Thermodynamics of amyloid fibril formation from chemical depolymerization.

Amyloid fibrils are homo-molecular protein polymers that play an important role in disease and biological function. While much is known about their kinetics and mechanisms of formation, the origin and magnitude of their thermodynamic stability has received significantly less attention. This is despite the fact that the thermodynamic stability of amyloid fibrils is an important determinant of their lifetimes and processing in vivo.

Nitrogenase Inhibition Limited Oxygenation of Earth's Proterozoic Atmosphere.

Cyanobacteria produced the oxygen that began to accumulate on Earth 2.5 billion years ago, at the dawn of the Proterozoic Eon. By 2.

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

Archaeal Histone Contributions to the Origin of Eukaryotes.

The eukaryotic lineage arose from bacterial and archaeal cells that underwent a symbiotic merger. At the origin of the eukaryote lineage, the bacterial partner contributed genes, metabolic energy, and the building blocks of the endomembrane system. What did the archaeal partner donate that made the eukaryotic experiment a success? The archaeal partner provided the potential for complex information processing.

Discovery of potent polyphosphate kinase 1 (PPK1) inhibitors using structure-based exploration of PPK1Pharmacophoric space coupled with docking analyses.

Inorganic polyphosphate (polyP) is present in all living forms of life. Studied mainly in prokaryotes, polyP and its associated enzymes are vital in diverse metabolic activities, in some structural functions, and most importantly in stress responses. Bacterial species, including many pathogens, encode a homolog of a major polyP synthesis enzyme, Poly Phosphate Kinase (PPK) with 2 different genes coding for PPK1 and PPK2.

Ubiquitylation-independent activation of Notch signalling by Delta.

Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling.

A Comparison of 2- and 3-dimensional Healing Assessment after Endodontic Surgery Using Cone-beam Computed Tomographic Volumes or Periapical Radiographs.

Introduction: The aim of this study was to compare the assessment of healing after endodontic microsurgery using 2-dimensional (2D) periapical films versus 3-dimensional (3D) cone-beam computed tomographic (CBCT) imaging.

Methods: The healing of 51 teeth from 44 patients was evaluated using Molven's criteria (2D) and modified PENN 3D criteria. The absolute area (2D) and volume (3D) changes of apical lesions preoperatively and at follow-up were calculated by segmentation using OsiriX software (Pixmeo, Bernex, Switzerland) and ITK-Snap (free software).

Dopamine D3 Receptor Antagonists as Potential Therapeutics for the Treatment of Neurological Diseases.

D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse.

In vivo quantification of the secretion rates of the hemolysin A Type I secretion system.

Type 1 secretion systems (T1SS) of Gram-negative bacteria secrete a broad range of substrates into the extracellular space. Common to all substrates is a C-terminal secretion sequence and nonapeptide repeats in the C-terminal part that bind Ca(2+) in the extracellular space, to trigger protein folding. Like all T1SS, the hemolysin A (HlyA) T1SS of Escherichia coli consists of an ABC transporter, a membrane fusion protein and an outer membrane protein allowing the one step translocation of the substrate across both membranes.

Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses.

High expression of Nek2 has been detected in several types of cancer and it represents a novel target for human cancer. In the current study, structure-based pharmacophore modeling combined with multiple linear regression (MLR)-based QSAR analyses was applied to disclose the structural requirements for NEK2 inhibition. Generated pharmacophoric models were initially validated with receiver operating characteristic (ROC) curve, and optimum models were subsequently implemented in QSAR modeling with other physiochemical descriptors.

Direct acceleration of electrons by a CO2 laser in a curved plasma waveguide.

Laser plasma interaction with micro-engineered targets at relativistic intensities has been greatly promoted by recent progress in the high contrast lasers and the manufacture of advanced micro- and nano-structures. This opens new possibilities for the physics of laser-matter interaction. Here we propose a novel approach that leverages the advantages of high-pressure CO2 laser, laser-waveguide interaction, as well as micro-engineered plasma structure to accelerate electrons to peak energy greater than 1 GeV with narrow slice energy spread (~1%) and high overall efficiency.

Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

Discovery of potent adenosine A2a antagonists as potential anti-Parkinson disease agents. Non-linear QSAR analyses integrated with pharmacophore modeling.

Adenosine A2A receptor antagonists are of great interest in the treatment for Parkinson's disease. In this study, we combined extensive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent Adenosine A2A antagonists. Genetic function algorithm (GFA) joined with k nearest neighbor (kNN) analyses were applied to build predictive QSAR models.

Accumulation of formamide in hydrothermal pores to form prebiotic nucleobases.

Formamide is one of the important compounds from which prebiotic molecules can be synthesized, provided that its concentration is sufficiently high. For nucleotides and short DNA strands, it has been shown that a high degree of accumulation in hydrothermal pores occurs, so that temperature gradients might play a role in the origin of life [Baaske P, et al. (2007)Proc Natl Acad Sci USA104(22):9346-9351].

Directionality of substrate translocation of the hemolysin A Type I secretion system.

Type 1 secretion systems (T1SS) of Gram-negative bacteria are responsible for the secretion of various proteases, lipases, S-layer proteins or toxins into the extracellular space. The paradigm of these systems is the hemolysin A (HlyA) T1SS of Escherichia coli. This multiple membrane protein complex is able to secrete the toxin HlyA in one step across both E.

Cytotoxic acyl amides from the soil fungus Gymnascella dankaliensis.

The soil fungus Gymnascella dankaliensis was collected in the vicinity of the Giza pyramids, Egypt. When grown on solid rice medium the fungus yielded four new compounds including 11'-carboxygymnastatin N (1), gymnastatin S (2), dankamide (3), and aranorosin-2-methylether (4), the latter having been reported previously only as a semisynthetic compound. In addition, six known metabolites (5-10) were isolated.

A re-examination of the selection of the sensory organ precursor of the bristle sensilla of Drosophila melanogaster.

The bristle sensillum of the imago of Drosophila is made of four cells that arise from a sensory organ precursor cell (SOP). This SOP is selected within proneural clusters (PNC) through a mechanism that involves Notch signalling. PNCs are defined through the expression domains of the proneural genes, whose activities enables cells to become SOPs.

Experimental amine-epoxide sealer: a physicochemical study in comparison with AH Plus and EasySeal.

Aim: To compare selected physicochemical and biological properties of an experimental sealer with those of two commercially available sealers.

Methodology: AH Plus and EasySeal were used as model materials for commercially available amine-epoxide sealers. They were mixed as stated by the manufacturer.

pAUL: a gateway-based vector system for adaptive expression and flexible tagging of proteins in Arabidopsis.

Determination of protein function requires tools that allow its detection and/or purification. As generation of specific antibodies often is laborious and insufficient, protein tagging using epitopes that are recognized by commercially available antibodies and matrices appears more promising. Also, proper spatial and temporal expression of tagged proteins is required to prevent falsification of results.

Meroterpenes from endophytic fungus A1 of mangrove plant Scyphiphora hydrophyllacea.

Four new meroterpenes, guignardones F-I (1-4), together with two known compounds guignardones A (5) and B (6) were isolated from the endophytic fungus A1 of the mangrove plant Scyphiphora hydrophyllacea. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray crystallography. A possible biogenetic pathway of compounds 1-6 was also proposed.

The amount of neoadjuvant chemotherapy for Barrett's carcinoma does not correlate with long-term survival.

Introduction: Several studies have proven an ameliorated prognosis after a neoadjuvant therapy for locally advanced Barrett's carcinoma in case of response. The necessary amount of neoadjuvant chemotherapy within a multimodal therapy concept with following oesophageal resection has never been evaluated so far.

Methods: The clinical course of 122 patients with Barrett's carcinoma, who all underwent a neoadjuvant chemotherapy with cisplatin, five fluorouracil and leucovorin and following oesophagectomy, was reviewed.

Prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment.

Objective: Treatment options for patients with diffuse type gastric cancer (linitis plastica) are discussed controversial. It is sometimes discussed that these patients should be treated primarily in palliative intention conservative without resection.

Methods: In a single-center analysis, we investigated 120 patients with diffuse type gastric cancer.