SPASM and Twitch Domains in S-Adenosylmethionine (SAM) Radical Enzymes

S-Adenosylmethionine (SAM, also known as AdoMet) radical enzymes use SAM and a [4Fe-4S] cluster to catalyze a diverse array of reactions. They adopt a partial triose-phosphate isomerase (TIM) barrel fold with N- and C-terminal extensions that tailor the structure of the enzyme to its specific function. One extension, termed a SPASM domain, binds two auxiliary [4Fe-4S] clusters and is present within peptide-modifying enzymes. The first structure of a SPASM-containing enzyme, anaerobic sulfatase-maturating enzyme (anSME), revealed unexpected similarities to two non-SPASM proteins, butirosin biosynthetic enzyme 2-deoxy-scyllo-inosamine dehydrogenase (BtrN) and molybdenum cofactor biosynthetic enzyme (MoaA). The latter two enzymes bind one auxiliary cluster and exhibit a partial SPASM motif, coined a Twitch domain. Here we review the structure and function of auxiliary cluster domains within the SAM radical enzyme superfamily.Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Fellowship)National Science Foundation (U.S.) (Grant MCB-0543833

Analysis of meteorology-chemistry interactions during air pollution episodes using online coupled models within AQMEII Phase-2

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).This study reviews the top ranked meteorology and chemistry interactions in online coupled models recommended by an experts’ survey conducted in COST Action EuMetChem and examines the sensitivity of those interactions during two pollution episodes: the Russian forest fires 25 Jul -15 Aug 2010 and a Saharan dust transport event from 1 Oct -31 Oct 2010 as a part of the AQMEII phase-2 exercise. Three WRF-Chem model simulations were performed for the forest fire case for a baseline without any aerosol feedback on meteorology, a simulation with aerosol direct effects only and a simulation including both direct and indirect effects. For the dust case study, eight WRF-Chem and one WRF-CMAQ simulations were selected from the set of simulations conducted in the framework of AQMEII. Of these two simulations considered no feedbacks, two included direct effects only and five simulations included both direct and indirect effects. The results from both episodes demonstrate that it is important to include the meteorology and chemistry interactions in online-coupled models. Model evaluations using routine observations collected in AQMEII phase-2 and observations from a station in Moscow show that for the fire case the simulation including only aerosol direct effects has better performance than the simulations with no aerosol feedbacks or including both direct and indirect effects. The normalized mean biases are significantly reduced by 10-20% for PM10 when including aerosol direct effects. The analysis for the dust case confirms that models perform better when including aerosol direct effects, but worse when including both aerosol direct and indirect effects, which suggests that the representation of aerosol indirect effects needs to be improved in the model.Peer reviewedFinal Published versio

Hyperlipidemia is a risk factor for osteonecrosis in children and young adults with acute lymphoblastic leukemia

TesisLa intoxicación con plomo es un problema de trascendental importancia para la salud pública por sus efectos en la calidad de vida de las personas, particularmente de los niños expuestos. La presente investigación fue de tipo descriptivo transversal y se realizó con la finalidad de determinar los niveles de plomo sanguíneo en los habitantes del Centro Poblado de Taca, durante los meses de junio y julio de 2013. Participaron del estudio 42 personas voluntarias: 32 varones y 10 mujeres, cuya media de edad fue de 33,23 años (rango: 21-72 años). Se tomaron muestras de sangre mediante venopunción previo consentimiento informado, utilizando tubos al vacío con anticoagulante, se mantuvieron bajo refrigeración a 8 °C, se trataron con mezcla sulfonítrica - ácido nítrico concentrado a ebullición lenta en un equipo de digestión y luego leídas en un espectrofotómetro de absorción atómica Thermo Scientific ¡CE 3300 a 217 nm. Se obtuvieron los siguientes resultados: todos los sujetos estudiados presentan algún grado de contaminación con plomo, encontrándose un nivel de plumbemia medio de 26,62 ug/dl y los niveles de plomo en sangre de varones y mujeres de 18 a 72 años de edad, encontrándose medias de 33,96 y 3,16 ug/dl, respectivamente, existiendo relación entre el género y plumbemia (p<0,05). El nivel de plomo en sangre de los habitantes del Centro Poblado de Taca, Distrito Canaria, Provincia de Víctor Fajardo, se incrementa en función del tiempo de residencia, por lo que existe relación entre estas dos variables (P<0,05)

TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways

TNF membrane receptors are usually co-expressed in many tissues but their relative contribution to cellular TNF responses is for most situations unknown. In a TNF cytotoxicity model of KYM-1, a human rhabdomyosarcoma cell line, we recently demonstrated that each of the two TNFRs is on its own capable of inducing cell death. Here we show that both receptors are able to induce apoptosis, as revealed from a similar onset of DNA fragmentation and typical morphologic criteria. To obtain additional information about the signaling pathways involved in TR60- and TR80-induced programmed cell death, we have used a series of selective inhibitors of intracellular signaling molecules. The overall pattern emerging from these experiments provides strong evidence for distinct signal pathway usage of TR60 and TR80, indicating protein kinase(s)-mediated control of TR60 signaling and a tight linkage of TR80 to arachidonate metabolism. The subsequent establishment of KYM-1·derived cell lines that display TNFR selective resistance further supports a segregation of TR60 and TR80 signaling pathways for induction of apoptotic cell death. Moreover, these results demonstrate an independent control of the distinct signaling cascades used by TR60 and TR80. This allows a highly flexible regulation of a cellular TNF response in those cases in which both receptors contribute to overall TNF responsiveness

The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor

AbstractThe 60 kDa tumor necrosis factor receptor (TNFR60) is regarded as the major signal transducer of TNF-induced cellular responses, whereas the signal capacity and role of the 80 kDa TNFR (TNFR80) remain largely undefined. We show here that the transmembrane form of TNF is superior to soluble TNF in activating TNFR80 in various systems such as T cell activation, thymocyte proliferation, and granulocyte/macrophage colony-stimulating factor production. Intriguingly, activation of TNFR80 by membrane TNF can lead to qualitatively different TNF responses such as rendering resistant tumor cells sensitive to TNF-mediated cytotoxicity. This study demonstrates that the diversity of TNF effects can be controlled through the differential sensitivity of TNFR80 for the two forms of TNF and suggests an important physiological role for TNFR80 in local inflammatory responses

A three-dimensional point process model for the spatial distribution of disease occurrence in relation to an exposure source

We study methods for how to include the spatial distribution of tumours when investigating the relation between brain tumours and the exposure from radio frequency electromagnetic fields caused by mobile phone use. Our suggested point process model is adapted from studies investigating spatial aggregation of a disease around a source of potential hazard in environmental epidemiology, where now the source is the preferred ear of each phone user. In this context, the spatial distribution is a distribution over a sample of patients rather than over multiple disease cases within one geographical area. We show how the distance relation between tumour and phone can be modelled nonparametrically and, with various parametric functions, how covariates can be included in the model and how to test for the effect of distance. To illustrate the models, we apply them to a subset of the data from the Interphone Study, a large multinational case-control study on the association between brain tumours and mobile phone use