Improving the interaction of Myc-interfering peptides with Myc using molecular dynamics simulations.

Previously, a Myc-interfering peptide (Mip) was identified for the targeted inactivation of the Myc:Max complex by the combination of rational design and an in vivo protein-fragment complementation assay. In the subsequent work presented here, molecular dynamics simulations and free energy calculations based on the molecular mechanics GBSA method were performed to define the contribution of the different amino acids in the Myc:Mip coiled coil domain, and compared to wild-type Myc:Max. For further optimization of the Myc interference, point mutations were introduced into Mip and analyzed, from which two showed much higher binding affinities in the computational studies in good agreement with the experiment.

iPEP: peptides designed and selected for interfering with protein interaction and function.

Semi-rational design is combined with PCAs (protein-fragment complementation assays) and phage-display screening techniques to generate a range of iPEPs (interfering peptides) that target therapeutically relevant proteins with much higher interaction stability than their native complexes. PCA selection has been improved to impose a competitive and negative design initiative on the library screen, thus simultaneously improving the specificity of assay 'winners'. The folding pathways of designed pairs imply that early events are dominated by hydrophobic collapse and helix formation, whereas later events account for the consolidation of more intricate intermolecular electrostatic interactions.

IkappaBalpha kinase inhibitor IKI-1 conferred tumor necrosis factor alpha sensitivity to pancreatic cancer cells and a xenograft tumor model.

Tumor necrosis factor alpha (TNFalpha) has been used to treat patients with certain tumor types. However, its antitumor activity has been undermined by the activation of IkappaBalpha kinase (IKK), which in turn activates nuclear factor-kappaB (NF-kappaB) to help cancer cells survive. Therefore, inhibition of TNFalpha-induced IKK activity with specific IKK inhibitor represents an attractive strategy to treat cancer patients.

A chemical genomics study identifies Snf1 as a repressor of GCN4 translation.

The Saccharomyces cerevisiae Snf1 kinase plays a critical role in recalibrating cellular metabolism in response to glucose depletion. Hundreds of genes show changes in expression levels when the SNF1 gene is deleted. However, cells can adapt to the absence of a specific gene when grown in long term culture.

Gelation mechanism of poly(N-isopropylacrylamide)-clay nanocomposite hydrogels synthesized by photopolymerization.

The gelation process of poly-(N-isopropylacrylamide)-clay nanocomposite hydrogels (PNIPAAm-clay NC gels) was investigated by dynamic and static light scattering (DLS and SLS), as well as by fluorescence correlation spectroscopy (FCS). The photopolymerization method chosen for the radical polymerizing system ensured that, when the irradiation is removed, the reaction stopped immediately. Experiments showed that shortly before the gelation threshold is reached, no changes in the DLS autocorrelation functions appear, while the monomer conversion can be observed by 1H NMR spectroscopy.

Unipolar radiofrequency treatment to improve the appearance of cellulite.

Background: Previous studies suggest that radiofrequency (RF) energy may be effective as a treatment for cellulite.

Objective: This bilateral paired blinded comparative study assesses the efficacy and safety of a unipolar RF device for improving the appearance of cellulite using a new quantitative cellulite grading system.

Methods: In this randomized, blinded, split-design study, 10 individuals (aged 32-57 years) with a clinically observable excess of subcutaneous fat and cellulite (minimum grade 2 out of 4) on the thighs received up to six unilateral treatments (number of treatments at the investigator's discretion) at 2-week intervals with unipolar RF.

Unipolar versus bipolar radiofrequency treatment of rhytides and laxity using a mobile painless delivery method.

Background: Previous studies have shown that radiofrequency (RF) energy is a safe and effective treatment for rhytide-reduction.

Objective: This randomized, blinded, split-face study assesses the safety and efficacy of the unipolar versus bipolar handpieces on an RF device with a mobile delivery method for the treatment of rhytides and laxity using quantitative grading.

Methods: In this randomized, blinded, split-face design study, 10 subjects (aged 18-75 years) with a clinically observable excess of rhytides and laxity (minimum grade 2 out of 4) on the face received four treatments at 1-week intervals with random assignment of unipolar RF to one side and bipolar RF to the contralateral side.

Selectional and mutational scope of peptides sequestering the Jun-Fos coiled-coil domain.

The activator protein-1 (AP-1) complex plays a crucial role in numerous pathways, and its ability to induce tumorigenesis is well documented. Thus, AP-1 represents an interesting therapeutic target. We selected peptides from phage display and compared their ability to disrupt the cFos/cJun interaction to a previously described in vivo protein-fragment complementation assay (PCA).

Anxiety-like behaviour in rats with mononeuropathy is reduced by the analgesic drugs morphine and gabapentin.

Anxiety has been described as an important comorbidity in patients suffering from chronic pain. However, in animals the connection between persistent pain and anxiety has hardly been investigated. Therefore, in the current study it was assessed whether chronic pain also causes anxiety-like behaviour in animals and if it can be reversed by analgesic or anxiolytic drugs.

Botulinum toxin and the facial feedback hypothesis: can looking better make you feel happier?

The facial feedback hypothesis suggests that muscular manipulations which result in more positive facial expressions may lead to more positive emotional states in affected individuals. In this essay, we hypothesize that the injection of botulinum toxin for upper face dynamic creases might induce positive emotional states by reducing the ability to frown and create other negative facial expressions. The use of botulinum toxin to pharmacologically alter upper face muscular expressiveness may curtail the appearance of negative emotions, most notably anger, but also fear and sadness.

Targeting the c-Myc coiled coil with interfering peptides.

c-Myc is one of the most frequently deregulated oncogenes in human cancers, and recent studies showed that even brief inactivation of Myc can be sufficient to induce tumor regression or loss. Consequently, inactivation of Myc provides a novel therapeutic opportunity and challenge, as the dimerization of Myc with Max is crucial for its function. We applied two strategies to specifically target this coiled coil mediated interaction with interfering peptides: a dominant-negative human Max sequence (Max) and a peptide selected from a genetic library (Mip).

The spectrum of laser skin resurfacing: nonablative, fractional, and ablative laser resurfacing.

Unlabelled: The drive to attain cosmetic facial enhancement with minimal risk and rapid recovery has inspired the field of nonsurgical skin rejuvenation. Laser resurfacing was introduced in the 1980s with continuous wave carbon dioxide (CO(2)) lasers; however, because of a high rate of side effects, including scarring, short-pulse, high-peak power, and rapidly scanned, focused-beam CO(2) lasers and normal-mode erbium-doped yttrium aluminium garnet lasers were developed, which remove skin in a precisely controlled manner. The prolonged 2-week recovery time and small but significant complication risk prompted the development of non-ablative and, more recently, fractional resurfacing in order to minimize risk and shorten recovery times.

Hydrogel-based piezoresistive pH sensors: investigations using FT-IR attenuated total reflection spectroscopic imaging.

The strong swelling ability of the pH-responsive poly(acrylic acid)/poly(vinyl alcohol) (PAA/PVA) hydrogel makes the development of a new type of sensor possible, which combines piezoresistive-responsive elements as mechanoelectrical transducers and the phase transition behavior of hydrogels as a chemomechanical transducer. The sensor consists of a pH-responsive PAA/PVA hydrogel and a standard pressure sensor chip. However, a time-dependent sensor output voltage mirrors only the physical swelling process of the hydrogel but not the corresponding chemical reactions.

Review on Hydrogel-based pH Sensors and Microsensors.

Stimuli-responsive hydrogels are materials with great potential for development of active functionalities in fluidics and micro-fluidics. Based on the current state of research on pH sensors, hydrogel sensors are described qualitatively and quantitatively for the first time. The review introduces the physical background of the special properties of stimuli-responsive hydrogels.

Discovery of benzisoxazoles as potent inhibitors of chaperone heat shock protein 90.

Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93.

Plasma skin regeneration technology.

Plasma skin regeneration is a novel type of skin rejuvenation technology developed over the last 3 years. Plasma is the fourth state of matter in which electrons are stripped from atoms to form an ionized gas. Although high temperature plasmas have been used in surgery for over a decade, plasma had previously been used as a conduction medium for electric current.

Access denied: Snf1 activation loop phosphorylation is controlled by availability of the phosphorylated threonine 210 to the PP1 phosphatase.

Phosphorylation of the Saccharomyces cerevisiae Snf1 kinase activation loop is determined by the integration of two reaction rates: the rate of phosphorylation by upstream kinases and the rate of dephosphorylation by Glc7. The activities of the Snf1-activating kinases do not appear to be glucose-regulated, since immune complex kinase assays with each of the three Snf1-activating kinases show similar levels of activity when prepared from cells grown in either high or low glucose. In contrast, the dephosphorylation of the Snf1 activation loop was strongly regulated by glucose.

CGRP antagonists: unravelling the role of CGRP in migraine.

Migraine is a complex, debilitating neurovascular disorder. Although knowledge on the main molecular players is still incomplete, recent preclinical and clinical findings indicate that there is a clear correlation between migraine-associated headache and the release of the neuropeptide calcitonin gene-related peptide (CGRP). BIBN4096 was the first CGRP antagonist to be tested in clinical trials for the treatment of migraine.

Regulation of histone modification and cryptic transcription by the Bur1 and Paf1 complexes.

The Bur1-Bur2 and Paf1 complexes function during transcription elongation and affect histone modifications. Here we describe new roles for Bur1-Bur2 and the Paf1 complex. We find that histone H3 K36 tri-methylation requires specific components of the Paf1 complex and that K36 tri-methylation is more strongly affected at the 5' ends of genes in paf1delta and bur2delta strains in parallel with increased acetylation of histones H3 and H4.

Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors.

With high-throughput screening, substituted dibenzo[c,f][2,7]naphthyridine 1 was identified as a novel potent and selective phosphoinositide-dependent kinase-1 (PDK-1) inhibitor. Various regions of the lead molecule were explored to understand the SAR requirement for this scaffold. The crystal structure of 1 with kinase domain of PDK-1 confirmed the binding in the active site.

Use of cutaneous lasers and light sources: appropriate training and delegation.

In recent years, there has been increasing concern among physicians, patient advocacy groups, and media watchdogs that laser, light, and cosmetic surgery are being practiced by poorly trained professionals, with resulting preventable injuries to patients. In response, several professional organizations have developed guidelines for the delegation of laser services to nonphysician providers. These guidelines delineate appropriate qualifications for delegating physicians and nonphysician providers, and also describe the circumstances and settings in which delegation is appropriate.

Evaluation of the 1,540-nm Erbium:Glass Laser in the Treatment of Inflammatory Facial Acne.

Background: The erbium:glass laser is approved to treat inflammatory acne on the back.

Objective: This aim of this study was to evaluate the use of the 1,540-nm erbium:glass laser in the treatment of moderate to severe inflammatory acne on the face.

Methods And Materials: An erbium:glass laser (Aramis, Quantel Medical, Clermont-Ferrand, France) was used to treat 15 patients with moderate to severe acne four times at 2-week intervals.