Integrative Network Analyses of Transcriptomics Data Reveal Potential Drug Targets for Acute Radiation Syndrome

Recent political unrest has highlighted the importance of understanding the short- and long-term effects of gamma-radiation exposure on human health and survivability. In this regard, effective treatment for acute radiation syndrome (ARS) is a necessity in cases of nuclear disasters. Here, we propose 20 therapeutic targets for ARS identified using a systematic approach that integrates gene coexpression networks obtained under radiation treatment in humans and mice, drug databases, disease-gene association, radiation-induced differential gene expression, and literature mining. By selecting gene targets with existing drugs, we identified potential candidates for drug repurposing. Eight of these genes (BRD4, NFKBIA, CDKN1A, TFPI, MMP9, CBR1, ZAP70, IDH3B) were confirmed through literature to have shown radioprotective effect upon perturbation. This study provided a new perspective for the treatment of ARS using systems-level gene associations integrated with multiple biological information. The identified genes might provide high confidence drug target candidates for potential drug repurposing for ARS

Effects of Cement Bases on the Stresses and Deflections in Composite Restorations

A model was used to show that tensile and shear stresses can occur in sufficient magnitude to cause failure in a cement base supporting a composite material in a posterior Class I restoration. Highest values of stress were observed when lining materials with a low modulus were used.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68080/2/10.1177_00220345760550010301.pd

Vesicle shape, molecular tilt, and the suppression of necks

Can the presence of molecular-tilt order significantly affect the shapes of lipid bilayer membranes, particularly membrane shapes with narrow necks? Motivated by the propensity for tilt order and the common occurrence of narrow necks in the intermediate stages of biological processes such as endocytosis and vesicle trafficking, we examine how tilt order inhibits the formation of necks in the equilibrium shapes of vesicles. For vesicles with a spherical topology, point defects in the molecular order with a total strength of $+2$ are required. We study axisymmetric shapes and suppose that there is a unit-strength defect at each pole of the vesicle. The model is further simplified by the assumption of tilt isotropy: invariance of the energy with respect to rotations of the molecules about the local membrane normal. This isotropy condition leads to a minimal coupling of tilt order and curvature, giving a high energetic cost to regions with Gaussian curvature and tilt order. Minimizing the elastic free energy with constraints of fixed area and fixed enclosed volume determines the allowed shapes. Using numerical calculations, we find several branches of solutions and identify them with the branches previously known for fluid membranes. We find that tilt order changes the relative energy of the branches, suppressing thin necks by making them costly, leading to elongated prolate vesicles as a generic family of tilt-ordered membrane shapes.Comment: 10 pages, 7 figures, submitted to Phy. Rew.

Gulf-Wide Decreases in the Size of Large Coastal Sharks Documented by Generations of Fishermen

Large sharks are top predators in most coastal and marine ecosystems throughout the world, and evidence of their reduced prominence in marine ecosystems has been a serious concern for fisheries and ecosystem management. Unfortunately, quantitative data to document the extent, timing, and consequences of changes in shark populations are scarce, thwarting examination of long-term (decadal, century) trends, and reconstructions based on incomplete data sets have been the subject of debate. Absence of quantitative descriptors of past ecological conditions is a generic problem facing many fields of science but is particularly troublesome for fisheries scientists who must develop specific targets for restoration. We were able to use quantitative measurements of shark sizes collected annually and independently of any scientific survey by thousands of recreational fishermen over the last century to document decreases in the size of large sharks from the northern Gulf of Mexico. Based on records from fishing rodeos in three U.S. coastal states, the size (weight or length) of large sharks captured by fishermen decreased by 50–70% during the 20 years after the 1980s. The pattern is largely driven by reductions in the occurrence and sizes of Tiger Sharks Galeocerdo cuvier and Bull Sharks Carcharhinus leucas and to a lesser extent Hammerheads Sphyrna spp. This decrease occurred despite increasing fishing effort and advances in technology, but it is coincident with the capitalization of the U.S. commercial shark long-line fishery in the GOM

Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity

We have identified a novel autoantibody specificity in scleroderma that we term anti-chromo. These antibodies recognize several chromosomal antigens with apparent molecular mass of between 23 and 25 kDa, as determined by immunoblots. Anti-chromo autoantibodies occur in 10-15% of sera from patients with anti-centromere antibodies (ACA). We used anti-chromo antibodies to screen a human expression library and obtained cDNA clones encoding a 25 kDa chromosomal autoantigen. DNA sequence analysis reveals this protein to be a human homologue of HP1, a heterochromatin protein of Drosophila melanogaster. We designate our cloned protein HP1Hs alpha. Epitope mapping experiments using both human and Drosophila HP1 reveal that anti-chromo antibodies target a region at the amino terminus of the protein. This region contains a conserved motif, the chromo domain (or HP1/Pc box), first recognized by comparison of Drosophila HP1 with the Polycomb gene product. Both proteins are thought to play a role in creating chromatin structures in which gene expression is suppressed. Anti-chromo thus defines a novel type of autoantibody that recognizes a conserved structural motif found on a number of chromosomal proteins

CcpA regulates arginine biosynthesis in Staphylococcus aureus through repression of proline catabolism.

Staphylococcus aureus is a leading cause of community-associated and nosocomial infections. Imperative to the success of S. aureus is the ability to adapt and utilize nutrients that are readily available. Genomic sequencing suggests that S. aureus has the genes required for synthesis of all twenty amino acids. However, in vitro experimentation demonstrates that staphylococci have multiple amino acid auxotrophies, including arginine. Although S. aureus possesses the highly conserved anabolic pathway that synthesizes arginine via glutamate, we demonstrate here that inactivation of ccpA facilitates the synthesis of arginine via the urea cycle utilizing proline as a substrate. Mutations within putA, rocD, arcB1, argG and argH abolished the ability of S. aureus JE2 ccpA::tetL to grow in the absence of arginine, whereas an interruption in argJBCF, arcB2, or proC had no effect. Furthermore, nuclear magnetic resonance demonstrated that JE2 ccpA::ermB produced (13)C(5) labeled arginine when grown with (13)C(5) proline. Taken together, these data support the conclusion that S. aureus synthesizes arginine from proline during growth on secondary carbon sources. Furthermore, although highly conserved in all sequenced S. aureus genomes, the arginine anabolic pathway (ArgJBCDFGH) is not functional under in vitro growth conditions. Finally, a mutation in argH attenuated virulence in a mouse kidney abscess model in comparison to wild type JE2 demonstrating the importance of arginine biosynthesis in vivo via the urea cycle. However, mutations in argB, argF, and putA did not attenuate virulence suggesting both the glutamate and proline pathways are active and they, or their pathway intermediates, can complement each other in vivo

Peptidomics analysis reveals changes in small urinary peptides in patients with interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating pain disorder of the bladder and urinary tract with poorly understood etiology. A definitive diagnosis of IC/BPS can be challenging because many symptoms are shared with other urological disorders. An analysis of urine presents an attractive and non-invasive resource for monitoring and diagnosing IC/BPS. The antiproliferative factor (APF) peptide has been previously identified in the urine of IC/BPS patients and is a proposed biomarker for the disorder. Nevertheless, other small urinary peptides have remained uninvestigated in IC/BPS primarily because protein biomarker discovery efforts employ protocols that remove small endogenous peptides. The purpose of this study is to investigate the profile of endogenous peptides in IC/BPS patient urine, with the goal of identifying putative peptide biomarkers. Here, a non-targeted peptidomics analysis of urine samples collected from IC/BPS patients were compared to urine samples from asymptomatic controls. Our results show a general increase in the abundance of urinary peptides in IC/BPS patients, which is consistent with an increase in inflammation and protease activity characteristic of this disorder. In total, 71 peptides generated from 39 different proteins were found to be significantly altered in IC/BPS. Five urinary peptides with high variable importance in projection (VIP) coefficients were found to reliably differentiate IC/ BPS from healthy controls by receiver operating characteristic (ROC) analysis. In parallel, we also developed a targeted multiple reaction monitoring method to quantify the relative abundance of the APF peptide from patient urine samples. Although the APF peptide was found in moderately higher abundance in IC/BPS relative to control urine, our results show that the APF peptide was inconsistently present in urine, suggesting that its utility as a sole biomarker of IC/BPS may be limited. Overall, our results revealed new insights into the profile of urinary peptides in IC/BPS that will aid in future biomarker discovery and validation efforts

Peptidomics analysis reveals changes in small urinary peptides in patients with interstitial cystitis/bladder pain syndrome

Interstitial cystitis or bladder pain syndrome (IC/BPS) is a chronic and debilitating pain disorder of the bladder and urinary tract with poorly understood etiology. Symptomatic criteria to aid in the diagnosis of IC/BPS includes bladder pain, an increase in urinary urgency or Hunner’s ulcers on the bladder wall. Our study revealed differences in the profiles of small urinary peptides for IC/BPS patients compared to age-matched controls which is consistent with increased protease activity in IC/BPS. Our study also enabled the direct measurement of APF peptide abundance in IC/BPS and control urine. Our results indicate that the full-length APF peptide was not consistently found in the urine of IC/BPS patients at levels sufficient to reliably differentiate IC/BPS patients from healthy individuals