Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict ...incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.
Hydrology is an integrative discipline linking the broad array of water‐related research with physical, ecological, and social sciences. The increasing breadth of hydrological research, often where ...subdisciplines of hydrology partner with related sciences, reflects the central importance of water to environmental science, while highlighting the fractured nature of the discipline itself. This lack of coordination among hydrologic subdisciplines has hindered the development of hydrologic theory and integrated models capable of predicting hydrologic partitioning across time and space. The recent development of the concept of the critical zone (CZ), an open system extending from the top of the canopy to the base of groundwater, brings together multiple hydrological subdisciplines with related physical and ecological sciences. Observations obtained by CZ researchers provide a diverse range of complementary process and structural data to evaluate both conceptual and numerical models. Consequently, a cross‐site focus on “critical zone hydrology” has potential to advance the discipline of hydrology and to facilitate the transition of CZ observatories into a research network with immediate societal relevance. Here we review recent work in catchment hydrology and hydrochemistry, hydrogeology, and ecohydrology that highlights a common knowledge gap in how precipitation is partitioned in the critical zone: “how is the amount, routing, and residence time of water in the subsurface related to the biogeophysical structure of the CZ?” Addressing this question will require coordination among hydrologic subdisciplines and interfacing sciences, and catalyze rapid progress in understanding current CZ structure and predicting how climate and land cover changes will affect hydrologic partitioning.
Key Points:
The disparate nature of hydrologic research hinders theoretical advancement
Coordinated research on subsurface hydrologic partitioning to ET or streamflow can address this gap
Multiple areas of research identify extensive groundwater interaction with streamflow and atmosphere
The development of gene-editing technology holds tremendous potential for accelerating crop trait improvement to help us address the need to feed a growing global population. However, the delivery ...and access of gene-editing tools to the host genome and subsequent recovery of successfully edited plants form significant bottlenecks in the application of new plant breeding technologies. Moreover, the methods most suited to achieve a desired outcome vary substantially, depending on species' genotype and the targeted genetic changes. Hence, it is of importance to develop and improve multiple strategies for delivery and regeneration in order to be able to approach each application from various angles. The use of transient transformation and regeneration of plant protoplasts is one such strategy that carries unique advantages and challenges. Here, we will discuss the use of protoplast regeneration in the application of new plant breeding technologies and review pertinent literature on successful protoplast regeneration.
Astrocytes are the second most abundant cell type in the central nervous system and serve various functions, many of which maintain homeostasis of the intracellular milieu in the face of constant ...change. In order to accomplish these important functions, astrocytes must regulate their cell volume. In astrocytes, cell volume regulation involves multiple channels and transporters, including AQP4, TRPV4, TRPM4, VRAC, Na
/K
ATPase, NKCC1 and Kir4.1. AQP4 is a bidirectional water channel directly involved in astrocyte cell volume regulation. AQP4 also forms heteromultimeric complexes with other channels and transporters involved in cell volume regulation. TRPV4, a mechanosensitive channel in involved in osmotic regulation in various cell types, forms a complex with AQP4 to decrease cell volume in response to cell swelling. TRPM4 also forms a complex with AQP4 and SUR1 in response to injury resulting in cell swelling. Another complex forms between Na
/K
ATPase, AQP4, and mGluR5 to regulate the perisynaptic space. NKCC1 is a co-transporter involved in cell volume increases either independently through cotransport of water or a functional interaction with AQPs. VRAC is implicated in regulatory volume decreases and may also functionally interact with AQP4. Although Kir4.1 colocalizes with AQP4, its role in cell volume regulation is debated. In diseases where fluid/electrolyte homeostasis is disturbed such as stroke, ischemic injury, inflammation, traumatic brain injury and hydrocephalus, cell volume regulation is challenged, sometimes past the point of recovery. Thus, a greater understanding of signaling pathways which regulate transport proteins as well as the functional and physical interactions that exist between transporters will provide a basis for the development of pharmaceutical targets to treat these prevalent and often devastating diseases.
An update of the chapter on Mental, Behavioral and Neurodevelopmental Disorders in the International Classification of Diseases and Related Health Problems (ICD) is of great interest around the ...world. The recent approval of the 11th Revision of the ICD (ICD-11) by the World Health Organization (WHO) raises broad questions about the status of nosology of mental disorders as a whole as well as more focused questions regarding changes to the diagnostic guidelines for specific conditions and the implications of these changes for practice and research. This Forum brings together a broad range of experts to reflect on key changes and controversies in the ICD-11 classification of mental disorders. Taken together, there is consensus that the WHO's focus on global applicability and clinical utility in developing the diagnostic guidelines for this chapter will maximize the likelihood that it will be adopted by mental health professionals and administrators. This focus is also expected to enhance the application of the guidelines in non-specialist settings and their usefulness for scaling up evidence-based interventions. The new mental disorders classification in ICD-11 and its accompanying diagnostic guidelines therefore represent an important, albeit iterative, advance for the field.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Framing the Narrative Manekin, Devorah; Wood, Reed M.
The Journal of conflict resolution,
10/2020, Letnik:
64, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Female combatants play a central role in rebel efforts to cultivate and disseminate positive narratives regarding the movement and its political goals. Yet, the effectiveness of such strategies in ...shaping audience attitudes or generating tangible benefits for the group remains unclear. We propose and test a theory regarding the channels through which female fighters advance rebel goals. We argue that female fighters positively influence audience attitudes toward rebel groups by strengthening observers’ beliefs about their legitimacy and their decision to use armed tactics. We further contend that these effects directly help them secure support from transnational nonstate actors and indirectly promote state support. We assess our arguments by combining a novel survey experiment in two countries with analyses of new cross-national data on female combatants and information about transnational support for rebels. The empirical results support our arguments and demonstrate the impact of gender framing on rebel efforts to secure support.
A methodological framework is proposed for participatory scenario development on the basis of evidence from the literature, and is tested and refined through the development of scenarios for the ...future of UK uplands. The paper uses a review of previous work to justify a framework based around the following steps: i) define context and establish whether there is a basis for stakeholder engagement in scenario development; ii) systematically identify and represent relevant stakeholders in the process; iii) define clear objectives for scenario development with stakeholders including spatial and temporal boundaries; iv) select relevant participatory methods for scenario development, during initial scenario construction, evaluation and to support decision-making based on scenarios; and v) integrate local and scientific knowledge throughout the process. The application of this framework in case study research suggests that participatory scenario development has the potential to: i) make scenarios more relevant to stakeholder needs and priorities; ii) extend the range of scenarios developed; iii) develop more detailed and precise scenarios through the integration of local and scientific knowledge; and iv) move beyond scenario development to facilitate adaptation to future change. It is argued that participatory scenario development can empower stakeholders and lead to more consistent and robust scenarios that can help people prepare more effectively for future change.
•A methodological framework is proposed develop scenarios with stakeholders that can inform decision-making.•This has the potential to empower stakeholders and make scenarios more relevant to their needs.•Integrating local and scientific knowledge can increase the diversity, detail and precision of scenarios.•In this way, more consistent and robust scenarios can be developed to help people prepare more effectively for future change.
Widespread groundwater overdraft in alluvial aquifer systems like the Central Valley (CV) in California, USA, has increased interest in managed aquifer recharge (MAR). Like most clastic sedimentary ...basins, recharge to the productive semi-confined CV aquifer system remains a challenge due to the presence of nearly ubiquitous, multiple confining units (silt and clay) that limit recharge pathways. Previous studies suggest the presence of interconnected networks of coarse-texture sand and gravel deposits that bypass regional confining units over a small fraction of the CV near the American and Cosumnes rivers. Here, variably saturated infiltration and recharge processes were simulated across a domain that includes high-resolution representation of the heterogeneous alluvial geologic architecture in this area. Results show that recharge potential is highly dependent on subsurface geologic architecture, with a nearly 2 order-of-magnitude range of recharge across the domain. Where interconnected coarse-texture recharge pathways occur, results show that these features can (1) accommodate rapid, high-volume MAR and (2) propagate widespread and rapid pressure responses over multi-kilometer distances in the semi-confined aquifer system. For all MAR simulations, results show that the majority of MAR is accommodated by filling unsaturated-zone (UZ) pore volume. Results also show that coarse-texture UZ facies (where present) accommodate the majority of MAR volume during early time, but fine-texture facies ultimately accommodate the majority of the total MAR volume, even for coarse-dominated sites. These findings highlight the large variability of MAR potential across the landscape and demonstrate the importance of fine-texture facies for accommodating MAR in alluvial aquifer systems.
The authors estimated the prevalence and severity of cutaneous allodynia (CA) in individuals with primary headaches from the general population.
We mailed questionnaires to a random sample of 24,000 ...headache sufferers previously identified from the population. The questionnaire included the validated Allodynia Symptom Checklist (ASC) as well as measures of headache features, disability, and comorbidities. We modeled allodynia as an outcome using headache diagnosis, frequency and severity of headaches, and disability as predictor variables in logistic regression. Covariates included demographic variables, comorbidities, use of preventive medication, and use of opioids.
Complete surveys were returned by 16,573 individuals. The prevalence of CA of any severity (ASC score >or=3) varied with headache type. Prevalence was significantly higher in transformed migraine (TM, 68.3%) than in episodic migraine (63.2%, p < 0.01) and significantly elevated in both of these groups compared with probable migraine (42.6%), other chronic daily headaches (36.8%), and severe episodic tension-type headache (36.7%). The prevalence of severe CA (ASC score >or=9) was also highest in TM (28.5%) followed by migraine (20.4%), probable migraine (12.3%), other chronic daily headaches (6.2%), and severe episodic tension-type headache (5.1%). In the migraine and TM groups, prevalence of CA was higher in women and increased with disability score. Among migraineurs, CA increased with headache frequency and body mass index. In all groups, ASC scores were higher in individuals with major depression.
Cutaneous allodynia (CA) is more common and more severe in transformed migraine and migraine than in other primary headaches. Among migraineurs, CA is associated with female sex, headache frequency, increased body mass index, disability, and depression.
The serendipitous discovery in 1961 of dibenzo-18-crown-6 by Charles J. Pedersen marked the beginning of research on cyclic polyether macrocyclic compounds. These compounds have a remarkably ...selective affinity for certain metal ions and provide a framework for studying molecular recognition processes. Pedersen's work excited much interest in the scientific community and fueled important advances in macrocyclic and supramolecular chemistry. Born in Korea of a Japanese mother and a Norwegian engineer father, he was educated in Japan and later graduated from the University of Dayton (BS, chemical engineering) and Massachusetts Institute of Technology (MS, chemistry). He worked at du Pont for 42 years as a research chemist. His research talent at du Pont earned him an appointment as a Research Associate allowing him to pursue research as he chose. This freedom served him well making it possible for him to devote all his efforts following his discovery of dibenzo-18-crown-6 until his retirement to synthesis of cyclic polyethers and evaluation of their metal ion complexation properties. His influence on macrocyclic and supramolecular chemistry has been pervasive. He was co-recipient of the 1987 Nobel Prize in chemistry for development and use of molecules with structure-specific interactions of high selectivity. The year 2017 marks the fiftieth anniversary of the publication of his first paper describing his synthesis of over 50 crown ethers.
A remarkable person, Charles J. Pedersen's legacy to chemistry was the serendipitous discovery of crown ethers that netted him the 1987 Nobel Prize.
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