Salivary and gut microbiomes play a significant role in in vitro oral bioaccessibility, biotransformation, and intestinal absorption of arsenic from food

The release of a toxicant from a food matrix during the gastrointestinal digestion is a crucial determinant of the toxicant's oral bioavailability. We present a modified setup of the human simulator of the gut microbial ecosystem (SHIME), with four sequential gastrointestinal reactors (oral, stomach, small intestine, and colon), including the salivary and colonic microbiomes. Naturally arsenic-containing rice, mussels, and nori seaweed were digested in the presence of microorganisms and in vitro oral bioaccessibility, bioavailability, and metabolism of arsenic species were evaluated following analysis by using HPLC/mass spectrometry. When food matrices were digested with salivary bacteria, the soluble arsenic in the gastric digestion stage increased for mussel and nori samples, but no coincidence impact was found in the small intestinal and colonic digestion stages. However, the simulated small intestinal absorption of arsenic was increased in all food matrices (1.2-2.7 fold higher) following digestion with salivary microorganisms. No significant transformation of the arsenic species occurred except for the arsenosugars present in mussels and nori. In those samples, conversions between the oxo arsenosugars were observed in the small intestinal digestion stage whereupon the thioxo analogs became major metabolites. These results expand our knowledge on the likely metabolism and oral bioavailabiltiy of arsenic during human digestion, and provide valuable information for future risk assessments of dietary arsenic

Ubiquitous outflows in DEEP2 spectra of star-forming galaxies at z=1.4

Galactic winds are a prime suspect for the metal enrichment of the intergalactic medium and may have a strong influence on the chemical evolution of galaxies and the nature of QSO absorption line systems. We use a sample of 1406 galaxy spectra at z~1.4 from the DEEP2 redshift survey to show that blueshifted Mg II 2796, 2803 A absorption is ubiquitous in starforming galaxies at this epoch. This is the first detection of frequent outflowing galactic winds at z~1. The presence and depth of absorption are independent of AGN spectral signatures or galaxy morphology; major mergers are not a prerequisite for driving a galactic wind from massive galaxies. Outflows are found in coadded spectra of galaxies spanning a range of 30x in stellar mass and 10x in star formation rate (SFR), calibrated from K-band and from MIPS IR fluxes. The outflows have column densities of order N_H ~ 10^20 cm^-2 and characteristic velocities of ~ 300-500 km/sec, with absorption seen out to 1000 km/sec in the most massive, highest SFR galaxies. The velocities suggest that the outflowing gas can escape into the IGM and that massive galaxies can produce cosmologically and chemically significant outflows. Both the Mg II equivalent width and the outflow velocity are larger for galaxies of higher stellar mass and SFR, with V_wind ~ SFR^0.3, similar to the scaling in low redshift IR-luminous galaxies. The high frequency of outflows in the star-forming galaxy population at z~1 indicates that galactic winds occur in the progenitors of massive spirals as well as those of ellipticals. The increase of outflow velocity with mass and SFR constrains theoretical models of galaxy evolution that include feedback from galactic winds, and may favor momentum-driven models for the wind physics.Comment: Accepted by ApJ. 25 pages, 17 figures. Revised to add discussions of intervening absorbers and AGN-driven outflows; conclusions unchange

Disruption of the Arsenic (+3 Oxidation State) Methyltransferase Gene in the Mouse Alters the Phenotype for Methylation of Arsenic and Affects Distribution and Retention of Orally Administered Arsenate

The arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a 43 kDa protein that catalyzes methylation of inorganic arsenic. Altered expression of AS3MT in cultured human cells controls arsenic methylation phenotypes, suggesting a critical role in arsenic metabolism. Because methylated arsenicals mediate some toxic or carcinogenic effects linked to inorganic arsenic exposure, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be instructive. This study compared retention and distribution of arsenic in As3mt knockout mice and in wild-type C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [73As]-arsenate. Mice were radioassayed for up to 96 hours after dosing; tissues were collected at 2 and 24 hours after dosing. At 2 and 24 hours after dosing, livers of As3mt knockouts contained a greater proportion of inorganic and monomethylated arsenic than did livers of C57BL/6 mice. A similar predominance of inorganic and monomethylated arsenic was found in the urine of As3mt knockouts. At 24 hours after dosing, As3mt knockouts retained significantly higher percentages of arsenic dose in liver, kidneys, urinary bladder, lungs, heart, and carcass than did C57BL/6 mice. Whole body clearance of [73As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 hours after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 hours, As3mt knockouts retained about 20% and C57BL/6 mice retained less than 2% of the dose. These data confirm a central role for As3mt in metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation, indicating a close linkage between the metabolism and retention of arsenicals

Does using a femoral nerve block for total knee replacement decrease postoperative delirium?

<p>Abstract</p> <p>Background</p> <p>The effect of peripheral nerve blocks on postoperative delirium in older patients has not been studied. Peripheral nerve blocks may reduce the incidence of postoperative opioid use and its side effects such as delirium via opioid-sparing effect.</p> <p>Methods</p> <p>A prospective cohort study was conducted in patients who underwent total knee replacement. Baseline cognitive function was assessed using the Telephone Interview for Cognitive Status. Postoperative delirium was measured using the Confusion Assessment Method postoperatively. Incidence of postoperative delirium was compared in two postoperative management groups: femoral nerve block ± patient-controlled analgesia and patient-controlled analgesia only. In addition, pain levels (using numeric rating scales) and opioid use were compared in two groups.</p> <p>Results</p> <p>85 patients were studied. The overall incidence of postoperative delirium either on postoperative day one or day two was 48.1%. Incidence of postoperative delirium in the femoral nerve block group was lower than patient controlled analgesia only group (25% vs. 61%, <it>P </it>= 0.002). However, there was no significant difference between the groups with respect to postoperative pain level or the amount of intravenous opioid use.</p> <p>Conclusions</p> <p>Femoral nerve block reduces the incidence of postoperative delirium. These results suggest that a larger randomized control trial is necessary to confirm these preliminary findings.</p

Inhibition of HIV virus by neutralizing Vhh attached to dual functional liposomes encapsulating dapivirine

Although highly active antiretroviral therapy (HAART) has greatly improved the life expectancy of HIV/AIDS patients, the treatment is not curative. It is a global challenge which fosters an urgent need to develop an effective drug or neutralizing antibody delivery approach for the prevention and treatment of this disease. Due to the low density of envelope spikes with restricted mobility present on the surface of HIV virus, which limit the antibody potency and allow virus mutation and escape from the immune system, it is important for a neutralizing antibody to form bivalent or multivalent bonds with the virus. Liposome constructs could fulfil this need due to the flexible mobility of the membrane with its attached antibodies and the capacity for drug encapsulation. In this study, we evaluated the neutralization activity of a range of liposome formulations in different sizes coated with anti-gp120 llama antibody fragments (Vhhs) conjugated via either non-covalent metal chelation or a covalent linkage. The non-covalent construct demonstrated identical binding affinity to HIV-1 envelope glycoprotein gp120 and neutralizing ability for HIV virus as free Vhh. Although covalently linked Vhh showed significant binding affinity to gp120, it unexpectedly had a lower neutralization potency. This may be due to the comparability in size of the viral and liposome particles restricting the number which can be bound to the liposome surface so involving only a fraction of the antibodies, whereas non-covalently attached antibodies dissociate from the surface after acting with gp120 and free the remainder to bind further viruses. Covalently conjugated Vhh might also trigger the cellular uptake of a liposome-virion complex. To explore the possible ability of the antibody-coated liposomes to have a further function, we encapsulated the hydrophobic antiviral drug dapivirine into both of the non-covalently and covalently conjugated liposome formulations, both of which revealed high efficacy in reducing viral replication in vitro. Thus, dual function liposomes may lead to a novel strategy for the prophylaxis of HIV/AIDS by combining the neutralizing activity of Vhh with antiviral effects of high drug concentrations

Life Cycle-Dependent Cytoskeletal Modifications in Plasmodium falciparum Infected Erythrocytes

10.1371/journal.pone.0061170PLoS ONE84

Sparing effects of selenium and ascorbic acid on vitamin C and E in guinea pig tissues

BACKGROUND: Selenium (Se), vitamin C and vitamin E function as antioxidants within the body. In this study, we investigated the effects of reduced dietary Se and L-ascorbic acid (AA) on vitamin C and α-tocopherol (AT) status in guinea pig tissues. METHODS: Male Hartley guinea pigs were orally dosed with a marginal amount of AA and fed a diet deficient (Se-D/MC), marginal (Se-M/MC) or normal (Se-N/MC) in Se. An additional diet group (Se-N/NC) was fed normal Se and dosed with a normal amount of AA. Guinea pigs were killed after 5 or 12 weeks on the experimental diets at 24 and 48 hours post AA dosing. RESULTS: Liver Se-dependent glutathione peroxidase activity was decreased (P < 0.05) in guinea pigs fed Se or AA restricted diets. Plasma total glutathione concentrations were unaffected (P > 0.05) by reduction in dietary Se or AA. All tissues examined showed a decrease (P < 0.05) in AA content in Se-N/MC compared to Se-N/NC guinea pigs. Kidney, testis, muscle and spleen showed a decreasing trend (P < 0.05) in AA content with decreasing Se in the diet. Dehydroascorbic acid concentrations were decreased (P < 0.05) in several tissues with reduction in dietary Se (heart and spleen) or AA (liver, heart, kidney, muscle and spleen). At week 12, combined dietary restriction of Se and AA decreased AT concentrations in most tissues. In addition, restriction of Se (liver, heart and spleen) and AA (liver, kidney and spleen) separately also reduced AT in tissues. CONCLUSION: Together, these data demonstrate sparing effects of Se and AA on vitamin C and AT in guinea pig tissues

Cascading signaling pathways improve the fidelity of a stochastically and deterministically simulated molecular RS latch

<p>Abstract</p> <p>Background</p> <p>While biological systems have often been compared with digital systems, they differ by the strong effect of crosstalk between signals due to diffusivity in the medium, reaction kinetics and geometry. Memory elements have allowed the creation of autonomous digital systems and although biological systems have similar properties of autonomy, equivalent memory mechanisms remain elusive. Any such equivalent memory system, however, must silence the effect of crosstalk to maintain memory fidelity.</p> <p>Results</p> <p>Here, we present a system of enzymatic reactions that behaves like an RS latch (a simple memory element in digital systems). Using both a stochastic molecular simulator and ordinary differential equation simulator, we showed that crosstalk between two latches operating in the same spatial localization disrupts the memory fidelity of both latches. Crosstalk was reduced or silenced when simple reaction loops were replaced with multiple step or cascading reactions, showing that cascading signaling pathways are less susceptible to crosstalk.</p> <p>Conclusion</p> <p>Thus, the common biological theme of cascading signaling pathways is advantageous for maintaining the fidelity of a memory latch in the presence of crosstalk. The experimental implementation of such a latch system will lead to novel approaches to cell control using synthetic proteins and will contribute to our understanding of why cells behave differently even when given the same stimulus.</p

Search for gravitational waves associated with the InterPlanetary Network short gamma ray bursts

We outline the scientific motivation behind a search for gravitational waves associated with short gamma ray bursts detected by the InterPlanetary Network (IPN) during LIGO's fifth science run and Virgo's first science run. The IPN localisation of short gamma ray bursts is limited to extended error boxes of different shapes and sizes and a search on these error boxes poses a series of challenges for data analysis. We will discuss these challenges and outline the methods to optimise the search over these error boxes.Comment: Methods paper; Proceedings for Eduardo Amaldi 9 Conference on Gravitational Waves, July 2011, Cardiff, U

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN