Atomistic simulations of the human proteasome inhibited by a covalent ligand

The proteasome is a large biomolecular complex responsible for protein degradation. It is under intense research due to its fundamental role in cellular homeostasis, and tremendous potential for medicinal applications. Recent data from X-ray crystallography and cryo-electron microscopy have suggested that there is a large-scale structural change upon binding of an inhibitor. We carried out atomistic molecular dynamics simulations of the native and inhibited proteasomes to understand the molecular details of the inhibition. Here we describe the technical details of the simulations and assess the quality of the trajectories obtained. The biochemical aspects of the proteasome are under further investigation and will be published elsewhere. This work was a part of the GCS-Prot project at the HLRS, run on the Cray XC40 supercomputing system

TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia

BACKGROUND: Mutations in the three-prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). However, the endogenous expression of TREX1 in human brain has not been studied. METHODS: We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame-shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin-fixed, paraffin-embedded samples from normal controls and patients with RVCL and ischemic stroke. RESULTS: After validating the specificity of our anti-TREX1 rabbit pAb, WB analysis was utilized to detect the endogenous wild-type and frame-shift mutant of TREX1 in cell lysates. Dual staining in human brain tissues from patients with RVCL and normal controls localized TREX1 to a subset of microglia and macrophages. Quantification of immunohistochemical staining of the cerebral cortex revealed that TREX1 CONCLUSIONS: TREX1 is expressed by a subset of microglia in normal human brain, often in close proximity to the microvasculature, and increases in the setting of ischemic lesions. These findings suggest a role for TREX

355, 532, and 1064 nm picosecond laser interaction with grass tissues

In this article, we investigate how 355, 532, and 1064 nm picosecond lasers interact with grass tissues. We have identified five interaction regimes, and based on this classification, interaction maps have been constructed from a systematic experiment. The optical properties of light absorbing grass constituents are studied theoretically in order to understand how and how much light is absorbed by grass tissues. Scanning electron microscopy and optical microscopy are employed for observing morphological and structural changes of grass tissues. To the best of the authors' knowledge, this is the first investigation into laser interaction with plant leaves and reveals some fundamental findings regarding how a laser interacts with grass tissues and how plant leaves can be processed using lasers.open1

Folding of VemP into translation-arresting secondary structure is driven by the ribosome exit tunnel

The ribosome is a fundamental biomolecular complex that synthesizes proteins in cells. Nascent proteins emerge from the ribosome through a tunnel, where they may interact with the tunnel walls or small molecules such as antibiotics. These interactions can cause translational arrest with notable physiological consequences. Here, we studied the arrest caused by the regulatory peptide VemP, which is known to form alpha-helices inside the ribosome tunnel near the peptidyl transferase center under specific conditions. We used all-atom molecular dynamics simulations of the entire ribosome and circular dichroism spectroscopy to study the driving forces of helix formation and how VemP causes the translational arrest. To that aim, we compared VemP dynamics in the ribosome tunnel with its dynamics in solution. We show that the VemP peptide has a low helical propensity in water and that the propensity is higher in mixtures of water and trifluorethanol. We propose that helix formation within the ribosome is driven by the interactions of VemP with the tunnel and that a part of VemP acts as an anchor. This anchor might slow down VemP progression through the tunnel enabling alpha-helix formation, which causes the elongation arrest

Stratospheric Observatory for Infrared Astronomy (SOFIA) Acoustical Resonance Technical Assessment Report

A request was submitted on September 2, 2004 concerning the uncertainties regarding the acoustic environment within the Stratospheric Observatory for Infrared Astronomy (SOFIA) cavity, and the potential for structural damage from acoustical resonance or tones, especially if they occur at or near a structural mode. The requestor asked for an independent expert opinion on the approach taken by the SOFIA project to determine if the project's analysis, structural design and proposed approach to flight test were sound and conservative. The findings from this assessment are recorded in this document

All Stable Characteristic Classes of Homological Vector Fields

An odd vector field $Q$ on a supermanifold $M$ is called homological, if $Q^2=0$. The operator of Lie derivative $L_Q$ makes the algebra of smooth tensor fields on $M$ into a differential tensor algebra. In this paper, we give a complete classification of certain invariants of homological vector fields called characteristic classes. These take values in the cohomology of the operator $L_Q$ and are represented by $Q$-invariant tensors made up of the homological vector field and a symmetric connection on $M$ by means of tensor operations.Comment: 17 pages, references and comments adde

Automated Glaucoma Detection Using Hybrid Feature Extraction in Retinal Fundus Images

Glaucoma is one of the most common causes of blindness. Robust mass screening may help to extend the symptom-free life for affected patients. To realize mass screening requires a cost-effective glaucoma detection method which integrates well with digital medical and administrative processes. To address these requirements, we propose a novel low cost automated glaucoma diagnosis system based on hybrid feature extraction from digital fundus images. The paper discusses a system for the automated identification of normal and glaucoma classes using higher order spectra (HOS), trace transform (TT), and discrete wavelet transform (DWT) features. The extracted features are fed to a support vector machine (SVM) classifier with linear, polynomial order 1, 2, 3 and radial basis function (RBF) in order to select the best kernel for automated decision making. In this work, the SVM classifier, with a polynomial order 2 kernel function, was able to identify glaucoma and normal images with an accuracy of 91.67%, and sensitivity and specificity of 90% and 93.33%, respectively. Furthermore, we propose a novel integrated index called Glaucoma Risk Index (GRI) which is composed from HOS, TT, and DWT features, to diagnose the unknown class using a single feature. We hope that this GRI will aid clinicians to make a faster glaucoma diagnosis during the mass screening of normal/glaucoma images

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology