317 research outputs found

    Beta cell connectivity in pancreatic islets:a type 2 diabetes target?

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    A spatial investigation of the environmental controls over cryoconite aggregation on Longyearbreen glacier, Svalbard.

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    A cryoconite granule is a near-spherical aggregation of biota and abiotic particles found upon glacier surfaces. Recently, microstructural studies have revealed that photosynthetic microorganisms and extracellular polymeric substances (EPS) are omnipresent within cryoconite granules and have suggested their importance as biological "forming factors". To assess these forming factors, and their biological control over aggregate size and stability, across a typical Arctic valley glacier surface, a suite of rapid, spectrophotometric, microplate methods were utilised. Subsequent spatial mapping of these data revealed distinct patterns. Labile carbohydrates were found to increase up-glacier, suggestive of EPS production for cryoprotection and nutrient assimilation. Conversely, pigment concentrations were found to increase towards the glacier terminus and valley sides, suggestive of allochthonous input, a general reduction in physical disturbance and of the build-up of photosynthetic pigments and less labile cyanobacterial sheath material. Aggregate size was found to increase towards the glacier edges, linked to the input of particulate matter from the valley sides, and to broadly increase down-glacier, in the same way as pigment concentrations. Statistical analyses of transect data revealed that the photoautotrophic count and carbohydrate–chlorophyll ratio of the cryoconite sampled could explain 83% of the measured variation in aggregate size and stability. Considering solely aggregate size, the number and length of photoautotrophic filaments could explain 92% of the variation in this parameter. These findings demonstrate the two-dimensional distribution of key biological controls upon cryoconite aggregation for the first time, and highlight the importance of filamentous cyanobacteria and EPS production to the development of stable cryoconite granules

    Fine‐tuned photochromic sulfonylureas for optical control of beta cell Ca <sup>2+</sup> fluxes

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    We previously developed, synthesized and tested light-activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light-dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push-pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine-tuned, light-activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine-, pyrrolidine- and piperidine-based sulfonylureas all increased beta cell Ca2+ -spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine-based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine-azobenzenes as chemical photoswitches across drug classes

    Marked Seasonal Changes in the Microbial Production, Community Composition, and Biogeochemistry of Glacial Snowpack Ecosystems in the Maritime Antarctic

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    We describe seasonal changes in the biogeochemistry, microbial community and ecosystem production of two glacial snowpacks in the maritime Antarctic during a cold summer. Frequent snowfall and low, intermittent melt on the glaciers suppressed surface photosynthesis and promoted net heterotrophy. Concentrations of autotrophic cells (algae and cyanobacteria) were therefore low (average: 150 - 500 cells mL-1), and short-term estimates of primary production were almost negligible in early summer ( 104 cells mL-1 in basal ice near the penguin colony). The ratio of bacteria to autotrophs also increased throughout the summer, and short-term bacterial production rates (0.2 – 2000 ”g C L-1 d-1) usually exceeded primary production, especially in basal ice (10 – 1400 ”g C L-1 d-1). The basal ice represented the least diverse but most productive habitat, and a striking feature was its low pH (down to 3.3). Furthermore, all of the overlying snow cover became increasingly acidic as the summer season progressed, which is attributed to enhanced emissions from wet guano in the penguin colony. The study demonstrates that active microbial communities can be expected, even when snowmelt is intermittent in the Antarctic summer

    Median eminence blood flow influences food intake by regulating ghrelin access to the metabolic brain

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    Central integration of peripheral appetite-regulating signals ensures maintenance of energy homeostasis. Thus, plasticity of circulating molecule access to neuronal circuits involved in feeding behavior plays a key role in the adaptive response to metabolic changes. However, the mechanisms involved remain poorly understood despite their relevance for therapeutic development. Here, we investigated the role of median eminence mural cells, including smooth muscle cells and pericytes, in modulating gut hormone effects on orexigenic/anorexigenic circuits. We found that conditional activation of median eminence vascular cells impinged on local blood flow velocity and altered ghrelin-stimulated food intake by delaying ghrelin access to target neurons. Thus, activation of median eminence vascular cells modulates food intake in response to peripheral ghrelin by reducing local blood flow velocity and access to the metabolic brain.</p

    Enzyme self-label-bound ATTO700 in single-molecule and super-resolution microscopy

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    Herein, we evaluate near-infrared ATTO700 as an acceptor in SNAP- and Halo-tag protein labelling for Förster Resonance Energy Transfer (FRET) by ensemble and single molecule measurements. Microscopy of cell surface proteins in live cells is perfomed including super-resolution stimulated emission by depletion (STED) nanoscopy

    The PTEN Phosphatase Functions Cooperatively with the Fanconi Anemia Proteins in DNA Crosslink Repair

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    Fanconi anemia (FA) is a genetic disease characterized by bone marrow failure and increased cancer risk. The FA proteins function primarily in DNA interstrand crosslink (ICL) repair. Here, we have examined the role of the PTEN phosphatase in this process. We have established that PTEN-deficient cells, like FA cells, exhibit increased cytotoxicity, chromosome structural aberrations, and error-prone mutagenic DNA repair following exposure to ICL-inducing agents. The increased ICL sensitivity of PTEN-deficient cells is caused, in part, by elevated PLK1 kinase-mediated phosphorylation of FANCM, constitutive FANCM polyubiquitination and degradation, and the consequent inefficient assembly of the FA core complex, FANCD2, and FANCI into DNA repair foci. We also establish that PTEN function in ICL repair is dependent on its protein phosphatase activity and ability to be SUMOylated, yet is independent of its lipid phosphatase activity. Finally, via epistasis analysis, we demonstrate that PTEN and FANCD2 function cooperatively in ICL repair

    Quantifying wheat blast disease induced yield and production losses of wheat: A quasi-natural experiment

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    Applying the difference-in-difference (DID) estimation procedure, this study quantifies the wheat blast (Magnaporthe oryzae pathotype Triticum) induced losses in wheat yield, quantity of wheat sold, consumed, or stored, as well as wheat grain value in Bangladesh in 2016 following a disease outbreak that affected over 15,000 ha. Estimates show that the blast-induced yield loss was 540 kg ha−1 on average for households in blast-affected districts. Estimated total wheat production loss was approximately 8,205 tons worth USD 2.1 million in during the 2016 outbreak. Based on these insights, we discuss the need for long-term assured investment and concerted research efforts in controlling transboundary diseases such as wheat blast, including the importance of weather forecast driven early warning systems and the dissemination of blast-resistant varieties
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