Urinary eicosanoid metabolites in HIV-infected women with central obesity switching to raltegravir: an analysis from the women, integrase, and fat accumulation trial.

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m(2) completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus -0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥ 50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study

Terahertz photoconductivity and plasmon modes in double-quantum-well field-effect transistors

Double-quantum-well field-effect transistors with a grating gate exhibit a sharply resonant, voltage tuned terahertz photoconductivity. The voltage tuned resonance is determined by the plasma oscillations of the composite structure. The resonant photoconductivity requires a double-quantum well but the mechanism whereby plasma oscillations produce changes in device conductance is not understood. The phenomenon is potentially important for fast, tunable terahertz detectors

HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors

An important target in the understanding of the pathogenesis of acute myeloid leukemias (AML) relies on deciphering the molecular features of normal and leukemic hemopoietic progenitors. In particular, the analysis of the mechanisms involved in the regulation of cell proliferation is decisive for the establishment of new targeted therapies. To gain further insight into this topic we report herein a novel approach by analyzing the role of HERG K+ channels in the regulation of hemopoietic cell proliferation. These channels, encoded by the human ether-a-go-go-related gene (herg), belong to a family of K, channels, whose role in oncogenesis has been recently demonstrated. We report here that herg is switched off in normal peripheral blood mononuclear cells (PBMNC) as well as in circulating CD34(+) cells, however, it is rapidly turned on in the latter upon induction of the mitotic cycle. Moreover, herg appears to be constitutively activated in leukemic cell lines as well as in the majority of circulating blasts from primary AML. Evidence is also provided that HERG channel activity regulates cell proliferation in stimulated CD34(+) as well as in blast cells from AML patients. These results open new perspectives on the pathogenetic role of HERG K+ channels in leukemias

Activation pathway to amino acid adducts

Funding: This work was supported in part by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013 and IF/ 01091/2013/CP1163/CT0001), and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. RW, ALG, ILM and SGH thank FCT for postdoctoral and doctoral fellowships (SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010 and SFRH/BD/ 80690/2011, respectively). AMM also acknowledges Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013), and the LRI Innovative Science Award. We thank the Portuguese NMR and MS networks (IST nodes) for providing access to the facilities.Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Frémy's salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Frémy's salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events.publishersversionpublishe

The evolution of the Aristolochia pallida complex (Aristolochiaceae) challenges traditional taxonomy and reflects large-scale glacial refugia in the Mediterranean

The taxonomy of the Mediterranean Aristolochia pallida complex has been under debate since several decades with the following species currently recognized: A. pallida, A. lutea, A. nardiana, A. microstoma, A. merxmuelleri, A. croatica, and A. castellana. These taxa are distributed from Iberia to Turkey. To reconstruct phylogenetic and biogeographic patterns, we employed cpDNA sequence variation using both noncoding (intron and spacer) and protein-coding regions (i.e., trnK intron, matK gene, and trnK-psbA spacer). Our results show that the morphology-based traditional taxonomy was not corroborated by our phylogenetic analyses. Aristolochia pallida, A. lutea, A. nardiana, and A. microstoma were not monophyletic. Instead, strong geographic signals were detected. Two major clades, one exclusively occurring in Greece and a second one of pan-Mediterranean distribution, were found. Several subclades distributed in Greece, NW Turkey, Italy, as well as amphi-Adriatic subclades, and a subgroup of southern France and Spain, were revealed. The distribution areas of these groups are in close vicinity to hypothesized glacial refugia areas in the Mediterranean. According to molecular clock analyses the diversification of this complex started around 3–3.3 my, before the onset of glaciation cycles, and the further evolution of and within major lineages falls into the Pleistocene. Based on these data, we conclude that the Aristolochia pallida alliance survived in different Mediterranean refugia rarely with low, but often with a high potential for range extension, and a high degree of morphological diversity.Turkish Science Foundatio

Herg1 gene and HERG1 protein are overespressed in colorectal cancers and regulate cell invasion of tumor cells

The acquisition of the capacity to invade surrounding tissues confers a more malignant phenotype to tumor cells and is necessary for the establishment of metastases. The understanding of the molecular mechanisms underlying cell invasion in human solid tumors such as colorectal cancers could provide not only more sensitive prognostic analyses but also novel molecular targets for cancer therapy.We report in this article that K+ ion channels belonging to the HERG family are important determinants for the acquisition of an invasive phenotype in colorectal cancers. The herg1 gene and HERG1 protein are expressed in many colon cancer cell lines, and the activity of HERG channels modulates colon cancer cell invasiveness. Moreover, the amount of HERG1 protein expressed on the plasma membrane is directly related to the invasive phenotype of colon cancer cells.Finally, both the herg1 gene and HERG1 protein were expressed in a high percentage of primary human colorectal cancers, with the highest incidence occurring in metastatic cancers, whereas no expression could be detected either in normal colonic mucosa or in adenomas

Urinary Eicosanoid Metabolites in HIV-Infected Women with Central Obesity Switching to Raltegravir: An Analysis from the Women, Integrase, and Fat Accumulation Trial

Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m2 completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus −0.02; P=0.06). Baseline PGI-M was lower in the RAL arm (P=0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho=0.45; P=0.04) and TxB2 (rho=0.44; P=0.005) changes, with a trend seen for PGE-M (rho=0.41; P=0.07). In an adjusted model, age ≥ 50 years (N=8) was associated with increased PGE-M (P=0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study

Fungi hijack a ubiquitous plant apoplastic endoglucanase to release a ROS scavenging beta-glucan decasaccharide to subvert immune responses

Plant pathogenic and beneficial fungi have evolved several strategies to evade immunity and cope with host-derived hydrolytic enzymes and oxidative stress in the apoplast, the extracellular space of plant tissues. Fungal hyphae are surrounded by an inner insoluble cell wall layer and an outer soluble extracellular polysaccharide (EPS) matrix. Here, we show by proteomics and glycomics that these two layers have distinct protein and carbohydrate signatures, and hence likely have different biological functions. The barley (Hordeum vulgare) β-1,3-endoglucanase HvBGLUII, which belongs to the widely distributed apoplastic glycoside hydrolase 17 family (GH17), releases a conserved β-1,3;1,6-glucan decasaccharide (β-GD) from the EPS matrices of fungi with different lifestyles and taxonomic positions. This low molecular weight β-GD does not activate plant immunity, is resilient to further enzymatic hydrolysis by β-1,3-endoglucanases due to the presence of three β-1,6-linked glucose branches and can scavenge reactive oxygen species. Exogenous application of β-GD leads to enhanced fungal colonization in barley, confirming its role in the fungal counter-defensive strategy to subvert host immunity. Our data highlight the hitherto undescribed capacity of this often-overlooked EPS matrix from plant-associated fungi to act as an outer protective barrier important for fungal accommodation within the hostile environment at the apoplastic plant–microbe interface

HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium

HERG K+channels, besides contributing to regulate cardiac and neuronal excitability, are preferentially expressed in tumour cell lines of different histogenesis, where their role in the development and maintenance of the neoplastic phenotype is under study. We show here that both herg gene and HERG protein are expressed with high frequency in primary human endometrial cancers, as compared to normal and hyperplastic endometrium. RT-PCR and immunohistochemistry, using specific anti-HERG antibodies developed in our laboratory, were applied to tissue specimens obtained from 18 endometrial cancers and 11 non-cancerous endometrial tissues. herg RNA and HERG protein are expressed in 67% and 82%, respectively, of cancerous, while in only 18% of non-cancerous tissues. In particular, no expression was found in endometrial hyperplasia. Moreover, electrophysiological experiments confirmed the presence of functioning HERG channels on the plasma membrane of tumour cells. On the whole, these data are the first demonstration of the presence of HERG channels in primary human neoplasias, and could candidate HERG as a potential tool capable of marking cancerous versus hyperplastic endometrial growth. © 2000 Cancer Research Campaign http://www.bjcancer.co

Measurement of the branching ratio of the decay Ξ0→Σ+μ−νˉμ\Xi^{0}\rightarrow \Sigma^{+} \mu^{-} \bar{\nu}_{\mu}

From the 2002 data taking with a neutral kaon beam extracted from the CERN-SPS, the NA48/1 experiment observed 97 $\Xi^{0}\rightarrow \Sigma^{+} \mu^{-} \bar{\nu}_{\mu}$ candidates with a background contamination of $30.8 \pm 4.2$ events. From this sample, the BR($\Xi^{0}\rightarrow \Sigma^{+} \mu^{-} \bar{\nu}_{\mu}$) is measured to be $(2.17 \pm 0.32_{\mathrm{stat}}\pm 0.17_{\mathrm{syst}})\times10^{-6}$