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Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N-Heterocyclic motifs can be prepared through the cyclization of α-haloamides; however, slow rotation around the amide C–N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ-, δ-, ε-, and ζ-lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent ‘ene’ reductases affords the highest level of product selectivity. We suggest that through selective binding of the cis-amide isomer, the enzyme preorganizes the substrate for cyclization, helping to avoid premature radical termination.

The PERCIVAL detector is a CMOS imager designed for the soft X-ray regime at photon sources. Although still in its final development phase, it has recently seen its first user experiments: ptychography at a free-electron laser, holographic imaging at a storage ring and preliminary tests on X-ray photon correlation spectroscopy. The detector performed remarkably well in terms of spatial resolution achievable in the sample plane, owing to its small pixel size, large active area and very large dynamic range; but also in terms of its frame rate, which is significantly faster than traditional CCDs. In particular, it is the combination of these features which makes PERCIVAL an attractive option for soft X-ray science.

Autorzy: Abe K., Adrich P., Aihara H., Akutsu, R., Alekseev I., Ali A. , Ameli F., Anghel I., Anthony L. H. V., Antonova M. , Araya A., Asaoka Y., Ashida Y., Aushev V., Ballester F., Bandac I., Barbi M., Barker G. J., Barr G., Batkiewicz-Kwasniak M., Bellato M., Berardi V., Bergevin M., Bernard L., Bernardini E., Berns L., Bhadra S., Bian J., Blanchet A., Blaszczyk F. d. M., Blonde A., Boiano A., Bolognesi S., Bonavera L., Booth N., Borjabad S., Boschi, T., Bose D., Boyd S . B., Bozza C., Bravar A., Bravo-Berguño D., Bronner C., Brown L., Bubak Arkadiusz, Buchowicz A., Buizza Avanzini M., Cafagna F. S., Calabria N. F., Calvo-Mozota J. M., Cao S., Cartwright S.L., Carroll A., Catanesi M. G., Cebriàn, S., Chabera M., Chakraborty, S., Checchia C., Choi J.H., Choubey S., Cicerchia M., Coleman J., Collazuol G., Cook L., Cowan G., Cuen-Rochin, S., Danilov M., Díaz López G., De la Fuente E., de Perio P., De Rosa G., Dealtry T., Densham C. J., Dergacheva A., Deshmukh N., Devi M. M., Di Lodovico F., Di Meo, P., Di Palma I., Doyle T. A., Drakopoulou E., Drapier O., Dumarchez J., Dunne P., Dziewiecki M., Eklund L., El Hedri S., Ellis J., Emery S., Esmaili A., Esteve R., Evangelisti A., Feely M., Fedotov S., Feng J., Fernandez P., Fernández-Martinez E., Ferrario P., Ferrazzi,B., Feusels T., Finch A., Finley C., Fiorentini A., Fiorillo G., Fitton M., Frankiewicz K., Friend M., Fujii Y., Fukuda Y., Galinski G., Gao J., Garde C., Garfagnini A., Garode S., Gialanella L., Giganti C., Gomez-Cadenas J.J., Gonin M., González-Nuevo J., Gorin A., Gornea R., Gousy-Leblanc V. Gramegna F. Grassi M. Grella G. Guigue M. Gumplinger P. Hadley D.R. Harada M., Hartfiel B., Hartz M., Hassani S., Hastings N.C., Hayato Y., Hernando-Morata J.A., Herrero V., Hill J., Hiraide K., Hirota S., Holin A., Horiuchi S., Hoshina K., Hultqvist K., Iacob F., Ichikawa A.K., Idrissi Ibnsalih W., Iijima T., Ikeda M., Inomoto M., Inoue K., Insler J., Ioannisian A., Ishida T., Ishidoshiro K., Ishino H., Ishitsuka M., Ito H., Ito S., Itow Y., Iwamoto K., Izmaylov A., Izumi N., Izumiyama S., Jakkapu M., Jamieson B., Jang H.I., Jang J.S., Jenkins S.J., Jeon S.H., Jiang M., Jo H.S., Jonsson P., Joo K.K., Kajita T., Kakuno H., Kameda J., Kano Y., Kalaczynski P., Karlen D., Kasperek J., Kataoka Y., Kato A., Katori T., Kazarian N., Kearns E., Khabibullin M., Khotjantsev A., Kikawa T., Kekic M., Kim J.H., Kim J.Y., Kim S.B., Kim S.Y., King S., Kinoshita T., Kisiel Jan, Klekotko A., Kobayashi T., Koch L., Koga M., Koerich L., Kolev N., Konaka A., Kormos L.L., Koshio Y., Korzenev A., Kotsar Y., Kouzakov K.A., Kowalik K.L., Kravchuk L., Kryukov A.P., Kudenko Y., Kumita T., Kurjata R., Kutter T., Kuze M., Kwak K., La Commara M., Labarga L., Lagoda J., Lamers James J., Lamoureux M., Laveder M., Lavitola L., Lawe M., Learned J.G., Lee J., Leitner R., Lezaun V., Lim I.T., Lindner T., Litchfield R.P., Long K.R., Longhin A., Loverre P., Lu X., Ludovici L., Maekawa Y., Magaletti L., Magar K., Mahn K., Makida Y., Malek M., Malinský M., Marchi T., Maret L., Mariani C., Marinelli A., Martens K., Marti L., Martin J.F. Martin D., Marzec J., Matsubara T., Matsumoto R., Matsuno S., Matusiak M., Mazzucato E., McCarthy M., McCauley N., McElwee J., McGrew C., Mefodiev A., Medhi A., Mehta P., Mellet L., Menjo H., Mermod P., Metelko C., Mezzetto M., Migenda J., Migliozzi P., Mijakowski P., Miki S., Miller E.W., Minakata H., Minamino A., Mine S., Mineev O., Mitra A., Miura M., Moharana R., Mollo C.M., Mondal T., Mongelli M., Monrabal F., Moon D.H., Moon C.S., Mora F.J., Moriyama S., Mueller Th.A., Munteanu L., Murase K., Nagao Y., Nakadaira T., Nakagiri K., Nakahata M., Nakai S., Nakajima Y., Nakamura K., Nakamura KI., Nakamura H., Nakano Y., Nakaya T., Nakayama S., Nakayoshi K., Nascimento Machado L., Naseby C.E.R., Navarro-Garcia B., Needham M., Nicholls T., Niewczas K., Nishimura Y., Noah E., Nova F., Nugent J.C., Nunokawa H., Obrebski W., Ochoa-Ricoux J.P., O’Connor E., Ogawa N., Ogitsu T., Ohta K., Okamoto K., O’Keeffe H.M., Okumura K., Onishchuk Y., Orozco-Luna F., Oshlianskyi A., Ospina N., Ostrowski M., O’Sullivan E., O’Sullivan L., Ovsiannikova T., Oyama Y., Ozaki H., Pac M.Y., Paganini P., Palladino V., Paolone V., Pari M., Parsa S., Pasternak J., Pastore C., Pastuszak G., Patel D.A., Pavin M., Payne D., Peña-Garay C., Pidcott C., Pinzon Guerra E., Playfer S., Pointon B.W., Popov A., Popov B., Porwit Kamil, Posiadala-Zezula M., Poutissou J.M., Pozimski J., Pronost G., Prouse N.W., Przewlocki P., Quilain B., Quiroga A.A., Radicioni E., Radics B., Rajda P.J., Renner J., Rescigno M., Retiere F., Ricciardi G., Riccio C., Richards B., Rondio E., Rose H.J., Roskovec B., Roth S., Rott C., Rountree S.D., Rubbia A., Ruggeri A.C., Ruggles C., Russo S., Rychter A., Ryu D., Sakashita K., Samani S., Sánchez F., Sánchez M.L., Sanchez M.C., Sano S., Santos J.D., Santucci G., Sarmah P., Sashima I., Sato K., Scott M., Seiya Y., Sekiguchi T., Sekiya H., Seo J.W., Seo S.H., Sgalaberna D., Shaikhiev A., Shan Z., Shaykina A., Shimizu I., Shin C.D., Shinoki M., Shiozawa M., Sinnis G., Skrobova N., Skwarczynski K., Smy M.B., Sobczyk J., Sobel H.W., Soler F. J. P., Sonoda Y., Spina R., Spisso B., Spradlin B., Stankevich K.L., Stawarz L., Stellacci S.M., Stopa K., Studenikin A.I., Suárez Gómez S.L., Suganuma T., Suvorov S., Suwa Y., Suzuki A.T., Suzuki S.Y., Suzuki Y., Svirida D., Svoboda R., Taani M., Tada M., Takeda A., Takemoto Y., Takenaka A., Taketa A., Takeuchi Y., Takhistov V., Tanaka H., Tanaka H.A., Tanaka H.I., Tanaka M., Tashiro T., Thiesse M., Thompson L.F., Toledo J., Tomatani-Sánchez A.K., Tortone G., Tsui K.M., Tsukamoto T., Tzanov M., Uchida Y., Vagins M.R., Valder S., Valentino V., Vasseur G., Vijayvargi A., Vilela C., Vinning W. G. S., Vivolo D., Vladisavljevic T., Vogelaar R.B., Vyalkov M.M., Wachala T., Walker J., Wark D., Wascko M.O., Wendell R.A., Wilkes R.J., Wilking M.J., Wilson M.R., Wronka S., Xia J., Xie Z., Xin T., Yamaguchi Y., Yamamoto K., Yanagisawa C., Yano T., Yen S., Yershov N., Yeum D.N., Yokoyama M., Yonenaga M., Yoo J., Yu I., Yu M., Zakrzewski T., Zaldivar B., Zalipska J., Zaremba K., Zarnecki G., Ziembicki M., Zietara K., Zito M., Zsoldos S., Core-collapse supernovae are among the most magnificent events in the observable universe. They produce many of the chemical elements necessary for life to exist and their remnants-neutron stars and black holes-are interesting astrophysical objects in their own right. However, despite millennia of observations and almost a century of astrophysical study, the explosion mechanism of core-collapse supernovae is not yet well understood. Hyper-Kamiokande is a next-generation neutrino detector that will be able to observe the neutrino flux from the next galactic core-collapse supernova in unprecedented detail. We focus on the first 500 ms of the neutrino burst, corresponding to the accretion phase, and use a newly-developed, high-precision supernova event generator to simulate Hyper-Kamiokandeʼs response to five different supernova models. We show that Hyper-Kamiokande will be able to distinguish between these models with high accuracy for a supernova at a distance of up to 100 kpc. Once the next galactic supernova happens, this ability will be a powerful tool for guiding simulations toward a precise reproduction of the explosion mechanism observed in nature.

Journal of synchrotron radiation 28(1), 131 - 145 (2021). doi:10.1107/S1600577520013958, In this paper the back-side-illuminated Percival 2-Megapixel (P2M) detector is presented, along with its characterization by means of optical and X-ray photons. For the first time, the response of the system to soft X-rays (250 eV to 1 keV) is presented. The main performance parameters of the first detector are measured, assessing the capabilities in terms of noise, dynamic range and single-photon discrimination capability. Present limitations and coming improvements are discussed., Published by Wiley-Blackwell, [S.l.]

Photoenzymes are biological catalysts that use light to convert starting materials to products. These catalysts require photon absorption for each turnover, making quantum efficiency an important optimization parameter. Flavin-dependent 'ene'-reductases (EREDs) display latent photoenzymatic activity for synthetically valuable hydroalkylations; however, protein engineering has not been used to optimize this non-natural function. Here, we describe a protein engineering platform for the high throughput optimization of photoenzymes. A single round of engineering results in improved catalytic function toward the synthesis of 𝛾 , 𝛿 , 𝜀 -lactams, and acyclic amides. Mechanistic studies indicate that key mutations can alter the enzyme's excited state dynamics, enhance its photon efficiency, and ultimately increase catalyst performance. Transient absorption spectroscopy reveals that engineered variants display dramatically decreased radical lifetimes - indicating an evolution toward a concerted mechanism. Overall, this platform enables the development and optimization of photoenzymes for tailored applications in chemical synthesis.

HEXITECMHZ is an ASIC developed to deliver spectroscopic x-ray imaging at frame rates up to 1MHz for future high-flux-rate applications. Optimised for sensing electron signals from detector materials such as CdTe, CZT, GaAs, and p-type silicon detectors, the design has an array of 80×80 pixels on a pitch of 250 μm, with each pixel capable of measuring single x-ray photons up to energies of 200 keV, with a resolution of 1 keV FWHM. Further improvements in the spatial and spectroscopic resolution are possible due to the pixel’s ability to simultaneously sense positive signals up to 20 keV induced by internal weighting-potential effects from electron signals on neighbouring pixels. A count rate limit of around 106 photons s-1 mm-2 is achieved by converting the signals from all pixels every 1 μs using 12-bit time-to-digital converters – an improvement of two orders of magnitude over previous HEXITEC ASICs. To save power, each converter is shared between groups of eight pixels. Each 76.8kbit data frame is Aurora 64b/66b encoded and serialised over twenty lanes of differential CML, all operating in parallel at 4.1 Gbit/s. In this paper, we present details of the design, including preliminary test results from the ASIC.

BACKGROUND & AIMS: Thioesterase superfamily member 2 (Them2) is highly expressed in liver and oxidative tissues, where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2(−/−)) are protected against diet-induced obesity, hepatic steatosis and insulin resistance, liver-specific Them2(−/−) mice remain susceptible. The aim of this study was to test whether Them2 activity in extrahepatic oxidative tissues is a primary determinant of hepatic steatosis and insulin resistance. APPROACH & RESULTS: Upon observing insulin resistance and upregulation of Them2 in skeletal, but not cardiac muscle of high-fat fed wild type compared to Them2(−/−) mice, we created mice with Them2 specifically deleted in skeletal (S-Them2(−/−)) and cardiac muscle (C-Them2(−/−)), as well as in adipose tissue (A-Them2(−/−)). When fed a high-fat diet, S-Them2(−/−) but not C-Them2(−/−) or A-Them2(−/−) mice exhibited reduced weight gain and improved glucose homeostasis and insulin sensitivity. Reconstitution of Them2 expression in skeletal muscle of global Them2(−/−) mice using adeno-associated virus was sufficient to restore excess weight gain. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2(−/−) mice contributed to protection from high-fat diet-induced hepatic steatosis by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in the production of skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and pentose phosphate pathway intermediates, as well as in the expression of myokines that modulate insulin responsiveness. CONCLUSIONS: These results reveal a key role for skeletal muscle Them2 in the pathogenesis of hepatic steatosis and insulin resistance, and implicate it as a target in the management of non-alcoholic fatty liver disease.

Photoenzymes are biological catalysts that use light to convert starting materials to products. These catalysts require photon absorption for each catalyst turnover, making quantum efficiency an important optimization parameter. Flavin-dependent 'ene’-reductases (EREDs) display latent photoenzymatic activity for synthetically valuable hydroalkylations; however, protein engineering has not been used to optimize this non-natural function. Here, we describe a protein engineering platform for the high throughput optimization of photoenzymes. A single round of engineering results in improved catalytic function toward the synthesis of 𝛾, 𝛿, 𝜀-lactams, and acyclic amides. Mechanistic studies indicate that key mutations can alter the enzyme's excited state dynamics, enhance its photon efficiency, and ultimately increase catalyst performance. Transient absorption spectroscopy reveals that engineered variants display dramatically decreased radical lifetimes – indicating a shift toward a concerted mechanism. Overall, this platform enables the development and optimization of photoenzymes for tailored applica-tions in chemical synthesis.

Thioesterase superfamily member 2 (Them2) is highly expressed in oxidative tissues where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/-) are protected against diet-induced obesity, insulin resistance and hepatic steatosis, liver-specificThem2-/-mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle (S-Them2-/-), cardiac muscle (C-Them2-/-) or adipose tissue (A-Them2-/-). When fed a high-fat diet,S-Them2-/-but notC-Them2-/-orA-Them2-/-mice exhibited reduced weight gain. OnlyS-Them2-/-mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle ofS-Them2-/-mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis inS-Them2-/-mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.

Disruption of circadian glucocorticoid oscillations in Cushing's disease and chronic stress results in obesity and adipocyte hypertrophy, which is believed to be a main source of the harmful effects of obesity. Here, we recapitulate stress due to jet lag or work-life imbalances by flattening glucocorticoid oscillations in mice. Within 3 days, mice achieve a metabolic state with persistently high insulin, but surprisingly low glucose and fatty acids in the bloodstream, that precedes a more than 2-fold increase in brown and white adipose tissue mass within 3 weeks. Transcriptomic and Cd36-knockout mouse analyses show that hyperinsulinemia-mediated de novo fatty acid synthesis and Cd36-mediated fatty acid uptake drive fat mass increases. Intriguingly, this mechanism by which glucocorticoid flattening causes acute hyperinsulinemia and adipocyte hypertrophy is unexpectedly beneficial in preventing high levels of circulating fatty acids and glucose for weeks, thus serving as a protective response to preserve metabolic health during chronic stress.

In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure., Cold exposure activates thermogenesis and fatty acid oxidation in brown fat, a process suppressed by Them1. Here, the authors show that cold induces Them1 phosphorylation and loss of puncta that suppress fatty acid use, leading to a diffuse localization and increased energy expenditure in mice.

In brown adipose tissue, cold exposure promotes thermogenesis, in large part by increasing mitochondrial β-oxidation of lipid droplet-derived fatty acids. This process is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is highly upregulated by cold ambient temperatures. Them1 reduces fatty acid availability for β-oxidation in mitochondria and limits thermogenesis by cellular mechanisms that are not well defined. We show that Them1 regulates metabolism by undergoing marked intracellular conformational changes that occur in response to β-adrenergic stimulation. Mechanistically, Them1 formed puncta that were localized near LD and mitochondria in an immortalized brown adipose cell line. In response to stimulation by norepinephrine, Them1 was phosphorylated by PKCβ at S15, which specifically inhibited puncta formation and resulted in a diffuse intracellular localization. This change in Them1 localization also occurred after stimulation in vivo. Puncta formation activated Them1 metabolic activity in vitro, as evidenced by suppression of oxygen consumption following β-adrenergic stimulation. We show by correlative light and electron microscopy that puncta are biomolecular condensates (also known as membraneless organelles) that typically form by phase separation. Them1 contains one intrinsically disordered region at the N-terminus with multiple interacting motifs that is frequently observed in phase-separating proteins. Phosphorylation, which is known to disrupt phase separation and aggregation, results in a diffuse Them1 localization. Our data thus establish that Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 thus provides fine-tuning of thermogenesis and energy expenditure.

Mice fed a methionine- and choline-deficient (MCD) diet develop steatohepatitis that recapitulates key features of nonalcoholic steatohepatitis (NASH) in humans. Phosphatidylcholine is the most abundant phospholipid in the surfactant monolayer that coats and stabilizes lipid droplets within cells, and choline is required for its major biosynthetic pathway. Phosphatidylcholine-transfer protein (PC-TP), which exchanges phosphatidylcholines among membranes, is enriched in hepatocytes. PC-TP also regulates fatty acid metabolism through interactions with thioesterase superfamily member 2. We investigated the contribution of PC-TP to steatohepatitis induced by the MCD diet. Pctp−/−and wild-type control mice were fed the MCD diet for 5 wk and were then euthanized for histopathologic and biochemical analyses, as well as determinations of mRNA and protein expression. Whereas all mice developed steatohepatitis, plasma alanine aminotransferase and aspartate aminotransferase activities were only elevated in wild-type mice, indicating that Pctp−/−mice were protected from MCD diet-induced hepatocellular injury. Reduced hepatotoxicity due to the MCD diet in the absence of PC-TP expression was further evidenced by decreased activation of c-Jun and reduced plasma concentrations of fibroblast growth factor 21. Despite similar total hepatic concentrations of phosphatidylcholines and other lipids, the relative abundance of microvesicular lipid droplets within hepatocytes was reduced in Pctp−/−mice. Considering that the formation of larger lipid droplets may serve to protect against lipotoxicity in NASH, our findings suggest a pathogenic role for PC-TP that could be targeted in the management of this condition.NEW & NOTEWORTHY Phosphatidylcholine-transfer protein (PC-TP) is a highly specific phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacting partner thioesterase superfamily member 2 (Them2). This study identifies a pathogenic role for PC-TP, independent of Them2, in the methionine- and choline-deficient diet model of experimental steatohepatitis. Our current observations suggest that PC-TP promotes liver injury by mediating the intermembrane transfer of phosphatidylcholines, thus stabilizing more pathogenic microvesicular lipid droplets.

X-ray computed micro-tomography (μCT) is one of the most advanced and common non-destructive techniques in the field of medical imaging and material science. It allows recreating virtual models (3D models), without destroying the original objects, by measuring three-dimensional X-ray attenuation coefficient maps of samples on the (sub) micrometer scale. The quality of the images obtained using μCT is strongly dependent on the performance of the associated X-ray detector i.e. to the acquisition of information of the X-ray beam traversing the patient/sample being precise and accurate. Detectors for μCT have to meet the requirements of the specific tomography procedure in which they are going to be used. In general, the key parameters are high spatial resolution, high dynamic range, uniformity of response, high contrast sensitivity, fast acquisition readout and support of high frame rates. At present the detection devices in commercial μCT scanners are dominated by charge-coupled devices (CCD), photodiode arrays, CMOS acquisition circuits and more recently by hybrid pixel detectors. Monolithic CMOS imaging sensors, which offer reduced pixel sizes and low electronic noise, are certainly excellent candidates for μCT and may be used for the development of novel high-resolution imaging applications. The uses of monolithic CMOS based detectors such as the PERCIVAL detector are being recently explored for synchrotron and FEL applications. PERCIVAL was developed to operate in synchrotron and FEL facilities in the soft X-ray regime from 250 eV to 1 keV and it could offer all the aforementioned technical requirements needed in μCT experiments. In order to adapt the system for a typical tomography application, a scintillator is required, to convert incoming X-ray radiation (∼ tens of KeV) into visible light which may be detected with high efficiency. Such a taper-based scintillator was developed and mounted in front of the sensitive area of the PERCIVAL imager. In this presentation we will report the setup of the detector system and preliminary results of first μCTs of reference objects, which were performed in the TomoLab at ELETTRA.

In this paper, we are presenting the results of the first test of the Percival P2M-FSI detector with tender x-rays photons at a synchrotron beamline. Percival is a monolithic CMOS Imager for detection of x-rays in Synchrotron Rings and Free Electron Lasers: the Front-Side-Illuminated (FSI) version of the detector has been proven able to successfully distinguish tender (2keV) x-ray single photons.

High brilliance synchrotrons and FELs require high performing detector systems to realise their full potential. High dynamic range, low noise and high frame rate are all of great importance. In this paper we present first optical characterization results of the P2M CMOS sensor, designed for soft X-ray detection at such facilities. Previous work is summarised and an overview of the sensor is presented. Test results for the sensor’s column-parallel ADC and readout chain are presented, and first test results for the pixel acquired using the Photon Transfer Curve (PTC) method are shown. Finally, an outline of future work is provided.

Summary Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial microbial perturbations induced by cold ambient temperatures, influenced energy expenditure during cold exposure or high-fat feeding. Nevertheless, we demonstrated a critical role for gut microbial metabolism in maintaining euglycemia through the production of amino acid metabolites that optimized hepatic TCA (tricarboxylic acid) cycle fluxes in support of gluconeogenesis. These results distinguish the dispensability of the gut microbiome for the regulation of energy expenditure from its critical contribution to the maintenance of glucose homeostasis.

We report a direct observation of fast Type II twin boundary motion under a pulsed magnetic field excitation in Ni–Mn–Ga 5 M martensite, utilizing high-speed camera technique. Our results demonstrate saturation velocities up to ~ 39 m/s measured along [100] direction for individual boundaries moving at RT, showing an order of magnitude larger values as compared to the earlier studies. Actuation response times of ~ 1 μs were observed using laser vibrometry technique. The reported results show a minor role of magneto-static forces and emphasize the role of inertia and internal friction in twin boundary dynamics at the measured speeds.

Objective Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. Methods We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. Results Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). Conclusions These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients., Highlights • Upon weight loss in mice liver insulin sensitivity rapidly improves. • Upon weight loss in mice fat retains metabolic inflammation and insulin resistance. • Weight gain upon successful weight reduction in mice is driven by increased food intake. • A proportion of human subjects undergoing bariatric surgery retain AT-inflammation.

To cool a high mobility two-dimensional electron gas (2DEG) at a GaAs–AlGaAs heterojunction to milliKelvin temperatures, we have fabricated low resistance Ohmic contacts based on alloys of Au, Ni, and Ge. The Ohmic contacts have a typical contact resistance of R C ≈ 0.8 Ω at 4.2 K, which drops to 0.2 Ω below 0.9 K. Scanning electron microscope images establish that the contacts have the same inhomogeneous microstructure that has been observed in previous studies. Measurements of the contact resistance R C, the four-terminal resistance along the top of a single contact, and the vertical resistance RV all show that there is a superconductor in the Ohmic contact, which can be turned completely normal with a magnetic field of 0.15 T. We briefly discuss how this superconductivity may be affecting the electrical transport measurements of 2DEGs, especially how it may hinder the cooling of electrons in a 2DEG below 0.1 K.

2019 26th IEEE International Conference on Electronics, Circuits and Systems (ICECS), Genoa, Italy, 27 Nov 2019 - 29 Nov 2019; ... IEEE International Symposium on Circuits and Systems proceedings 51, 50 (2019). doi:10.1109/ICECS46596.2019.8964996, High brilliance synchrotrons and Free Electron Lasers (FELs) require high performing detector systems to realise their full potential. High dynamic range, low noise and high frame rate are all of great importance. In this paper we describe the P2M CMOS sensor, designed for soft X-ray detection at such facilities. We refer to previous work on test devices demonstrating a noise of 5Me- and quantum efficiency of >80% at 400eV (and with good sensitivity even below this value). Initial test results on the first Front Side Illuminated (FSI) 2 Megapixel device are also presented, and an outline of future work is described., Published by Inst. of Electr. and Electronics Engineers, New York, N.Y.

In this paper, we are presenting the Percival detector, a monolithic CMOS Imager for detection of soft x-rays in Synchrotron Rings and Free Electron Lasers. The imager consists in a 2D array of many (2M) small (27um pitch) pixels, without dead or blind zones in the imaging area. The imager achieves low noise and high dynamic range by means of an adaptive-gain in-pixel circuitry, that has been validated on prototypes. The imager features on-chip Analogue-to-Digital conversion to 12+1 bits, and has a readout speed which is compatible with most of Free Electron Laser Facilities. For direct detection of low-energy x-rays, the imager is back-illuminated and post-processed to achieve 100% fill factor.

The PERCIVAL collaboration to develop a soft X-ray imager able to address the challenges of high brilliance light sources, such as new-generation synchrotrons and Free Electron Lasers, has reached one of its major milestones: a full 2-MegaPixel (P2M) system (uninterrupted 4 × 4 cm2 active area) has already seen its first light.Smaller prototypes of the device, a monolithic active pixel sensor based on CMOS technology, have already been fully characterised, and have demonstrated high frame rate, large dynamic range, and relatively high quantum efficiency.The PERCIVAL modular layout allows for clover-leaf like arrangement of up to four P2M systems. Moreover, it will be post-processed in order to achieve a high quantum efficiency in its primary energy range (250 eV to 1 keV).We will present the P2M system, its status and newest results, bring these in context with achieved prototype performance, and outline future steps.

A three million pixel photon counting large area detector has been commissioned for the coherent diffraction imaging beamline (I13) of Diamond Light Source. Challenging requirements of small pixel size, large area and fast frame rates required the construction of a detector based upon a tiling of a large number of the latest generation of the Medipix family of photon counting ASICs, Medipix3RX and a highly parallel readout system based upon the Front End Module cards developed by STFC. Such a detector provides a significant improvement in field of view whilst maintaining the resolution afforded by the small pixel size, when compared to previously available Medipix-based detectors such as the quad-chip Merlin. A number of commissioning experiments have been performed on the beamline, and this Conference Record provides intial results from these measurements and determines the capabilities of the detector and beamline system.

Summary Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.

T2K is a second generation long-baseline experiment in Japan, designed to perform precision studies of neutrino oscillations. A neutrino beam originating at the J-PARC facility is sampled by two near detectors, approximately 280 m distant from the source and directed towards the Kamioka underground facility, 295 km distant, where the Super-Kamiokande water Cerenkov detector is situated. Both the on-axis (INGRID) and off-axis (ND280) near detectors employ the MIDAS framework for their data acquisition systems. Events are selected via a flexible hardware trigger, which allows mixed operating modes incorporating beam spill, cosmic and calibration triggers. Data are acquired from the front-end electronics over optical Gigabit Ethernet links by custom MIDAS front-end applications distributed over a cluster of Linux computers. Event fragments from all sub-detectors are merged and logged on a central backend processor and then copied to remote storage for long-term archival. The system is also designed to allow flexible partitioning of sub-detectors for standalone diagnostics and calibration. We present the design of the DAQ system and report on experience gathered during early operation of the near detectors. © 2006 IEEE.

The T2K experiment is a long baseline neutrino oscillation experiment aiming to observe the appearance of νe in a νμ beam. The νμ beam is produced at the Japan Proton Accelerator Research Complex (J-PARC), observed with the 295 km distant Super-Kamiokande Detector and monitored by a suite of near detectors at 280 m from the proton target. The near detectors include a magnetized off-axis detector (ND280) which measures the unoscillated neutrino flux and neutrino cross-sections. The present paper describes the outermost component of ND280 which is a Side Muon Range Detector (SMRD) composed of scintillation counters with embedded wavelength shifting fibers and Multi-Pixel Photon Counter readout. The components, performance and response of the SMRD are presented. © 2012 Elsevier B.V.

OBJECTIVE The fatty acid translocase and scavenger receptor CD36 is important in the recognition and uptake of lipids. Accordingly, we hypothesized that it plays a role in saturated fatty acid–induced macrophage lipid accumulation and proinflammatory activation. RESEARCH DESIGN AND METHODS In vitro, the effect of CD36 inhibition and deletion in lipid-induced macrophage inflammation was assessed using the putative CD36 inhibitor, sulfosuccinimidyl oleate (SSO), and bone marrow–derived macrophages from mice with (CD36KO) or without (wild-type) global deletion of CD36. To investigate whether deletion of macrophage CD36 would improve insulin sensitivity in vivo, wild-type mice were transplanted with bone marrow from CD36KO or wild-type mice and then fed a standard or high-fat diet (HFD) for 20 weeks. RESULTS SSO treatment markedly reduced saturated fatty acid–induced lipid accumulation and inflammation in RAW264.7 macrophages. Mice harboring CD36-specific deletion in hematopoietic-derived cells (HSC CD36KO) fed an HFD displayed improved insulin signaling and reduced macrophage infiltration in adipose tissue compared with wild-type mice, but this did not translate into protection against HFD-induced whole-body insulin resistance. Contrary to our hypothesis and our results using SSO in RAW264.7 macrophages, neither saturated fatty acid–induced lipid accumulation nor inflammation was reduced when comparing CD36KO with wild-type bone marrow–derived macrophages. CONCLUSIONS Although CD36 does not appear important in saturated fatty acid–induced macrophage lipid accumulation, our study uncovers a novel role for CD36 in the migration of proinflammatory phagocytes to adipose tissue in obesity, with a concomitant improvement in insulin action.

The peak brilliance reached by today's Free-Electron Laser and Synchrotron light sources requires photon detectors matching their output intensity and other characteristics in order to fully realiz ...

Recent work has identified the important roles of M1 pro-inflammatory and M2 anti-inflammatory macrophages in the regulation of insulin sensitivity. Specifically, increased numbers of M2 macrophages and a decrease in M1 macrophages within the adipose tissue are associated with a state of enhanced insulin sensitivity. IL-10 is an anti-inflammatory cytokine and is a critical effector molecule of M2 macrophages.In the present study, we examined the contribution of haematopoietic-cell-derived IL-10 to the development of obesity-induced inflammation and insulin resistance. We hypothesised that haematopoietic-cell-restricted deletion of IL-10 would exacerbate obesity-induced inflammation and insulin resistance. Lethally irradiated wild-type recipient mice receiving bone marrow from either wild-type or Il10-knockout mice were placed on either a chow or a high-fat diet for a period of 12 weeks and assessed for alterations in body composition, tissue inflammation and glucose and insulin tolerance.Contrary to our hypothesis, neither inflammation, as measured by the activation of pro-inflammatory stress kinases and gene expression of several pro-inflammatory cytokines in the adipose tissue and liver, nor diet-induced obesity and insulin resistance were exacerbated by the deletion of haematopoietic-cell-derived IL-10. Interestingly, however, Il10 mRNA expression and IL-10 protein production in liver and/or adipose tissue were markedly elevated in Il10-knockout bone-marrow-transplanted mice relative to wild-type bone marrow-transplanted mice.These data show that deletion of IL-10 from the haematopoietic system does not potentiate high-fat diet-induced inflammation or insulin resistance.

The PERCIVAL (Pixelated Energy Resolving CMOS Imager, Versatile And Large) soft X-ray 2D imaging detector is based on stitched, wafer-scale sensors possessing a thick epi-layer, which together with back-thinning and back-side illumination yields elevated quantum efficiency in the photon energy range of 125–1000 eV. Main application fields of PERCIVAL are foreseen in photon science with FELs and synchrotron radiation. This requires high dynamic range up to 105 ph @ 250 eV paired with single photon sensitivity with high confidence at moderate frame rates in the range of 10–120 Hz. These figures imply the availability of dynamic gain switching on a pixel-by-pixel basis and a highly parallel, low noise analog and digital readout, which has been realized in the PERCIVAL sensor layout. Different aspects of the detector performance have been assessed using prototype sensors with different pixel and ADC types. This work will report on the recent test results performed on the newest chip prototypes with the improved pixel and ADC architecture. For the target frame rates in the 10–120 Hz range an average noise floor of 14e− has been determined, indicating the ability of detecting single photons with energies above 250 eV. Owing to the successfully implemented adaptive 3-stage multiple-gain switching, the integrated charge level exceeds 4 10^6 e− or 57000 X-ray photons at 250 eV per frame at 120 Hz. For all gains the noise level remains below the Poisson limit also in high-flux conditions. Additionally, a short overview over the updates on an oncoming 2 Mpixel (P2M) detector system (expected at the end of 2016) will be reported.

HLA antigen frequencies were determined in patients who had suffered adverse reaction to the beta-adrenergic blocking agent, practolol. No statistically significant differences were observed between these patients and control groups. The latter were selected to include two separate groups, normal random healthy population controls, and controls who had taken practolol with no apparent adverse effects. Patients suffering from the very severe form of reaction, sclerosing peritonitis, were analysed separately from those with other lesion e.g. ocular symptoms, but did not show any significant differences. Altered HLA antigen frequencies were observed for those control patients whose primary diagnosis was hypertension but this was considered to be due to selection bias.

Artículo escrito por muchos autores, sólo se referencian el primero, los autores que firman como Universidad Autónoma de Madrid y el grupo de colaboración en el caso de que aparezca en el artículo, Hyper-Kamiokande will be a next-generation underground water Cherenkov detector with a total (fiducial) mass of 0.99 (0.56) million metric tons, approximately 20 (25) times larger than that of Super-Kamiokande. One of the main goals of Hyper-Kamiokande is the study of CP asymmetry in the lepton sector using accelerator neutrino and anti-neutrino beams. In this paper, the physics potential of a long-baseline neutrino experiment using the Hyper- Kamiokande detector and a neutrino beam from the J-PARC proton synchrotron is presented. The analysis uses the framework and systematic uncertainties derived from the ongoing T2K experiment. With a total exposure of 7.5 MW ×107 s integrated proton beam power (corresponding to 1.56 × 1022 protons on target with a 30 GeV proton beam) to a 2.5° off-axis neutrino beam, it is expected that the leptonic CP phase δCP can be determined to better than 19 degrees for all possible values of δCP, and CP violation can be established with a statistical significance of more than 3 σ (5 σ) for 76% (58%) of the δCP parameter space. Using both νeappearance and νμ disappearance data, the expected 1 σ uncertainty of sin2 Θ23 is 0.015(0.006) for sin2 Θ23= 0.5(0.45), This work was supported by a MEXT Grant-in-Aid for Scientific Research on Innovative Areas Number 25105004, titled “Unification and Development of the Neutrino Science Frontier.” In addition, the participation of individual researchers has been further supported by funds from JSPS, Japan; the European Union ERC-207282, H2020 RISE-GA644294-JENNIFER, and H2020 RISE-GA641540-SKPLUS; RSF, RFBR, and MES, Russia; and JSPS and RFBR under the Japan–Russia Research Cooperative Program

The stresses in circular saws together with classical theories and new methods of stress determination are reviewed. The use of the Finite Element Analysis package (ANSYS) for the determination of these stresses and their combined effects is discussed.