The PAS-domain kinase PASKIN: a new sensor in energy homeostasis

The PAS domain kinase PASKIN, also termed PAS kinase or PASK, is an evolutionarily conserved potential sensor kinase related to the heme-based oxygen sensors of nitrogen-fixing bacteria. In yeast, the two PASKIN homologs link energy flux and protein synthesis following specific stress conditions. In mammals, PASKIN may regulate glycogen synthesis and protein translation. Paskin knock-out mice do not show any phenotype under standard animal husbandry conditions. Interestingly, these mice seem to be protected from the symptoms of the metabolic syndrome when fed a high-fat diet. Energy turnover might be increased in specific PASKIN-deficient cell types under distinct environmental conditions. According to the current model, binding of a putative ligand to the PAS domain disinhibits the kinase domain and activates PASKIN auto- and target phosphorylation. Future research needs to be conducted to elucidate the nature of the putative ligand and the molecular mechanisms of downstream signalling by PASKIN

The plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo

Malaria parasites in the blood stage express a single transmembrane transport protein for the release of the glycolytic end product l-lactate/H(+) from the cell. This transporter is a member of the strictly microbial formate-nitrite transporter (FNT) family and a novel putative drug target. Small, drug-like FNT inhibitors potently block lactate transport and kill Plasmodium falciparum parasites in culture. The protein structure of Plasmodium falciparum FNT (PfFNT) in complex with the inhibitor has been resolved and confirms its previously predicted binding site and its mode of action as a substrate analog. Here, we investigated the mutational plasticity and essentiality of the PfFNT target on a genetic level, and established its in vivo druggability using mouse malaria models. We found that, besides a previously identified PfFNT G107S resistance mutation, selection of parasites at 3 x IC(50) (50% inhibitory concentration) gave rise to two new point mutations affecting inhibitor binding: G21E and V196L. Conditional knockout and mutation of the PfFNT gene showed essentiality in the blood stage, whereas no phenotypic defects in sexual development were observed. PfFNT inhibitors mainly targeted the trophozoite stage and exhibited high potency in P. berghei- and P. falciparum-infected mice. Their in vivo activity profiles were comparable to that of artesunate, demonstrating strong potential for the further development of PfFNT inhibitors as novel antimalarials

13th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies for organ toxicity.

In the past decade in vitro tests have been developed that represent a range of anatomic structure from perfused whole organs to subcellular fractions. To assess the use of in vitro tests for toxicity testing, we describe and evaluate the current status of organotypic cultures for the major target organs of toxic agents. This includes liver, kidney, neural tissue, the hematopoietic system, the immune system, reproductive organs, and the endocrine system. The second part of this report reviews the application of in vitro culture systems to organ specific toxicity and evaluates the application of these systems both in industry for safety assessment and in government for regulatory purposes. Members of the working group (WG) felt that access to high-quality human material is essential for better use of in vitro organ and tissue cultures in the risk assessment process. Therefore, research should focus on improving culture techniques that will allow better preservation of human material. The WG felt that it is also important to develop and make available relevant reference compounds for toxicity assessment in each organ system, to organize and make available via the Internet complete in vivo toxicity data, including human data, containing dose, end points, and toxicokinetics. The WG also recommended that research should be supported to identify and to validate biological end points for target organ toxicity to be used in alternative toxicity testing strategies

Plasma-Induced Frequency Chirp of Intense Femtosecond Lasers and Its Role in Shaping High-Order Harmonic Spectral Lines

We investigate the self-phase modulation of intense femtosecond laser pulses propagating in an ionizing gas and its effects on collective properties of high-order harmonics generated in the medium. Plasmas produced in the medium are shown to induce a positive frequency chirp on the leading edge of the propagating laser pulse, which subsequently drives high harmonics to become positively chirped. In certain parameter regimes, the plasma-induced positive chirp can help to generate sharply peaked high harmonics, by compensating for the dynamically-induced negative chirp that is caused by the steep intensity profile of intense short laser pulses.Comment: 5 pages, 5 figure

Measurement of Superluminal optical tunneling times in double-barrier photonic bandgaps

Tunneling of optical pulses at 1.5 micron wavelength through double-barrier periodic fiber Bragg gratings is experimentally investigated. Tunneling time measurements as a function of barrier distance show that, far from the resonances of the structure, the transit time is paradoxically short, implying Superluminal propagation, and almost independent of the distance between the barriers. These results are in agreement with theoretical predictions based on phase time analysis and also provide an experimental evidence, in the optical context, of the analogous phenomenon expected in Quantum Mechanics for non-resonant superluminal tunneling of particles across two successive potential barriers. [Attention is called, in particular, to our last Figure]. PACS nos.: 42.50.Wm, 03.65.Xp, 42.70.Qs, 03.50.De, 03.65.-w, 73.40.GkComment: LaTeX file (8 pages), plus 5 figure

Pluripotent stem cell assays: Modalities and applications for predictive developmental toxicity

This manuscript provides a review focused on embryonic stem cell-based models and their place within the landscape of alternative developmental toxicity assays. Against the background of the principles of developmental toxicology, the wide diversity of alternative methods using pluripotent stem cells developed in this area over the past half century is reviewed. In order to provide an overview of available models, a systematic scoping review was conducted following a published protocol with inclusion criteria, which were applied to select the assays. Critical aspects including biological domain, readout endpoint, availability of standardized protocols, chemical domain, reproducibility and predictive power of each assay are described in detail, in order to review the applicability and limitations of the platform in general and progress moving forward to implementation. The horizon of innovative routes of promoting regulatory implementation of alternative methods is scanned, and recommendations for further work are given

Simultaneous exposure of rats to dioxin and carbon monoxide reduces the xenobiotic but not the hypoxic response.

Aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor-1alpha (HIF-1alpha) are conditionally regulated transcription factor subunits that form heterodimeric complexes with their common partner, AhR nuclear translocator (ARNT/HIF-1beta). Whereas the environmentally toxic compound 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) initiates the trans-activation activity of AhR:ARNT/HIF-1beta, hypoxic exposure stabilizes HIF-1alpha and functionally activates the HIF-1alpha:ARNT/HIF-1beta complex. To analyze a possible crosstalk between these two pathways in vivo, rats were given dioxin orally and/or were exposed to carbon monoxide (CO), causing functional anemia. We found that exposure to CO inhibited the xenobiotic response while dioxin application had no significant negative impact on hypoxia-mediated gene transcription

Negative group delay for Dirac particles traveling through a potential well

The properties of group delay for Dirac particles traveling through a potential well are investigated. A necessary condition is put forward for the group delay to be negative. It is shown that this negative group delay is closely related to its anomalous dependence on the width of the potential well. In order to demonstrate the validity of stationary-phase approach, numerical simulations are made for Gaussian-shaped temporal wave packets. A restriction to the potential-well's width is obtained that is necessary for the wave packet to remain distortionless in the travelling. Numerical comparison shows that the relativistic group delay is larger than its corresponding non-relativistic one.Comment: 10 pages, 5 figure

CEOs from Orthopaedic Centers Worldwide Meet to Discuss Common Challenges: 2010 Annual Meeting of the International Society of Orthopaedic Centers

The International Society of Orthopaedic Centers was formed in 2006 as a think tank that would bring together thought leaders in orthopaedic surgery from major orthopaedic academic centers around the world. The Society’s mission is to share knowledge and strategies, improve patient care, and foster clinical, educational, and scientific collaboration. As the Society’s agendas developed, the members recognized that many of their aims intersected with those of hospital leadership. Thus, CEOs from member centers were invited to join their physician colleagues at the 2010 meeting in Bologna, Italy in order to explore solutions to administrative challenges related to patient care, volume growth, and costs. This paper describes the dialogue that took place at the meeting

Helmholtz theorem and the v-gauge in the problem of superluminal and instantaneous signals in classical electrodynamics

In this work we substantiate the applying of the Helmholtz vector decomposition theorem (H-theorem) to vector fields in classical electrodynamics. Using the H-theorem, within the framework of the two-parameter Lorentz-like gauge (so called v-gauge), we show that two kinds of magnetic vector potentials exist: one of them (solenoidal) can act exclusively with the velocity of light c and the other one (irrotational) with an arbitrary finite velocity $v$ (including a velocity more than c . We show also that the irrotational component of the electric field has a physical meaning and can propagate exclusively instantaneously.Comment: This variant has been accepted for publication in Found. Phys. Letter