Enhancing financial stability: the case of financial market utilities

The sweeping overhaul of the nation’s financial regulatory system that was signed into law on July 21, 2010, will touch virtually every aspect of financial markets. This Chicago Fed Letter focuses on provisions in the Dodd–Frank Wall Street Reform and Consumer Protection Act that affect “financial market utilities,” critical behind-the-scenes institutions and arrangements that ensure the smooth functioning of financial markets.Financial crises ; Financial markets

Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain

Tyro3, a member of TAM receptor tyrosine kinase family, has been implicated in the regulation of melanoma progression and survival. In this study, we sought the molecular mechanism of Tyro3 effects avoiding endogenous background by overexpression of Tyro3 in fibroblasts that have negligible levels of Tyro3. This introduction triggers the tyrosyl-phosphorylation of ACTN4, a member of actin binding protein family involved in motility, a behavior critical for invasive progression, as shown by siRNA to Tyro3 limiting melanoma cell migration and invasion. Tyro3-mediated phosphorylation of ACTN4 required FAK activation at tyrosine 397 and the EGF receptor cascade, but not EGFR ligand binding. Using PCR-based mutagenesis, the sites of Tyro3-mediated ACTN4 phosphorylation were mapped to ACTN4 tyrosine 11 and 13, and this occurs in conjunction with EGF-mediated phosphorylation on Y4 and Y31. Interestingly, Tyro3-mediated phosphorylation only slightly decreases the actin binding activity of ACTN4. However, this rendered the phosphorylated ACTN4 resistant to the m-calpain cleavage between Y13 and G14, a limited proteolysis that prevents growth factor regulation of ACTN4 interaction with F-actin. Overexpression of both WT ACTN4 and ACTN4Y11/13E, a mimic of ACTN4 phosphorylated at tyrosine 11 and 13, in melanoma WM983b cells resulted in a likely mesenchymal to amoeboidal transition. ACTN4Y11/13E-expressing cells were more amoeboidal, less migratory on collagen I gel coated surface but more invasive through collagen networks. In parallel, expression of ACTN4Y11/13E, in ACTN4 knockdown melanoma WM1158 cells resulted in an increase of invasion compared to WT ACTN4. These findings suggest that Tyro3-mediated phosphorylation of ACTN4 is involved in invasion of melanoma cells. Keywords: Actinin-4; Tyro3; Phosphorylation; Migratio

High stakes and low bars: How international recognition shapes the conduct of civil wars

When rebel groups engage incumbent governments in war for control of the state, questions of international recognition arise. International recognition determines which combatants can draw on state assets, receive overt military aid, and borrow as sovereigns—all of which can have profound consequences for the military balance during civil war. How do third-party states and international organizations determine whom to treat as a state's official government during civil war? Data from the sixty-one center-seeking wars initiated from 1945 to 2014 indicate that military victory is not a prerequisite for recognition. Instead, states generally rely on a simple test: control of the capital city. Seizing the capital does not foreshadow military victory. Civil wars often continue for many years after rebels take control and receive recognition. While geopolitical and economic motives outweigh the capital control test in a small number of important cases, combatants appear to anticipate that holding the capital will be sufficient for recognition. This expectation generates perverse incentives. In effect, the international community rewards combatants for capturing or holding, by any means necessary, an area with high concentrations of critical infrastructure and civilians. In the majority of cases where rebels contest the capital, more than half of its infrastructure is damaged or the majority of civilians are displaced (or both), likely fueling long-term state weakness

In silico and structural analyses demonstrate that intrinsic protein motions guide T cell receptor complementarity determining region loop flexibility

T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 Å in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions

The Impact and Cost-Effectiveness of a Four-Month Regimen for First-Line Treatment of Active Tuberculosis in South Africa.

BACKGROUND: A 4-month first-line treatment regimen for tuberculosis disease (TB) is expected to have a direct impact on patient outcomes and societal costs, as well as an indirect impact on Mycobacterium tuberculosis transmission. We aimed to estimate this combined impact in a high TB-burden country: South Africa. METHOD: An individual based M. tb transmission model was fitted to the TB burden of South Africa using a standard TB natural history framework. We measured the impact on TB burden from 2015-2035 of introduction of a non-inferior 4-month regimen replacing the standard 6-month regimen as first-line therapy. Impact was measured with respect to three separate baselines (Guidelines, Policy and Current), reflecting differences in adherence to TB and HIV treatment guidelines. Further scenario analyses considered the variation in treatment-related parameters and resistance levels. Impact was measured in terms of differences in TB burden and Disability Adjusted Life Years (DALYs) averted. We also examined the highest cost at which the new regimen would be cost-effective for several willingness-to-pay thresholds. RESULTS: It was estimated that a 4-month regimen would avert less than 1% of the predicted 6 million person years with TB disease in South Africa between 2015 and 2035. A similarly small impact was seen on deaths and DALYs averted. Despite this small impact, with the health systems and patient cost savings from regimen shortening, the 4-month regimen could be cost-effective at $436 [NA, 5983] (mean [range]) per month at a willingness-to-pay threshold of one GDP per capita ($6,618). CONCLUSION: The introduction of a non-inferior 4-month first-line TB regimen into South Africa would have little impact on the TB burden. However, under several scenarios, it is likely that the averted societal costs would make such a regimen cost-effective in South Africa

The JPSS-1 CrIS Instrument: Successful First-Year On-Orbit

No abstract availabl

Substance misuse in personality disorder and schizophrenia : findings and clinical implications from a high secure hospital

Purpose Substance misuse (SMU) is widely prevalent in mentally disordered offenders and is linked with violence and offending behaviour. There is however, a scarcity of literature dedicated to investigating SMU and its clinical correlates in relation to patients detained within high secure hospital settings. The purpose of this paper is to investigate the extent and severity of SMU and corresponding treatment needs in patients with a primary diagnosis of personality disorder (PD) in comparison with mental illness (MI) in a high secure hospital. Design/methodology/approach The responsible clinicians of all patients (n=240) detained in a high secure hospital were asked to record information using a SMU screening questionnaire over a ten-month period. Details requested included substance type, history of past use and assessment and treatment needs. Data were recorded and then analysed: descriptive statistics were conducted to report historical use of substances, cross tabulations and χ2 analysis explored the relationship between SMU and treatment status and diagnosis and offending behaviour and a means comparison analysis was employed to explore length of stay and treatment of SMU. Findings A total of 230 questionnaires were returned (95 per cent of the patient population). A history of SMU was reported in 88.6 per cent of the sample, with alcohol and cannabis misuse being the most prevalent. At least one substance had been abused by 74.3 per cent of the sample. In two-thirds of the sample, SMU was linked with the onset of mental health problems and symptom exacerbation, including violence. Interestingly, patients with a diagnosis of MI as compared with PD were more likely to have used substances (93.3 per cent compared to 81.9 per cent) and were more likely to need treatment for SMU (64.3 per cent compared to 36.8 per cent). In those with an MI diagnosis, SMU was more likely to be linked with violence and index offence (74.3 per cent compared to 59.0 per cent). Practical implications SMU is significantly prevalent in high risk mentally disordered offenders and linked to onset of mental health problems and offending. Patients with schizophrenia have a higher prevalence of SMU than PD and are likely to be more in need of treatment. Violence and offending are more likely to be related to SMU in schizophrenia than in PD. Originality/value This study substantiates existing evidence that SMU contributes to mental health problems and criminogenic behaviour. Furthermore, the study reports new findings that characterize differences of the relationship of SMU to offending in schizophrenia and PD in forensic psychiatric patients presenting to a high secure hospital. </jats:sec

Two-Dimensional Electronic Spectroscopy of Chlorophyll a: Solvent Dependent Spectral Evolution

The interaction of the monomeric chlorophyll Q-band electronic transition with solvents of differing physical-chemical properties is investigated through two-dimensional electronic spectroscopy (2DES). Chlorophyll constitutes the key chromophore molecule in light harvesting complexes. It is well-known that the surrounding protein in the light harvesting complex fine-tunes chlorophyll electronic transitions to optimize energy transfer. Therefore, an understanding of the influence of the environment on the monomeric chlorophyll electronic transitions is important. The Q-band 2DES is inhomogeneous at early times, particularly in hydrogen bonding polar solvents, but also in nonpolar solvents like cyclohexane. Interestingly this inhomogeneity persists for long times, even up to the nanosecond time scale in some solvents. The reshaping of the 2DES occurs over multiple time scales and was assigned mainly to spectral diffusion. At early times the reshaping is Gaussian-like, hinting at a strong solvent reorganization effect. The temporal evolution of the 2DES response was analyzed in terms of a Brownian oscillator model. The spectral densities underpinning the Brownian oscillator fitting were recovered for the different solvents. The absorption spectra and Stokes shift were also properly described by this model. The extent and nature of inhomogeneous broadening was a strong function of solvent, being larger in H-bonding and viscous media and smaller in nonpolar solvents. The fastest spectral reshaping components were assigned to solvent dynamics, modified by interactions with the solute