Diabetes is a leading cause of morbidity and mortality worldwide, and predicted to affect over 500 million people by 2030. However, this growing burden of disease has not been met with a comparable ...expansion in therapeutic options. The appreciation of the pancreatic β-cell as a central player in the pathogenesis of both type 1 and type 2 diabetes has renewed focus on ways to improve glucose homeostasis by preserving, expanding and improving the function of this key cell type. Here, we provide an overview of the latest developments in this field, with an emphasis on the most promising strategies identified to date for treating diabetes by targeting the β-cell.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Through detailed exploration of events in Tunisia, Egypt, Bahrain, Libya, Syria and Yemen, Sean Burns here breaks down the concept of professionalism within the armed forces into its component parts ...and demonstrates how variation in military structures determines their behaviour. In so doing, and by emphasising historical context and drawing on a wide range of political science theory, Burns sheds fresh light onto the ways in which military structure affects the potential for democratic transition or the course of civil war. With this book he presented a wide-ranging study of the Middle East which provides key tools to understanding the opportunities for democratisation, both during the Arab Spring and beyond, and which is therefore essential reading for anyone working on the Middle East, popular uprisings and the politics of repression.
Defects in insulin secretion play a central role in the pathogenesis of type 2 diabetes, yet the mechanisms driving beta-cell dysfunction remain poorly understood, and therapies to preserve ...glucose-dependent insulin release are inadequate. We report a luminescent insulin secretion assay that enables large-scale investigations of beta-cell function, created by inserting Gaussia luciferase into the C-peptide portion of proinsulin. Beta-cell lines expressing this construct cosecrete luciferase and insulin in close correlation, under both standard conditions or when stressed by cytokines, fatty acids, or ER toxins. We adapted the reporter for high-throughput assays and performed a 1,600-compound pilot screen, which identified several classes of drugs inhibiting secretion, as well as glucose-potentiated secretagogues that were confirmed to have activity in primary human islets. Requiring 40-fold less time and expense than the traditional ELISA, this assay may accelerate the identification of pathways governing insulin secretion and compounds that safely augment beta-cell function in diabetes.
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•Proinsulin-Gaussia luciferase fusion construct faithfully reports insulin secretion•Luciferase tracks closely with insulin under normal conditions and induced stress•Reporter enables large-scale study of beta-cell function rapidly and at low cost•1,600-compound screen using assay identifies new human glucose-dependent secretagogues
Current assays of beta-cell functions, while useful, have limitations. In this Resource, Burns et al. develop a luminescent reporter of insulin secretion that is 40 times less time-consuming and expensive than ELISA. They perform high-throughput assays of beta-cell function to identify drugs altering human insulin secretion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Northern hemisphere evergreen forests assimilate a significant fraction of global atmospheric CO₂ but monitoring large-scale changes in gross primary production (GPP) in these systems is challenging. ...Recent advances in remote sensing allow the detection of solar-induced chlorophyll fluorescence (SIF) emission from vegetation, which has been empirically linked to GPP at large spatial scales. This is particularly important in evergreen forests, where traditional remote-sensing techniques and terrestrial biosphere models fail to reproduce the seasonality of GPP. Here, we examined the mechanistic relationship between SIF retrieved from a canopy spectrometer system and GPP at a winter-dormant conifer forest, which has little seasonal variation in canopy structure, needle chlorophyll content, and absorbed light. Both SIF and GPP track each other in a consistent, dynamic fashion in response to environmental conditions. SIF and GPP are well correlated (R² = 0.62–0.92) with an invariant slope over hourly to weekly timescales. Large seasonal variations in SIF yield capture changes in photoprotective pigments and photosystem II operating efficiency associated with winter acclimation, highlighting its unique ability to precisely track the seasonality of photosynthesis. Our results underscore the potential of new satellite-based SIF products (TROPOMI, OCO-2) as proxies for the timing and magnitude of GPP in evergreen forests at an unprecedented spatiotemporal resolution.
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Recent successes in passive remote sensing of far-red solar-induced chlorophyll fluorescence (SIF) have spurred the development and integration of
canopy-level fluorescence models in global ...terrestrial biosphere models (TBMs) for climate and carbon cycle research. The interaction of fluorescence
with photochemistry at the leaf and canopy scales provides opportunities to diagnose and constrain model simulations of photosynthesis and related
processes, through direct comparison to and assimilation of tower, airborne, and satellite data. TBMs describe key processes related to the absorption of
sunlight, leaf-level fluorescence emission, scattering, and reabsorption throughout the canopy. Here, we analyze simulations from an ensemble of
process-based TBM–SIF models (SiB3 – Simple Biosphere Model, SiB4, CLM4.5 – Community Land Model, CLM5.0, BETHY – Biosphere Energy Transfer Hydrology, ORCHIDEE – Organizing Carbon and Hydrology In Dynamic Ecosystems, and BEPS – Boreal Ecosystems Productivity Simulator) and the SCOPE (Soil Canopy Observation Photosynthesis Energy) canopy radiation and vegetation model at a subalpine
evergreen needleleaf forest near Niwot Ridge, Colorado. These models are forced with local meteorology and analyzed against tower-based continuous
far-red SIF and gross-primary-productivity-partitioned (GPP) eddy covariance data at diurnal and synoptic scales during the growing season
(July–August 2017). Our primary objective is to summarize the site-level state of the art in TBM–SIF modeling over a relatively short time period
(summer) when light, canopy structure, and pigments are similar, setting the stage for regional- to global-scale analyses. We find that these models
are generally well constrained in simulating photosynthetic yield but show strongly divergent patterns in the simulation of absorbed photosynthetic
active radiation (PAR), absolute GPP and fluorescence, quantum yields, and light response at the leaf and canopy scales. This study highlights the need for
mechanistic modeling of nonphotochemical quenching in stressed and unstressed environments and improved the representation of light absorption (APAR),
distribution of light across sunlit and shaded leaves, and radiative transfer from the leaf to the canopy scale.
As global temperatures increase, the potential for longer growing seasons to enhance the terrestrial carbon sink has been proposed as a mechanism to reduce the rate of further warming. At the Niwot ...Ridge AmeriFlux site, a subalpine forest in the Colorado Rocky Mountains, we used a 9-year record (1999-2007) of continuous eddy flux observations to show that longer growing season length (GSL) actually resulted in less annual CO₂ uptake. Years with a longer GSL were correlated with a shallower snow pack, as measured using snow water equivalent (SWE). Furthermore, years with a lower SWE correlated with an earlier start of spring. For three years, 2005, 2006, and 2007, we used observations of stable hydrogen isotopes (δD) of snow vs. rain, and extracted xylem water from the three dominant tree species, lodgepole pine, Engelmann spruce, and subalpine fir, to show that the trees relied heavily on snow melt water even late into the growing season. By mid-August, 57% to 68% of xylem water reflected the isotopic signature of snow melt. By coupling the isotopic water measurements with an ecosystem model, SIPNET, we found that annual forest carbon uptake was highly dependent on snow water, which decreases in abundance during years with longer growing seasons. Once again, for the 3 years 2005, 2006, and 2007, annual gross primary productivity, which was derived as an optimized parameter from the SIPNET model was estimated to be 67% 77%, and 71% dependent on snow melt water, respectively. Past studies have shown that the mean winter snow pack in mountain ecosystems of the Western US has been declining for decades and is correlated with positive winter temperature anomalies. Since climate change models predict continuation of winter warming and reduced snow in mountains of the Western US, the strength of the forest carbon sink is likely to decline further.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Science depends on a communication system, and today, that is largely provided by digital technologies such as the internet and web. Despite the fact that digital technologies provide the ...infrastructure for this communication system, peer-reviewed journals continue to mimic workflows and processes from the print era. This paper focuses on one artifact from the print era, the journal issue, and describes how this artifact has been detrimental to the communication of science, and therefore, to science itself. To replace the journal issue, this paper argues that scholarly publishing and journals could more fully embrace digital technologies by creating digital libraries to present and organize scholarly output.
This study compared the results of data collected from a longitudinal query analysis of the MEDLINE database hosted on multiple platforms that include PubMed, EBSCOHost, Ovid, ProQuest, and Web of ...Science. The goal was to identify variations among the search results on the platforms after controlling for search query syntax. We devised twenty-nine cases of search queries comprised of five semantically equivalent queries per case to search against the five MEDLINE database platforms. We ran our queries monthly for a year and collected search result count data to observe changes. We found that search results varied considerably depending on MEDLINE platform. Reasons for variations were due to trends in scholarly publication such as publishing individual papers online first versus complete issues. Some other reasons were metadata differences in bibliographic records; differences in the levels of specificity of search fields provided by the platforms and large fluctuations in monthly search results based on the same query. Database integrity and currency issues were observed as each platform updated its MEDLINE data throughout the year. Specific biomedical bibliographic databases are used to inform clinical decision-making, create systematic reviews, and construct knowledge bases for clinical decision support systems. They serve as essential information retrieval and discovery tools to help identify and collect research data and are used in a broad range of fields and as the basis of multiple research designs. This study should help clinicians, researchers, librarians, informationists, and others understand how these platforms differ and inform future work in their standardization.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing β-cells is the primary means of β-cell replacement in ...rodents (2), it is unclear whether a similar principle applies to humans, as human β-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human β-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of β-cell proliferation by either 5-IT or harmine, another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes β-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human β-cell proliferation.
Understanding and predicting the relationship between leaf temperature (
) and air temperature (
) is essential for projecting responses to a warming climate, as studies suggest that many forests are ...near thermal thresholds for carbon uptake. Based on leaf measurements, the limited leaf homeothermy hypothesis argues that daytime
is maintained near photosynthetic temperature optima and below damaging temperature thresholds. Specifically, leaves should cool below
at higher temperatures (i.e., > ∼25-30°C) leading to slopes <1 in
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relationships and substantial carbon uptake when leaves are cooler than air. This hypothesis implies that climate warming will be mitigated by a compensatory leaf cooling response. A key uncertainty is understanding whether such thermoregulatory behavior occurs in natural forest canopies. We present an unprecedented set of growing season canopy-level leaf temperature (
) data measured with thermal imaging at multiple well-instrumented forest sites in North and Central America. Our data do not support the limited homeothermy hypothesis: canopy leaves are warmer than air during most of the day and only cool below air in mid to late afternoon, leading to
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slopes >1 and hysteretic behavior. We find that the majority of ecosystem photosynthesis occurs when canopy leaves are warmer than air. Using energy balance and physiological modeling, we show that key leaf traits influence leaf-air coupling and ultimately the
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relationship. Canopy structure also plays an important role in
dynamics. Future climate warming is likely to lead to even greater
, with attendant impacts on forest carbon cycling and mortality risk.
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