The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43.

The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.

Pancreatic Polypeptide Cell Proliferation in the Pancreas and Duodenum Coexisting in a Patient With Pancreatic Adenocarcinoma Treated With a GLP-1 Analog.

A partial pancreaticogastrodudenectomy was performed on a 66-year old man with type 2 diabetes mellitus because of an invasive, moderately differentiated adenocarcinoma in the head of the pancreas. In the adjacent grossly normal tissue of the uncinate process, there was a massive proliferation of pancreatic polypeptide (PP) cells confined to this region and showed invasive pattern. Strikingly, in the heaped area of his duodenum, there was a strikingly large number of PP, glucagon, a few insulin cells in a mini-islet-like patterns composed of glucagon and insulin cells. Among the etiological factors, the possible long-lasting effects of the GLP-1 analog, with which the patient was treated, are discussed. This is the first report in the literature of both the coexistence of a pancreatic adenocarcinoma and invasive PPoma and the occurrence of PP and insulin cells in human duodenal mucosa.

Effect of ferrous ion concentration on the kinetics of radiation-induced iron-oxide nanoparticle formation and growth.

Magnetite nanoparticles were formed by γ-radiolysis of solutions containing different initial concentrations of FeSO4 without any other chemical additives. The particles formed in a given [Fe2+]0 had a narrow size distribution and the average size increased with [Fe2+]0. Five hour irradiation at 0.8 Gy s-1 produced an average size ranging from 23 ± 2 nm to 300 ± 40 nm in 0.1 mM or 10 mM [Fe2+]0 solutions, respectively. To ascertain the size-determining mechanism, the kinetics of γ-radiation-induced particle formation and growth were investigated by simultaneously analyzing the [H2(g)] in the headspace, the [FeII] and [FeIII] dispersed in solution, UV-Vis absorbances at 304 nm and 380 nm, and the pH of the solution. The particles formed were characterized by TEM imaging and various spectroscopic analyses. For a given [Fe2+]0 the time-dependent behaviours of different analyses collectively show three distinct kinetic stages of iron oxidation. The [Fe2+]0 affects the oxidation kinetics of different stages and hence, the oxidation yields and the size of particles formed after irradiation. The main processes which cause the observed kinetics and yields in the three stages are proposed.

Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis.

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.

Radiation-induced formation of Co3O4 nanoparticles from Co(2+)(aq): probing the kinetics using radical scavengers.

The effects of the Co(2+) content and different radical scavengers on the kinetics of γ-radiation-induced Co3O4 nanoparticle formation and growth were investigated. There are four distinct stages of particle formation with different oxidation rates. Scavengers and [Co(2+)]0 affect the oxidation kinetics in the different stages and consequently the final size of the particles formed. Radiolysis model calculations were performed to obtain the time-evolution of the concentrations of key oxidants and reductants, and the effect of scavengers on those concentrations. Based on the model results and experimental data a reaction mechanism for Co3O4 particle formation by γ-irradiation of solutions containing Co(2+)(aq) is proposed. The main cobalt oxidation reaction changes with time. Oxidation of Co(2+)(aq) to Co(3+)(aq) by radiolytically produced ˙OH occurs first in the solution phase. This is followed by spontaneous co-precipitation of mixed Co(II)/Co(III) hydroxide nucleate particles. Adsorption of Co(II)(ad) followed by surface oxidation of Co(II)(ad) to CoOOH(ad) by H2O2 grows particles with a solid CoOOH(s) phase. In parallel, the solid-state transformation of CoOOH(s) and Co(II)(ad) to form Co3O4(s) occurs.

A mechanistic model for oxide growth and dissolution during corrosion of Cr-containing alloys.

We have developed a corrosion model that can predict metal oxide growth and dissolution rates as a function of time for a range of solution conditions. Our model considers electrochemical reactions at the metal/oxide and oxide/solution interfaces, and the metal cation flux from the metal to the solution phase through a growing oxide layer, and formulates the key processes using classical chemical reaction rate or flux equations. The model imposes mass and charge balance and hence, is labeled as the Mass Charge Balance (MCB) model. Mass and charge balance dictate that at any given time the oxidation (or metal cation) flux must be equal to the sum of the oxide growth flux and the dissolution flux. For each redox reaction leading to the formation of a specific oxide, the metal oxidation flux is formulated using a modified Butler-Volmer equation with an oxide-thickness-dependent effective overpotential. The oxide growth and dissolution fluxes have a first-order dependence on the metal cation flux. The rate constant for oxide formation also follows an Arrhenius dependence on the potential drop across the oxide layer and hence decreases exponentially with oxide thickness. This model is able to predict the time-dependent potentiostatic corrosion behaviour of both pure iron, and Co-Cr and Fe-Ni-Cr alloys.

Activation of the JAK/STAT pathway in Behcet's disease.

Th1/Th17-type T-cell responses are upregulated in Behcet's disease (BD). However, signaling pathways associated with this aberrant immune response are not clarified. Whole-genome microarray profiling was performed with human U133 (Plus 2.0) chips using messenger RNA of isolated CD14(+) monocytes and CD4(+) T cells from peripheral blood mononucleated cell (PBMC) in patients with BD (n = 9) and healthy controls (HCs) (n = 9). Flow cytometric analysis of unstimulated (US) and stimulated (phytohaemagglutinin) signal transducer and activator of transcription (STAT3) and pSTAT3 expressions of PBMCs were also analyzed (BD and HC, both n = 26). Janus family of kinase (JAK1) was observed to be upregulated in both CD14(+) monocytes (1.95-fold) and CD4(+) T lymphocytes (1.40-fold) of BD patients. Using canonical pathway enrichment analysis, JAK/STAT signaling was identified as activated in both CD14(+) monocytes (P = 9.55E-03) and in CD4(+) lymphocytes (P =8.13E-04) in BD. Interferon signaling was also prominent among upregulated genes in CD14(+) monocytes (P = 5.62E-05). Glucocorticoid receptor signaling and interleukin (IL-6) signaling were among the most enriched pathways in differentially expressed genes in CD14+ monocytes (P = 2.45E-09 and 1.00E-06, respectively). Basal US total STAT3 expression was significantly higher in BD (1.2 vs 3.45, P < 0.05). The JAK1/STAT3 signaling pathway is activated in BD, possibly through the activation of Th1/Th17-type cytokines such as IL-2, interferon (IFN-γ), IL-6, IL-17 and IL-23.

The bright optical flash and afterglow from the gamma-ray burst GRB 130427A.

The optical light generated simultaneously with x-rays and gamma rays during a gamma-ray burst (GRB) provides clues about the nature of the explosions that occur as massive stars collapse. We report on the bright optical flash and fading afterglow from powerful burst GRB 130427A. The optical and >100-megaelectron volt (MeV) gamma-ray flux show a close correlation during the first 7000 seconds, which is best explained by reverse shock emission cogenerated in the relativistic burst ejecta as it collides with surrounding material. At later times, optical observations show the emergence of emission generated by a forward shock traversing the circumburst environment. The link between optical afterglow and >100-MeV emission suggests that nearby early peaked afterglows will be the best candidates for studying gamma-ray emission at energies ranging from gigaelectron volts to teraelectron volts.

Gamma-radiolysis-assisted cobalt oxide nanoparticle formation.

The formation of Co(3)O(4) nano-scale colloid particles by gamma irradiation of CoSO(4) solutions was investigated. Solutions of 0.2-0.3 mM CoSO(4) at pH 6.0 and 10.6 (air-saturated and Ar-purged) were irradiated at an absorbed dose rate of 5.5 kGy h(-1). The resulting concentrations of H(2), H(2)O(2), Co(II) and Co(III) species in solution and the chemical composition and sizes of particles that were formed were measured as a function of irradiation time. Particle formation was observed only for initially air-saturated CoSO(4) solutions at pH 10.6. Analysis of the particle formation as a function of irradiation time shows that the particles evolve from Co(OH)(2) to CoOOH and then to Co(3)O(4). The radiolytic oxidation of Co(II) to Co(III) was completed in 100 min and the chemical composition of the final particles was identified as Co(3)O(4) by XPS, Raman and UV-Vis spectroscopy. Transmission electron microscopy (TEM) images show the final particles are approximately uniform in size, ranging from 8 to 20 nm. A mechanism is proposed to explain the particle formation. A key factor is the low solubility of Co(OH)(2) in air-saturated solutions at high pH. This mechanism for particle formation is compared with the mechanism previously reported for the radiolytic formation of γ-FeOOH nanoparticles.

Gamma-radiation induced formation of chromium oxide nanoparticles from dissolved dichromate.

The formation of chromium oxide nanoparticles by gamma radiolysis of Cr(VI) (CrO(4)(2-) or Cr(2)O(7)(2-)) solutions was investigated as a function of pH and initial Cr(VI) concentration by measuring [Cr(VI)], the particle concentration ([Cr(III)(col)]) and [H(2)], and by characterizing the particles using TEM, Raman, FTIR and XPS. The results show that Cr(VI) is easily reduced to Cr(III) by a homogeneous aqueous reaction with ˙e(aq)(-), but, due to the stability of Cr(III) colloids, the growth of the Cr(OH)(3) particles is very slow. As the particles grow the interior of the particle dehydrates to form Cr(2)O(3) while the outer layer remains hydrated. When most of the Cr(VI) that is initially present in the solution is converted to Cr(OH)(3) further redox reactions of chromium species occur on the particle surfaces. The redox system reaches a pseudo-equilibrium state due to cyclic reactions of Cr(III) with ˙OH and H(2)O(2), and reactions of Cr(VI) with ˙e(aq)(-) and H(2)O(2). The size distribution of the particles that are formed is controlled by these solution-solid interface reactions.

Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease.

BACKGROUND: von Willebrand factor (VWF) plays a key role in coagulation by tethering platelets to injured subendothelium through binding sites for collagen and platelet GPIb. Collagen binding assays (VWF:CB), however, are not part of the routine work-up for von Willebrand disease (VWD). OBJECTIVES: This study presents data on collagen binding for healthy controls and VWD subjects to compare three different collagens. PATIENTS/METHODS: VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen were examined for samples obtained from the Zimmerman Program. RESULTS: Mean VWF:CB in healthy controls was similar and highly correlated for types I, III and VI collagen. The mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen were 1.31, 1.19 and 1.21, respectively. In type 1 VWD subjects, VWF:CB was similar to VWF:Ag with mean VWF:CB/VWF:Ag ratios for types I, III and VI collagen of 1.32, 1.08 and 1.1, respectively. For type 2A and 2B subjects, VWF:CB was uniformly low, with mean ratios of 0.62 and 0.7 for type I collagen, 0.38 and 0.4 for type III collagen, and 0.5 and 0.47 for type VI collagen. CONCLUSIONS: Normal ranges for type I, III and VI collagen are correlated, but higher values were obtained with type I collagen as compared with types III and VI. The low VWF:CB in type 2A and 2B subjects suggests that VWF:CB may also supplement analysis of multimer distribution. However, these results reflect only one set of assay conditions per collagen type and therefore may not be generalizable to all collagen assays.

Iron oxyhydroxide nanoparticles formed by forced hydrolysis: dependence of phase composition on solution concentration.

Nanoparticles of single-phase lepidocrocite (γ-FeOOH) and goethite (α-FeOOH) have been synthesized by forced hydrolysis of ferric nitrate with no other additives, and the particles have been characterized by XRD, FT-IR and TEM. At low Fe(NO(3))(3) concentrations the hydrolysis product is predominantly γ-FeOOH, while at high concentrations it is α-FeOOH. These particles are nanometers in size and fall within narrow particle size distributions. The dependence of the oxyhydoxide phase on ferric nitrate concentration is attributed to two thermodynamic factors, the enthalpy of formation and the surface enthalpy of hydration at the oxide-water interface (which is a function of surface area). Two potential mechanisms for the phase-specific growth are proposed that explain the solution concentration dependence of the phase formed. Three other common nanoscale particles (α-Fe(2)O(3), Fe(3)O(4) and γ-Fe(2)O(3)) have also been prepared by relatively simple thermal/chemical treatment of the γ-FeOOH nanoparticles.

CO2 induced seawater acidification impacts sea urchin larval development I: elevated metabolic rates decrease scope for growth and induce developmental delay.

Anthropogenic CO(2) emissions are acidifying the world's oceans. A growing body of evidence is showing that ocean acidification impacts growth and developmental rates of marine invertebrates. Here we test the impact of elevated seawater pCO(2) (129 Pa, 1271 µatm) on early development, larval metabolic and feeding rates in a marine model organism, the sea urchin Strongylocentrotus purpuratus. Growth and development was assessed by measuring total body length, body rod length, postoral rod length and posterolateral rod length. Comparing these parameters between treatments suggests that larvae suffer from a developmental delay (by ca. 8%) rather than from the previously postulated reductions in size at comparable developmental stages. Further, we found maximum increases in respiration rates of +100% under elevated pCO(2), while body length corrected feeding rates did not differ between larvae from both treatments. Calculating scope for growth illustrates that larvae raised under high pCO(2) spent an average of 39 to 45% of the available energy for somatic growth, while control larvae could allocate between 78 and 80% of the available energy into growth processes. Our results highlight the importance of defining a standard frame of reference when comparing a given parameter between treatments, as observed differences can be easily due to comparison of different larval ages with their specific set of biological characters.

Effect of gamma irradiation on gas-ionic liquid and water-ionic liquid interfacial stability.

The effect of γ-radiation on gas-ionic liquid (IL) and water-IL interfacial stability was investigated. Three phosphonium-based ILs, which vary considerably in their viscosity, conductivity and miscibility with water, were examined. The gas phase above the IL samples (headspace gas) was analyzed using gas chromatography with a mass spectrometer detector while the changes in the IL and aqueous phases were followed by conductivity measurements and Raman spectroscopy. For the gas-IL systems, the headspace samples showed trace amounts of the radiolytic decomposition products of the ILs that were small and volatile enough to become airborne. The type of cover gas, air or Ar, had no effect on the gas speciation. Negligible changes in the conductivity and the Raman spectra of the IL phase due to irradiation indicate that γ-irradiation induces negligible chemical changes in the IL phase when it is in contact with a gas phase. For the water-IL systems, the initially immiscible layers slowly developed an interfacial emulsion layer, even in the absence of radiation. This layer started at the water-IL interface and then grew downwards, eventually converting the entire IL phase to an emulsion. Gamma-irradiation accelerated the conversion of the IL phase to an emulsion. The development of the emulsion layer was accompanied by changes in the conductivity and the Raman spectra of both the IL and water phases. Based on these results, a mechanism involving the formation of micelles at, or near, the water-IL interface has been proposed to explain the development of an emulsion layer. We also suggest that radiolytic decomposition of ILs produces surfactants that can accumulate at the interface and, even at low concentrations, accelerate the emulsification process.

Long-term γ-radiolysis kinetics of NO3(-) and NO2(-) solutions.

Radiolysis kinetics in NO(3)(-) and NO(2)(-) solutions during γ-irradiation were studied at an absorbed dose rate of 2.1 Gy·s(-1) at room temperature. Air- or argon-saturated nitrate or nitrite solutions at pH 6.0 and 10.6 were irradiated, and the aqueous concentrations of molecular water decomposition products, H(2) and H(2)O(2), and the variation in the concentrations of NO(3)(-) and NO(2)(-) were measured as a function of irradiation time. The experimental data were compared with computer simulations using a comprehensive radiolysis kinetic model to aid in interpretation of the experimental results. The effect of nitrate and nitrite, present at concentrations below 10(-3) M, on water radiolysis processes occurs through reactions with the radical species generated by water radiolysis, (•)e(aq)(-), (•)O(2)(-), and (•)OH. The changes in H(2) and H(2)O(2) concentrations observed in the presence of nitrate and nitrite under a variety of conditions can be explained by a reduction in the radical concentrations. The kinetic analysis shows that the main loss pathway for H(2) is the reaction with (•)OH and the main loss pathways for H(2)O(2) are reactions with (•)e(aq)(-) and (•)OH. Nitrate and nitrite compete for the radicals leading to an increase in the concentrations of H(2) and H(2)O(2). Post-irradiation measurements of H(2), H(2)O(2), NO(2)(-) and NO(3)(-) concentrations can be used to calculate the radical concentrations and provide information on the redox conditions of the irradiated aqueous solutions.

Iron oxyhydroxide colloid formation by gamma-radiolysis.

Gamma-irradiation of deaerated aqueous solutions containing FeSO(4) leads to the formation of uniform-sized colloidal particles of γ-FeOOH. At short irradiation times, or in solutions with a low initial [Fe(2+)](0), spherical particles with a size less than 10 nm are formed. These primary particles grow to form a dendritic structure upon longer irradiation, and the final size of the large particles is ∼60 nm with a very narrow size distribution. Further prolonged irradiation does not change the final particle size. The narrow size distribution is attributed to rapid homogeneous radiolytic oxidation of soluble Fe(2+) to relatively insoluble Fe(3+) hydroxides [Fe(H(2)O)(6-n)(OH)(n)](3-n) leading to particle nucleation by spontaneous condensation. These primary particles then grow into γ-FeOOH particles with a dendritic structure. The final size reached at long times is regulated by the steady-state redox conditions established during long-term irradiation at the aqueous-solid interface.

Hypoxia tolerance in animals: biology and application.

Many invertebrates and ectothermic vertebrates successfully cope with a fluctuating supply of ambient oxygen-and consequently, a highly variable tissue oxygenation-through increasing their antioxidant barriers. During chronic deprivation of oxygen, however, the hypometabolic defense mode of the fruit fly Drosophila, the hypoxia-induced behavioral hypothermia of the crayfish Pacifastacus leniusculus, and the production of ethanol during anoxia by the crucian carp Carassius carassius all indicate that these animals are also capable of utilizing a suite of genetic and physiological defenses to survive otherwise lethal reductions in tissue oxygenation. Normally, much of an organism's gene response to hypoxia is orchestrated via the hypoxia-inducible transcription factor HIF. Recent developments expand our view of HIF function even further by highlighting regulatory roles for HIF in the hypometabolism of insects, in the molting and the normoxic immune response of crustaceans, and in the control-via the downstream effector gene erythropoietin-of the hypoxic ventilatory response and pulmonary hypertension in mammals. These and related topics were collectively presented by the authors in a symposium of the 2008 ICA-CBP conference at Mara National Reserve, Kenya, Africa. This synthesis article communicates the essence of the symposium presentations to the wider community.

DNA methylome in human CD4+ T cells identifies transcriptionally repressive and non-repressive methylation peaks.

DNA methylation is an epigenetic mark that is critical in determining chromatin accessibility and regulating gene expression. This epigenetic mechanism has an important role in T-cell function. We used genome-wide methylation profiling to characterize the DNA methylome in primary human CD4+ T cells. We found that only 5% of CpG islands are methylated in CD4+ T cells, and that DNA methylation peak density is increased in subtelomeric chromosomal regions. We also found an inverse relationship between methylation peak density and chromosomal length. Our data indicate that DNA methylation in gene promoter regions is not always a repressive epigenetic mark. Indeed, about 27% of methylated genes are actively expressed in CD4+ T cells. We demonstrate that repressive methylation peaks are located closer to the transcription start site (TSS) compared with functionally non-repressive peaks (-893±110 bp versus -1342±218 bp (mean±s.e.m.), P-value <0.05). We also show that both a larger number and an increased CpG island density in promoter sequences predict transcriptional permissiveness of DNA methylation. TSS in the majority of genes with permissive DNA methylation peaks is in DNase I hypersensitive sites, indicating a failure of DNA methylation to induce chromatin inaccessibility in these loci.