Structure of mammalian poly(ADP-ribose) glycohydrolase reveals a flexible tyrosine clasp as a substrate-binding element.

Reversible post-translational modification by poly(ADP-ribose) (PAR) regulates chromatin structure, DNA repair and cell fate in response to genotoxic stress. PAR glycohydrolase (PARG) removes PAR chains from poly ADP-ribosylated proteins to restore protein function and release oligo(ADP-ribose) chains to signal damage. Here we report crystal structures of mammalian PARG and its complex with a substrate mimic that reveal an open substrate-binding site and a unique 'tyrosine clasp' enabling endoglycosidic cleavage of branched PAR chains.

Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters.

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme.

Mitomycin-C-treated peripheral blood mononuclear cells (PBMCs) prolong allograft survival in composite tissue allotransplantation.

Background: Composite tissue allotransplantation (CTA) was introduced as a potential treatment for complex reconstructive procedures and has become a clinical reality. Hand and face transplantation, the most widely recognized forms of CTA, have intensified immunological research in this emerging field of transplantation. Mitomycin C (MMC) is an alkylating agent that suppresses allogeneic T-cell responses.

The peculiar nature of molecular interactions between an imidazolium ionic liquid and acetone.

We present novel insights into the molecular interactions between polar solvents and imidazolium ionic liquids using the example of 1-ethyl-3-methylimidazolium ethyl sulfate and acetone. Recently published volumetric property data of this particular system have revealed peculiarities which could not be fully explained by steric effects. In order to shed light on the behavior at a molecular level, we apply IR spectroscopy and analyze solvent-induced line shifts as well as the excess IR spectra.

Molecular Characterization of a Patient's Small Cell Carcinoma of the Ovary of the Hypercalcemic Type.

Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare tumor type that mainly affects young women. We report a 21-year old woman with SCCOHT. The patient initially presented with stage T3AN1MX disease and treated with surgery.

Preclinical investigation of nanoparticle albumin-bound paclitaxel as a potential treatment for adrenocortical cancer.

Background: Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel).

Kinome-wide siRNA screening identifies molecular targets mediating the sensitivity of pancreatic cancer cells to Aurora kinase inhibitors.

Aurora kinases are a family of mitotic kinases that play important roles in the tumorigenesis of a variety of cancers including pancreatic cancer. A number of Aurora kinase inhibitors (AKIs) are currently being tested in preclinical and clinical settings as anti-cancer therapies. However, the antitumor activity of AKIs in clinical trials has been modest.

Shock wave treatment in composite tissue allotransplantation.

Introduction: Composite tissue allotransplantation is a newly emerged field of transplantation. Shock wave technology has already been used in the treatment of urologic and orthopedic disorders. Recent studies demonstrated a suppression of the early proinflammatory immune response.

Thermal dissociation of ethylene glycol vinyl ether.

The pyrolysis of ethylene glycol vinyl ether (EGVE), an initial product of 1,4-dioxane dissociation, was examined in a diaphragmless shock tube (DFST) using laser schlieren densitometry (LS) at 57 ± 2 and 122 ± 3 Torr over 1200-1800 K. DFST/time-of-flight mass spectrometry experiments were also performed to identify reaction products. EGVE was found to dissociate via two channels: (1) a molecular H atom transfer/C-O scission to produce C(2)H(3)OH and CH(3)CHO, and (2) a radical channel involving C-O bond fission generating ˙CH(2)CH(2)OH and ˙CH(2)CHO radicals, with the second channel being strongly dominant over the entire experimental range.

Assessment of the subjective benefit of electric acoustic stimulation with the abbreviated profile of hearing aid benefit.

Conclusion: This study demonstrates that electric-acoustic stimulation (EAS) significantly decreases the subjective impairment in speech perception.

Objectives: To assess the subjective benefit of EAS over the first 12 months after EAS fitting using the Abbreviated Profile of Hearing Aid Benefit (APHAB).

Method: Twenty-three EAS users, implanted with either the PULSAR(CI)(100) FLEX(EAS) provided with the DUET EAS processor or the COMBI40+ Medium provided with the TEMPO+ speech processor, were included.

Tips for success: Networking is not a bad word.

To many scientists, the word "networking" sounds like an enterprise only suitable for those who run in circles with the business elite. However in reality, most scientists depend on networking to generate and maintain professional relationships, disseminate and gather information, and to climb the professional ladder. Presented here are tips from three seasoned professors, Kathy Cheah, PhD, Susan Mango, PhD, and Randall Moon, PhD, who describe what networking means to them, why it is important, and how they go about doing it.

Attenuated total reflection infrared (ATR-IR) spectroscopy of a water-in-oil emulsion.

Water-in-oil (w/o) emulsions are of great interest in many areas including food technology and the oil and gas industry. However, the molecular mechanisms that lead to a stable emulsion are yet to be fully understood. In this article, the potential of attenuated total reflection (ATR) infrared (IR) spectroscopy for studying the influence of an emulsifier on the molecular water structure in a thin layer at the w/o interface is demonstrated.

Protection of inner ear function after cochlear implantation: compound action potential measurements after local application of glucocorticoids in the guinea pig cochlea.

Background: Cochlear implant users with residual hearing often benefit greatly from simultaneous electric and acoustic stimulation. However, implantation can cause trauma to the inner ear, resulting in poorer hearing postoperatively. We investigated whether a single local injection of glucocorticoids can reduce hearing loss in long-term implanted guinea pigs.

Primer and interviews: promises and realities of induced pluripotent stem cells.

In 2006, Yamanaka's group announced they had discovered the proverbial "fountain of youth" for human cells, forever changing the field of stem cell research. After misexpressing within them a cocktail of four genes, adult somatic cells revert into an embryonic stem cell (ESC)-like state. These so-called induced pluripotent stem cells (iPSCs) can differentiate into a wide variety of cell types, seemingly bypassing the need for politically charged ESCs.

Advancing a clinically relevant perspective of the clonal nature of cancer.

Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing.

Determination of physicochemical parameters of ionic liquids and their mixtures with solvents using laser-induced gratings.

The laser-induced gratings (LIGs) technique has been applied for the simultaneous determination of sound speed and thermal diffusivity in the room temperature ionic liquid (RTIL) 1-ethyl-3-methylimidazolium ethylsulfate, [EMIm][EtSO(4)], its mixture with 85.68 mol % acetone, C(3)H(6)O, and pure acetone. The measurements have been performed in a quartz glass cuvette at ambient pressure and temperature.

Awareness and education of patients receiving bisphosphonates.

Background: Bisphosphonates are used to fight osteoporosis and for treating malignancies. In 2003, the first case reports appeared that described bisphosphonate-induced osteonecrosis of the jaw (BONJ). The aim of this study was to assess patient awareness of the adverse effects of bisphosphonates in order to improve cooperation among doctors and between doctors and patients.

Electric-acoustic stimulation of the auditory system: a review of the first decade.

Electric-acoustic stimulation (EAS) was developed for individuals with a profound hearing loss in the high frequencies and a substantial residual low-frequency hearing (LFH). For this group of candidates, conventional hearing aids often neither provided sufficient amplification nor were they considered suitable for cochlear implantation due to the possible destruction of residual hearing capabilities. With EAS, combining electric stimulation with an ipsilateral acoustic stimulation, preservation of residual LFH and the development of a new speech processor uniting both strategies became essential.

MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres.

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.

Tips for success: getting more done in less time.

Whether a student or full professor, it seems there is never enough time in the day to get everything done. Yet as a scientist rises through the ranks, somehow she is expected to do even more. Excellent time management skills enable one to work more effectively, and to accomplish more in less time.

MMP-13 selective alpha-sulfone hydroxamates: identification of selective P1' amides.

Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1' substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8.

Genomic signatures of cancer: basis for individualized risk assessment, selective staging and therapy.

The development of DNA microarray and quantitative real-time polymerase chain reaction technologies has allowed for precise quantitation of RNA expression of hundreds to thousands of genes. These technologies have significantly impacted the study and understanding of cancer in terms of its molecular and genetic characteristics. In this review article, breast cancer, colon cancer, and adrenal carcinoma have been chosen to illustrate the principle and techniques of genomic profiling and to illustrate how such methods may be used to develop genomic signatures for personalized risk assessment and to individualize patient treatment.

Electronic structure and normal vibrations of the 1-ethyl-3-methylimidazolium ethyl sulfate ion pair.

Electronic and structural properties of the ion pair 1-ethyl-3-methylimidazolium ethyl sulfate are studied using density functional methods. Three locally stable conformers of the ion pair complex are considered to analyze molecular interactions between its cation and anion. Manifestations of these interactions in the vibrational spectra are discussed and compared with experimental IR and Raman spectroscopy data.

Structure analysis reveals the flexibility of the ADAMTS-5 active site.

A ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) succinamide derivative (here referred to as Compound 12) shows significant activity toward many matrix metalloproteinases (MMPs), including MMP-2, MMP-8, MMP-9, and MMP-13. Modeling studies had predicted that this compound would not bind to ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs-5) due to its shallow S1' pocket. However, inhibition analysis revealed it to be a nanomolar inhibitor of both ADAMTS-4 and -5.