Search for decays of B-0 -> e(+)e(-), B-0 -> mu(+)mu(-), B-0 -> e(+/-)mu(-/+)

We present a search for the decays B-0 -> e(+)e(-), B-0 ->mu(+)mu(-), and B-0 -> e(+/-)mu(-/+) in data collected at the Upsilon(4S) resonance with the BABAR detector at the SLAC B Factory. Using a data set of 111 fb(-1), we find no evidence for a signal in any of the three channels investigated and set the following branching fraction upper limits at the 90% confidence level: B(B-0 -> e(+)e(-))mu(+)mu(-)) e(+/-)mu(-/+))< 18x10(-8)

Métaux et sclérose latérale amyotrophique

La sclérose latérale amyotrophique (SLA) est une maladie humaine fatale et de mécanisme inconnu qui se traduit par une dégénérescence sélective des motoneurones. Des mutations de la superoxyde dismutase à cuivre/zinc (CuZnSOD) ont été identifiées dans des cas familiaux de SLA. L objet de ce travail est d étudier l impact de ces mutations sur la fixation du cuivre et du zinc dans l enzyme ainsi que leurs effets sur le métabolisme des métaux. Une technique de couplage de l isoélectrofocalisation et de l émission X induite par particules chargées a été développée pour mesurer le rapport Cu/Zn dans des formes mutées de superoxyde dismutase liées à la sclérose latérale amyotrophique. Des différences de rapport Cu/Zn ont été observées entre les isoformes actives des mutants A4V, G93A et D125H et les isoformes actives de la souche sauvage humaine. Les résultats sont proches de la valeur théorique attendue de 1 dans tous les cas, sauf pour le mutant D125H qui affecte le site de complexation du Cu. L imagerie chimique cellulaire de la levure Saccharomyces cerevisiae par rayonnement synchrotron a été mise en œuvre pour étudier l impact de la mutation A4V sur la distribution intracellulaire des éléments chimiques. Des cartographies de distribution intracellulaire du phosphore, soufre, chlore, potassium, calcium et fer ont été obtenues pour la première fois dans la levure avec une résolution submicrométrique et soulignent le rôle potentiel du fer dans la SLA.Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown mechanism. Copper/zinc superoxide dismutase (CuZnSOD) mutations have been implicated in subsets of ALS familial cases. The aim of this study is to investigate the effect of these mutations on copper and zinc binding in CuZnSOD and on metals metabolism. A technique involving isoelectrofocalization and particle induced X-ray emission has been developed to quantify Cu/Zn ratio in CuZnSOD mutants linked to ALS. Differences were observed between human wild-type isoforms and A4V, G93A and D125H mutant isoforms. Cu/Zn ratio values were found close to the theorical value 1 in all cases, except for D125H mutant known to disturb the Cu complexation site. Microchemical element imaging of yeast Saccharomyces cerevisiae using synchrotron X-ray microprobe has been applied to the study of A4V mutation impact on elemental intracellular distributions. Distribution maps of phosphorus, sulfur, chlorine, potassium, calcium and iron were obtained for the first time in yeast cells with a submicrometer resolution and underline the potential role of iron in ALS.BORDEAUX1-BU Sciences-Talence (335222101) / SudocSudocFranceF

Correlative nano-imaging of metals and proteins in primary neurons by synchrotron X-ray fluorescence and STED super resolution microscopy: Experimental validation

International audienceBackgroundIt is becoming increasingly clear that biological metals such as iron, copper or zinc are involved in synaptic functions, and in particular in the mechanisms of synaptogenesis and subsequent plasticity. Understanding the role of metals on synaptic functions is a difficult challenge due to the very low concentration of these elements in neurons and to the submicrometer size of synaptic compartments.New methodTo address this challenge we have developed a correlative nano-imaging approach combining metal and protein detection. First, stimulated emission depletion (STED) microscopy, a super resolution optical microscopy technique, is applied to locate fluorescently labeled proteins. Then, synchrotron radiation induced X-ray fluorescence (SXRF) is performed on the same regions of interest, e.g. synaptic compartments.ResultsWe present here the principle scheme that allows this correlative nano-imaging and its experimental validation. We applied this correlative nano-imaging to the study of the physiological distribution of metals in synaptic compartments of primary rat hippocampal neurons. We thus compared the nanometric distribution of metals with that of synaptic proteins, such as PSD95 or cytoskeleton proteins.Comparison with existing method(s)Compared to correlative imaging approaches currently used to characterize synaptic structures, such as electron microscopy correlated with optical fluorescence, our approach allows for ultra-sensitive detection of trace metals using highly focused synchrotron radiation beams.ConclusionWe provide proof-of-principle for correlative imaging of metals and proteins at the synaptic scale and discuss the present limitations and future developments in this are

Multimodal and multiscale correlative elemental imaging: From whole tissues down to organelles

International audienceChemical elements, especially metals, play very specific roles in the life sciences. The implementation of correlative imaging methods, of elements on the one hand and of molecules or biological structures on the other hand, is the subject of recent developments. The most commonly used spectro-imaging techniques for metals are synchrotron-induced X-ray fluorescence, mass spectrometry and fluorescence imaging of metal molecular sensors. These imaging methods can be correlated with a wide variety of other analytical techniques used for structural imaging (e.g., electron microscopy), small molecule imaging (e.g., molecular mass spectrometry) or protein imaging (e.g., fluorescence microscopy). The resulting correlative imaging is developed at different scales, from biological tissue to the subcellular level. The fields of application are varied, with some major research topics, the role of metals in the aetiology of neurodegenerative diseases and the use of metals for medical imaging or cancer treatment

Advances in element speciation analysis of biomedical samples using synchrotron-based techniques

Synchrotron-radiation X-ray absorption spectroscopy (XAS) is a direct method for speciation analysis with atomic resolution, providing information about the local chemical environment of the probed element. This article gives an overview of the basic principles of XAS and its application to element speciation in biomedical research. The basic principle and experimental modalities of XAS are introduced, followed by a discussion of both its limitations, such as beam damage or detection limits, and practical advices to improve experiments. An updated review of biomedical studies involving XAS published over the last 5 years is then provided, paying special attention to metal-based drug biotransformation, metal and nanoparticle toxicology, and element speciation in cancer, neurological, and general pathophysiology. Finally, trends and future developments such as hyphenated methods, in situ correlative imaging and speciation, in vivo X-ray Absorption Near Edge Spectroscopy (XANES), full-field XANES, and X-ray Free Electron Laser (XFEL) XAS are presented

How much manganese is safe for infants? A review of the scientific basis of intake guidelines and regulations relevant to the manganese content of infant formulas

International audienceBackgroundRecent research has uncovered the potential for excess manganese (Mn) intakes causing significant neurotoxic effects for early brain development.MethodsWe identified the Mn tolerable intakes (TI) published by the U.S. Institute of Medicine (IOM), World Health Organization (WHO), Agence nationale de sécurité sanitaire (ANSES), and U.S. Environmental Protection Agency (US EPA) and examined the primary studies on which regulatory TIs are based. We converted the TIs to μg of Mn/kg/day using standard assumptions specific to each agency. We estimated μg of Mn/kg/day intakes due to formulas. Using our estimates for formula intakes, weights, and kcal content, we converted regulatory maxima and minima from μg of Mn/100 kcals to estimates of μg of Mn/kg/day.ResultsExcept for the proposed ANSES TI for drinking water, none of the primary studies on which Mn intake guidelines and regulations are based measured health outcomes. Some infant formulas may exceed the regulatory TIs, especially if prepared with water containing considerable concentrations of Mn (e.g. 250 μg/L), even while meeting national and international regulatory standards or guidelines.ConclusionsInfant formula regulations must be revised to reduce the potential for excess manganese intakes and the practice of manganese supplementation of infant formulas should be ceased

Estimating daily intakes of manganese due to breast milk, infant formulas, or young child nutritional beverages in the United States and France: Comparison to sufficiency and toxicity thresholds

International audienceBackgroundAlthough manganese (Mn) is an essential nutrient, recent research has revealed that excess Mn in early childhood may have adverse effects on neurodevelopment.MethodsWe estimated daily total Mn intake due to breast milk at average body weights by reviewing reported concentrations of breast milk Mn and measurements of body weight and breast milk intake at 3 weeks, 4.25 months, 7 months, and 18 months. We compared these figures to the Mn content measured in 44 infant, follow-up, and toddler formulas purchased in the United States and France. We calculated Mn content of formula products made with ultra-trace elemental analysis grade water (0 μg Mn/L) and with water containing 250 μg Mn/L, a concentration which is relatively high but less than the World Health Organization Health-based value of 400 μg Mn/L or the United States Environmental Protection Agency Health Advisory of 350 μg Mn/L.ResultsEstimated mean daily Mn intake from breast milk ranged from 1.2 μg Mn/kg/day (3 weeks) to 0.16 μg Mn/kg/day (18 months), with the highest intakes at the youngest age stage we considered, 3 weeks. Estimated daily Mn intake from formula products reconstituted with 0 μg Mn/L water ranged from 130 μg Mn/kg/day (3 weeks) to 4.8 μg Mn/kg/day (18 months) with the highest intakes at 3 weeks. Formula products provided 28–520 times greater than the mean daily intake of Mn from breast milk for the 4 age stages that we considered. Estimated daily Mn intake from formula products reconstituted with water containing 250 μg Mn/L ranged from 12 μg Mn/kg/day to 170 μg Mn/kg/day, which exceeds the United States Environmental Protection Agency Reference Dose of 140 μg Mn/kg/day for adults.ConclusionsMn deficiency is highly unlikely with exclusive breast milk or infant formula feeding, but established tolerable daily intake levels for Mn may be surpassed by some of these products when following labeled instructions

Manganese Accumulates within Golgi Apparatus in Dopaminergic Cells as Revealed by Synchrotron X-ray Fluorescence Nanoimaging

International audienceChronic exposure to manganese results in neurological symptoms referred to as manganism and is identified as a risk factor for Parkinson's disease. In vitro, manganese induces cell death in the dopaminergic cells, but the mechanisms of manganese cytotoxicity are still unexplained. In particular, the subcellular distribution of manganese and its interaction with other trace elements needed to be assessed. Applying synchrotron X-ray fluorescence nanoimaging, we found that manganese was located within the Golgi apparatus of PC12 dopaminergic cells at physiologic concentrations. At increasing concentrations, manganese accumulates within the Golgi apparatus until cytotoxic concentrations are reached resulting in a higher cytoplasmic content probably after the Golgi apparatus storage capacity is exceeded. Cell exposure to manganese and brefeldin A, a molecule known to specifically cause the collapse of the Golgi apparatus, results in the striking intracellular redistribution of manganese, which accumulates in the cytoplasm and the nucleus. These results indicate that the Golai apparatus plays an important role in the cellular detoxification of manganese. In addition manganese exposure induces a decrease in total iron content, which could contribute to the overall neurotoxicity