Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
72
result(s) for
"Guglielmo, Mark"
Sort by:
The Contribution of Economists to Military Intelligence During World War II
Economists played a crucial role in military intelligence during World War II. Economists working at the Office of Strategic Services estimated enemy battle casualties, analyzed the intentions and capabilities of both enemies and allies, and helped to prepare for negotiations regarding the postwar settlement. Economists working at the Enemy Objectives Unit helped to select enemy targets for bombing. Finally, economists working at the Statistical Research Group worked on a variety of problems brought to them by the U.S. military services. As a consequence of their usefulness during the war, the military continued to employ economists after the war.
Journal Article
Government and the American economy
The American economy has provided a level of well-being that has consistently ranked at or near the top of the international ladder. A key source of this success has been widespread participation in political and economic processes. In The Government and the American Economy, leading economic historians chronicle the significance of America’s open-access society and the roles played by government in its unrivaled success story. America’s democratic experiment, the authors show, allowed individuals and interest groups to shape the structure and policies of government, which, in turn, have fostered economic success and innovation by emphasizing private property rights, the rule of law, and protections of individual freedom. In response to new demands for infrastructure, America’s federal structure hastened development by promoting the primacy of states, cities, and national governments. More recently, the economic reach of American government expanded dramatically as the populace accepted stronger limits on its economic freedoms in exchange for the increased security provided by regulation, an expanded welfare state, and a stronger national defense.
eBook
Illinois state bank failures in the Great Depression
In the four years between June 29, 1929 and June 30, 1933, almost half of the state banks in Illinois went out of business. This fact is even more remarkable given the amount of deposits that would have to be withdrawn to threaten a bank. A comparison of the June 29, 1929 balance sheets of failing and solvent banks reveals that banks with more of their portfolios invested in liquid assets such as U.S. government bonds and less invested in real estate were significantly less likely to fail. Banks with more capital and higher retained earnings were also less likely to fail. Chicago banks holding more of the deposits of other banks were also less likely to fail, perhaps indicating that bankers knew who the high risks were. However, evidence on deposits suggests that the public did not possess such information. But the most important predictor of bank failure during the Great Depression was the failure rate in the county in which a bank was located in, perhaps indicating that many failures were due to panic. This was not the case during the 1920s, in which there were no panics despite a large number of bank failures by the standards of the time. Contrary to the arguments of proponents of the Glass-Steagall Act, it is not found that banks involved in investment banking were more likely to fail. It is also not found that banks who got loans from the Reconstruction Finance Corporation that were disclosed were more likely to fail, but the reason for this is uncertain. A comparison of state banks across the United States reveals that states whose banks had more liquid assets, more capital and less real estate had significantly lower bank failure rates. State regulation that prohibited branch banking may have contributed to instability.
Dissertation
The Gilded Age
The Gilded Age was fraught with paradox. On the one hand, it was a period of economic centralization and integration; on the other, it was a period of social fragmentation and isolation. This paradox—this inevitable conflict between economic integration and social anomie, between the rise of big business and the ruination of smaller enterprises—runs through most of the major regulatory and legislative changes in the United States during the late nineteenth century. This chapter examines the changes at all levels of government during the Gilded Age. It looks at the turmoil in the agricultural sector of the economy, the rise of the Social Gospel movement, regulation of railroads and public utilities, antitrust laws and meat inspection, urbanization and state and local political economy, and patronage at the local level.
Book Chapter
Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis
Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR
S52P
. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α
2
-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.
ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.
Journal Article
Requirements for a global data infrastructure in support of CMIP6
The World Climate Research Programme (WCRP)'s Working Group on Climate Modelling (WGCM) Infrastructure Panel (WIP) was formed in 2014 in response to the explosive growth in size and complexity of Coupled Model Intercomparison Projects (CMIPs) between CMIP3 (2005–2006) and CMIP5 (2011–2012). This article presents the WIP recommendations for the global data infrastructure needed to support CMIP design, future growth, and evolution. Developed in close coordination with those who build and run the existing infrastructure (the Earth System Grid Federation; ESGF), the recommendations are based on several principles beginning with the need to separate requirements, implementation, and operations. Other important principles include the consideration of the diversity of community needs around data – a data ecosystem – the importance of provenance, the need for automation, and the obligation to measure costs and benefits.This paper concentrates on requirements, recognizing the diversity of communities involved (modelers, analysts, software developers, and downstream users). Such requirements include the need for scientific reproducibility and accountability alongside the need to record and track data usage. One key element is to generate a dataset-centric rather than system-centric focus, with an aim to making the infrastructure less prone to systemic failure.With these overarching principles and requirements, the WIP has produced a set of position papers, which are summarized in the latter pages of this document. They provide specifications for managing and delivering model output, including strategies for replication and versioning, licensing, data quality assurance, citation, long-term archiving, and dataset tracking. They also describe a new and more formal approach for specifying what data, and associated metadata, should be saved, which enables future data volumes to be estimated, particularly for well-defined projects such as CMIP6.The paper concludes with a future facing consideration of the global data infrastructure evolution that follows from the blurring of boundaries between climate and weather, and the changing nature of published scientific results in the digital age.
Journal Article
Prediction of myocardial blood flow under stress conditions by means of a computational model
Purpose
Quantification of myocardial blood flow (MBF) and functional assessment of coronary artery disease (CAD) can be achieved through stress myocardial computed tomography perfusion (stress-CTP). This requires an additional scan after the resting coronary computed tomography angiography (cCTA) and administration of an intravenous stressor. This complex protocol has limited reproducibility and non-negligible side effects for the patient. We aim to mitigate these drawbacks by proposing a computational model able to reproduce MBF maps.
Methods
A computational perfusion model was used to reproduce MBF maps. The model parameters were estimated by using information from cCTA and MBF measured from stress-CTP (MBF
CTP
) maps. The relative error between the computational MBF under stress conditions (MBF
COMP
) and MBF
CTP
was evaluated to assess the accuracy of the proposed computational model.
Results
Applying our method to 9 patients (4 control subjects without ischemia vs 5 patients with myocardial ischemia), we found an excellent agreement between the values of MBF
COMP
and MBF
CTP
. In all patients, the relative error was below 8% over all the myocardium, with an average-in-space value below 4%.
Conclusion
The results of this pilot work demonstrate the accuracy and reliability of the proposed computational model in reproducing MBF under stress conditions. This consistency test is a preliminary step in the framework of a more ambitious project which is currently under investigation, i.e., the construction of a computational tool able to predict MBF avoiding the stress protocol and potential side effects while reducing radiation exposure.
Journal Article
A novel mechano‐enzymatic cleavage mechanism underlies transthyretin amyloidogenesis
The mechanisms underlying transthyretin‐related amyloidosis
in vivo
remain unclear. The abundance of the 49–127 transthyretin fragment in
ex vivo
deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis
in vivo
. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.
Synopsis
Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
Shear forces are required to prime proteolysis of wild‐type and other variant TTRs and to release the amyloidogenic fragment.
These forces are present in the heart, offering an explanation for tissue specificity in cardiac TTR amyloidosis.
TTR stabilizers, currently used to treat amyloidosis, can inhibit this mechanism; however, their efficacy differs for each variant.
Graphical Abstract
Selective proteolysis of TTR generates a highly amyloidogenic truncated protomer. Shear stress generated by turbulent flow of physiological fluids makes TTR susceptible to cleavage. This mechanism may play a crucial role in the development of cardiac TTR amyloidosis, and offers new therapeutic targets for treating the disease.
Journal Article
CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing’s sarcoma
The post-genomic era has seen many advances inBaryza and G. Rice for helpful our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing’s sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing’s sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.
The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.
Journal Article