Whilst these cost-reducing mechanisms are recognized in scorpions, relatively little is understood about the factors that influence them. Here, we review evidence of the costs associated with venom use in scorpions and discuss the mechanisms that have evolved to minimize them

A model for microinstability destabilization and enhanced transport in the presence of shielded 3-D magnetic perturbations

A mechanism is presented that suggests shielded 3-D magnetic perturbations can destabilize microinstabilities and enhance the associated anomalous transport. Using local 3-D equilibrium theory, shaped tokamak equilibria with small 3-D deformations are constructed. In the vicinity of rational magnetic surfaces, the infinite-n ideal MHD ballooning stability boundary is strongly perturbed by the 3-D modulations of the local magnetic shear associated with the presence of nearresonant Pfirsch-Schluter currents. These currents are driven by 3-D components of the magnetic field spectrum even when there is no resonant radial component. The infinite-n ideal ballooning stability boundary is often used as a proxy for the onset of virulent kinetic ballooning modes (KBM) and associated stiff transport. These results suggest that the achievable pressure gradient may be lowered in the vicinity of low order rational surfaces when 3-D magnetic perturbations are applied. This mechanism may provide an explanation for the observed reduction in the peak pressure gradient at the top of the edge pedestal during experiments where edge localized modes have been completely suppressed by applied 3-D magnetic fields

Small molecules in the venom of the scorpion Hormurus waigiensis

Despite scorpion stings posing a significant public health issue in particular regions of the world, certain aspects of scorpion venom chemistry remain poorly described. Although there has been extensive research into the identity and activity of scorpion venom peptides, non-peptide small molecules present in the venom have received comparatively little attention. Small molecules can have important functions within venoms; for example, in some spider species the main toxic components of the venom are acylpolyamines. Other molecules can have auxiliary effects that facilitate envenomation, such as purines with hypotensive properties utilised by snakes. In this study, we investigated some non-peptide small molecule constituents of Hormurus waigiensis venom using LC/MS, reversed-phase HPLC, and NMR spectroscopy. We identified adenosine, adenosine monophosphate (AMP), and citric acid within the venom, with low quantities of the amino acids glutamic acid and aspartic acid also being present. Purine nucleosides such as adenosine play important auxiliary functions in snake venoms when injected alongside other venom toxins, and they may have a similar role within H. waigiensis venom. Further research on these and other small molecules in scorpion venoms may elucidate their roles in prey capture and predator defence, and gaining a greater understanding of how scorpion venom components act in combination could allow for the development of improved first aid

Transcranial Doppler Directed Dextran Therapy in the Prevention of Carotid Thrombosis: Three Hour Monitoring is as Effective as Six Hours

AbstractBackgroundsix hours» monitoring by transcranial Doppler (TCD) has been successful in directing Dextran therapy in patients at high risk of thrombotic stroke after carotid endarterectomy (CEA).Objectivesis 3 h of routine monitoring as effective as 6 h in the prevention of early postoperative thrombotic stroke?Designprospective, consecutive study in all patients with an accessible cranial window.Methodsone hundred and sixty-six patients undergoing CEA underwent 3 h of postoperative monitoring by TCD. Any patient with >25 emboli detected in any 10 min period or those with emboli that distorted the arterial waveform were commenced on an incremental infusion of dextran 40.Resultsthe majority of patients destined to embolise will do so within the first 2 postoperative hours. Dextran therapy was instituted in nine patients (5%) and rapidly controlled this phase of embolisation although the dose had to be increased in three (33%). No patient suffered a postoperative carotid thrombosis but one suffered a minor stroke on day 5 and was found to have profuse embolisation on TCD; high dose dextran therapy was again instituted, the embolus count rate fell rapidly and he made a good recovery thereafter. Overall, the death and disabling stroke rate was 1.2% and the death/any stroke rate was 2.4%.Conclusionthree hours of postoperative TCD monitoring is as effective as 6 h in the prevention of postoperative carotid thrombosis