Plant-soil distribution of potentially toxic elements in response to elevated atmospheric CO2.

The distribution of contaminant elements within ecosystems is an environmental concern because of these elements' potential toxicity to animals and plants and their ability to hinder microbial ecosystem services. As with nutrients, contaminants are cycled within and through ecosystems. Elevated atmospheric CO2 generally increases plant productivity and alters nutrient element cycling, but whether CO2 causes similar effects on the cycling of contaminant elements is unknown.

A practical guide to the synthesis and use of membrane-permeant acetoxymethyl esters of caged inositol polyphosphates.

This protocol describes a method for efficient chemical synthesis of an analog of inositol-1,4,5-trisphosphate (IP(3)) hexakis acetoxymethyl ester having an ortho-nitroveratryl photochemical caging group on the 6-hydroxyl position. The six esters render the probe membrane permeant, such that it can be loaded into intact living cells in vitro or in vivo. Inside cells, the caged IP(3) is inert until activated by two-photon excitation at 720 nm.

Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic.

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

Bidirectional control of arteriole diameter by astrocytes.

Astrocytes are the most numerous cells in the CNS. It is a defining feature of brain anatomy that every astrocyte has at least one contact with the vasculature, termed an endfoot. Collectively, all endfeet completely circumscribe all vessels in the brain.

Molecular characterization of pezizalean ectomycorrhizas associated with pinyon pine during drought.

Recent studies using molecular analysis of ectomycorrhizas have revealed that ascomycete fungi, especially members of the order Pezizales, can be important members of ectomycorrhizal (EM) fungal communities. However, little is known about the ecology and taxonomy of many of these fungi. We used data collected during a wet and a dry period to test the hypothesis that pezizalean EM fungi associated with pinyon pine (Pinus edulis) responded positively to drought stress.

A bacterium that can grow by using arsenic instead of phosphorus.

Life is mostly composed of the elements carbon, hydrogen, nitrogen, oxygen, sulfur, and phosphorus. Although these six elements make up nucleic acids, proteins, and lipids and thus the bulk of living matter, it is theoretically possible that some other elements in the periodic table could serve the same functions. Here, we describe a bacterium, strain GFAJ-1 of the Halomonadaceae, isolated from Mono Lake, California, that is able to substitute arsenic for phosphorus to sustain its growth.

Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial.

Background: Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).

Methods: A double-blind placebo-controlled randomized trial involving 240 subjects aged 37-87 years with 10-40 actinic keratoses was conducted at eight US academic medical centers.

Defining a process operating window for the synthesis of 5-methyluridine by transglycosylation of guanosine and thymine.

This paper describes a high yielding coupled enzymatic reaction using Bacillus halodurans purine nucleoside phosphorylase (PNP) and E. coli uridine phosphorylase (UP) for synthesis of 5-methyluridine (5-MU) by transglycosylation. Key parameters such as reaction temperature, pH, reactant loading, reactor configuration and enzyme loading were investigated.

Fine-needle aspiration biopsies for gene expression ratio-based diagnostic and prognostic tests in malignant pleural mesothelioma.

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive disease associated with median survival between 9 and 12 months. The correct diagnosis of MPM is sometimes challenging and usually requires solid tissue biopsies rather than fine-needle aspiration biopsies (FNA). We postulated that the accuracy of FNA-based diagnosis might be improved by the addition of molecular tests using a gene expression ratio-based algorithm and that prognostic tests could be similarly performed.

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial.

Background: Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder.

Aim: To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC.

Methods: Randomized, double-blind, placebo-controlled trial of patients (n=209 MG, n=96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding=0, mucosal appearance <2] who took MG 1.

Devonian rise in atmospheric oxygen correlated to the radiations of terrestrial plants and large predatory fish.

The evolution of Earth's biota is intimately linked to the oxygenation of the oceans and atmosphere. We use the isotopic composition and concentration of molybdenum (Mo) in sedimentary rocks to explore this relationship. Our results indicate two episodes of global ocean oxygenation.

Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ.

Recent work has highlighted roles for JAK (Janus kinase) family members in haemopoietic diseases. Although sequencing efforts have uncovered transforming JAK1 mutations in acute leukaemia, they have also identified non-transforming JAK1 mutations. Thus with limited knowledge of the mechanisms of JAK1 activation by mutation, sequencing may not readily identify transforming mutations.

Comprehensive gene expression profiling and functional analysis of matrix metalloproteinases and TIMPs, and identification of ADAM-10 gene expression, in a corneal model of epithelial resurfacing.

This study provides a comprehensive expression analysis for the entire matrix metalloproteinase (MMP) gene family during the process of epithelial resurfacing following corneal abrasion injury in the mouse. The mRNA levels for all known MMP genes expressed in mouse, the related enzyme ADAM-10, and the known tissue inhibitors of metalloproteinases (TIMPs) were determined semi-quantitatively by reverse transcriptase-polymerase chain reaction (RT-PCR) in the uninjured epithelium, and in the epithelial tissue resurfacing the abraded area or residing in its periphery at two time points: during the epithelial migration phase and immediately following wound closure. The mRNA levels for MMP-1a, -1b, -9, -10, -12, and -13 as well as TIMP-1 were significantly up-regulated in the migrating corneal epithelium.

Second generation sequencing of the mesothelioma tumor genome.

The current paradigm for elucidating the molecular etiology of cancers relies on the interrogation of small numbers of genes, which limits the scope of investigation. Emerging second-generation massively parallel DNA sequencing technologies have enabled more precise definition of the cancer genome on a global scale. We examined the genome of a human primary malignant pleural mesothelioma (MPM) tumor and matched normal tissue by using a combination of sequencing-by-synthesis and pyrosequencing methodologies to a 9.

Specific killing of Rb mutant cancer cells by inactivating TSC2.

The retinoblastoma (Rb) tumor suppressor is often inactivated in cancers. To identify genes that can be used to specifically target such cancers, we carried out a genetic screen in Drosophila. We identified gig (fly TSC2) and found that inactivation of rbf (fly Rb) and gig synergistically induced cell death.

Correlation between epithelial ingrowth and basement membrane remodeling in human corneas after laser-assisted in situ keratomileusis.

Objective: To further investigate the hypothesis that epithelial ingrowth in human corneas after laser-assisted in situ keratomileusis (LASIK) correlates with basement membrane remodeling, as suggested by the presence of matrix metalloproteinase 9 around epithelial cells in the lamellar scar.

Methods: Immunohistochemical analysis and transmission electron microscopy were applied to human postmortem corneas with post-LASIK epithelial ingrowth.

Results: Epithelial ingrowth into the flap margin was observed in 8 of 18 corneas (44%).

Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression.

Cortical spreading depression (SD) is a propagating wave of neuronal and glial depolarization that manifests in several brain disorders. However, the relative contribution of neurons and astrocytes to SD genesis has remained controversial. This is in part due to a lack of utilizing sophisticated experimental methodologies simultaneously to quantify multiple cellular parameters.

Rapid analysis of perchlorate, chlorate and bromate ions in concentrated sodium hypochlorite solutions.

A sensitive, rapid, and rugged liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for measuring concentrations of perchlorate, chlorate, and bromate ions in concentrated sodium hypochlorite solutions is presented. The LC-MS/MS method offers a practical quantitation limit (PQL) of 0.05 microg L(-1) for ClO(4)(-), 0.

Differentially expressed alternatively spliced genes in malignant pleural mesothelioma identified using massively parallel transcriptome sequencing.

Background: Analyses of Expressed Sequence Tags (ESTs) databases suggest that most human genes have multiple alternative splice variants. The alternative splicing of pre-mRNA is tightly regulated during development and in different tissue types. Changes in splicing patterns have been described in disease states.

Visual noise selectively degrades vision in migraine.

Purpose. Migraine is a disabling condition with underlying neuronal mechanisms that remain elusive. Migraineurs experience hyperresponsivity to visual stimuli and frequently experience visual disturbances.

Disparities in emptying velocity within the left atrial appendage.

Aims: Pulsed Doppler measurement of left atrial appendage (LAA) emptying velocity, a marker of left atrium contractile function, has been shown to predict success of cardioversion, thrombo-embolic risk, and maintenance of sinus rhythm after cardioversion and pulmonary vein isolation. However, in the published literature, emptying velocity measurement location is not uniform, and no standard currently exists. We assessed the hypothesis that emptying velocity when acquired near the LAA orifice differs from that at the LAA apex.

Arginine 15 stabilizes an S(N)Ar reaction transition state and the binding of anionic ligands at the active site of human glutathione transferase A1-1.

Arg15, conserved in class Alpha GSTs (glutathione transferases), is located at the interface between the G- and H-sites of the active site where its cationic guanidinium group might play a role in catalysis and ligand binding. Arg15 in human GSTA1-1 was replaced with a leucine and crystallographic, spectroscopic, thermodynamic and molecular docking methods were used to investigate the contribution made by Arg15 towards (i) the binding of glutathione (GSH) to the G-site, (ii) the pK(a) of the thiol group of GSH, (iii) the stabilization of an analog of the anionic transition state of the S(N)Ar reaction between 1-chloro-2,4-dinitrobenzene (CDNB) and GSH, and, (iv) the binding of the anionic non-substrate ligand 8-anilino-1-naphthalene sulphonate (ANS) to the H-site. While the R15L mutation substantially diminishes the CDNB-GSH conjugating activity of the enzyme, it has little effect on protein structure and stability.

Astrocyte-mediated distributed plasticity at hypothalamic glutamate synapses.

Afferent activity can induce fast, feed-forward changes in synaptic efficacy that are synapse specific. Using combined electrophysiology, caged molecule photolysis, and Ca(2+) imaging, we describe a plasticity in which the recruitment of astrocytes in response to afferent activity causes a fast and feed-forward, yet distributed increase in the amplitude of quantal synaptic currents at multiple glutamate synapses on magnocellular neurosecretory cells in the hypothalamic paraventricular nucleus. The plasticity is largely multiplicative, consistent with a proportional increase or "scaling" in the strength of all synapses on the neuron.

Biologic therapy in Crohn's disease.

Crohn's disease is a complex disease process causing transmural inflammation of the gastrointestinal tract, which produces a constellation of symptoms including abdominal pain, frequent loose stools, fistula formation, and extraintestinal manifestations. Biologic therapy, including tumor necrosis factor alpha inhibitors, are a growing class of agents, which have demonstrated efficacy in the treatment of moderate to severe Crohn's disease. Their indications for use have grown, as has the understanding of their associated safety concerns.