Realistically representing the present-day characteristics of extreme precipitation has been a challenge for global climate models, which is due in part to deficiencies in model resolution and ...physics, but is also due to a lack of consistency in gridded observations. In this study, we use three observation datasets, including gridded rain gauge and satellite data, to assess historical simulations from sixteen Coupled Model Intercomparison Project Phase 6 (CMIP6) models. We separately evaluate summer and winter precipitation over the United States (US) with a comprehensive set of extreme precipitation indices, including an assessment of precipitation frequency, intensity and spatial structure. The observations exhibit significant differences in their estimates of area-average intensity distributions and spatial patterns of the mean and extremes of precipitation over the US. In general, the CMIP6 multi-model mean performs better than most individual models at capturing daily precipitation distributions and extreme precipitation indices, particularly in comparison to gauge-based data. Also, the representation of the extreme precipitation indices by the CMIP6 models is better in the summer than winter. Although the 'standard' horizontal-resolution can vary significantly across CMIP6 models, from ∼0.7° to ∼2.8°, we find that resolution is not a good indicator of model performance. Overall, our results highlight common biases in CMIP6 models and demonstrate that no single model is consistently the most reliable across all indices.
Permanent magnet (PM) synchronous machines are utilized in a wide variety of applications due to their many desirable characteristics, including high torque density capability and high efficiency. In ...the near future, however, the demand for the PM rare earth materials is projected to exceed world production. As a result, electric machines that do not rely on rare earth materials, such as wound field synchronous machines (WFSMs), are receiving renewed attention for use in traction and wind energy applications. However, WFSMs require a current delivery mechanism to the rotor such as mechanical slip rings whose components require periodic replacement and generate adverse debris within the machine enclosure. Rotary transformers may replace slip rings but also introduce rotor speed dependences and magnetic coupling difficulties. This paper proposes a capacitive noncontact power transfer technique to eliminate the need for mechanical slip rings while also avoiding the pitfalls of rotating transformer technologies. The capacitive power transfer system is compared to traditional rotor power coupling techniques and its performance is validated with experimental results.
In his 1973 article The Structure of ill structured problems, Herbert Simon proposed that solving ill-structured problems could be modeled within the same information-processing framework developed ...for solving well-structured problems. This claim is reexamined within the context of over 40 years of subsequent research and theoretical development. Well-structured (puzzle) problems can be represented by a problem space consisting of well-defined initial and goal states that are connected by legal moves. In contrast, the initial, goal, and intermediate states of ill-structured (design) problems are incompletely specified. This article analyzes the similarities and differences among puzzles, insight puzzles, classroom problems, and design problems within Gick's (Educational Psychologist, 21, 99–120, 1986) theoretical framework consisting of representation construction, schema activation, and heuristic search. The analysis supports Simon's (Artificial Intelligence, 4, 181–201, 1973) claim that information-processing principles apply to all problems but apply differently as problems become more ill structured.
The field of adeno-associated virus (AAV) gene therapy has progressed rapidly over the past decade, with the advent of novel capsid serotype and organ-specific promoters, and an increasing ...understanding of the immune response to AAV administration. In particular, liver-directed therapy has made remarkable strides, with a number of clinical trials currently planned and ongoing in hemophilia A and B, as well as other liver disorders. This review focuses on liver-directed AAV gene therapy, including historic context, current challenges, and future developments.
Uncovering the genetic and evolutionary basis of local adaptation is a major focus of evolutionary biology. The recent development of cost-effective methods for obtaining high-quality genome-scale ...data makes it possible to identify some of the loci responsible for adaptive differences among populations. Two basic approaches for identifying putatively locally adaptive loci have been developed and are broadly used: one that identifies loci with unusually high genetic differentiation among populations (differentiation outlier methods) and one that searches for correlations between local population allele frequencies and local environments (genetic-environment association methods). Here, we review the promises and challenges of these genome scan methods, including correcting for the confounding influence of a species’ demographic history, biases caused by missing aspects of the genome, matching scales of environmental data with population structure, and other statistical considerations. In each case, we make suggestions for best practices for maximizing the accuracy and efficiency of genome scans to detect the underlying genetic basis of local adaptation. With attention to their current limitations, genome scan methods can be an important tool in finding the genetic basis of adaptive evolutionary change.
There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta‐analyses of epidemiological data show that people with diabetes ...are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro‐inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered.
Breast cancer is the most commonly diagnosed malignancy in women, and has the second highest mortality rate. Over 90% of all cancer-related deaths are due to metastasis, which is the spread of ...malignant cells from the primary tumor to a secondary site in the body. It is hypothesized that one cause of metastasis involves epithelial-mesenchymal transition (EMT). When epithelial cells undergo EMT and transition into mesenchymal cells, they display increased levels of cell proliferation and invasion, resulting in a more aggressive phenotype. While many factors regulate EMT, microRNAs have been implicated in driving this process. MicroRNAs are short noncoding RNAs that suppress protein production, therefore loss of microRNAs may promote the overexpression of specific target proteins important for EMT. The goal of this study was to investigate the role of miR-96 and miR-183 in EMT in breast cancer. Both miR-96 and miR-183 were found to be downregulated in post-EMT breast cancer cells. When microRNA mimics were transfected into these cells, there was a significant decrease in cell viability and migration, and a shift from a mesenchymal to an epithelial morphology (mesenchymal-epithelial transition or MET). These MET-related changes may be facilitated in part by the regulation of ZEB1 and vimentin, as both of these proteins were downregulated when miR-96 and miR-183 were overexpressed in post-EMT cells. These findings indicate that the loss of miR-96 and miR-183 may help facilitate EMT and contribute to the maintenance of a mesenchymal phenotype. Understanding the role of microRNAs in regulating EMT is significant in order to not only further elucidate the pathways that facilitate metastasis, but also identify potential therapeutic options for preventing or reversing this process.
miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) ...correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
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