A Simple Continuous Measure of Credit Risk

This paper introduces a simple continuous measure of credit risk that associates to each firm a risk parameter related to the firm's risk-neutral default intensity. These parameters can be computed from quoted bond prices and allow assignment of credit ratings much finer than those provided by various rating agencies. We estimate the risk measures on a daily basis for a sample of US firms and compare them with the corresponding ratings provided by Moody's and the distance to default measures calculated using the Merton (1974) model. The three measures group the sample of firms into various risk classes in a similar but far from identical way, possibly reflecting the models' different forecasting horizons. Among the three measures, the highest rank correlation is found between our continuous measure and Moody's ratings. The techniques in this paper can be used to extract the entire distribution of inter-temporal risk-neutral default intensities which is useful for time-to-default estimators as well as for pricing credit derivatives.

Design and Synthesis of Small-molecule Inhibitors and Degraders for Brachyury and NEK1

In recent years, the discovery and characterization of various small-molecule binding proteins have shed valuable insights into the molecular mechanisms underlying biological processes and the development of new strategies for the treatment of diseases.1 However, significant portions of the human proteome remain understudied, such as proteins implicated in the development and progression of rare diseases. Herein, we describe our efforts to study two unrelated, biologically understudied protein targets in chemical biology research using small molecule inhibitors and degraders: brachyury and NEK1. With the initial hit molecules identified from small-molecule fragment screening using X-ray crystallography, our team synthesized analogs of scaffolds such as lactams, quinazolines, benzamides, and benzimidazoles to target various binding pockets of brachyury. Following the development of lead compounds from these scaffolds, small-molecule degraders were developed by chemically linking lead inhibitors with cereblon, an E3 ligase that ubiquitinates target proteins for degradation via the ubiquitin- proteasome system.2 While the biological assay for testing the degradation capacities of these degraders was being developed, we began a separate project to develop inhibitors for the understudied protein Nima-related kinase 1 (NEK1) in hopes of investigating its role in various biological processes such as cell cycle control, ciliopathies, and cancer.3Bachelor of Scienc

Isolation and characterization of a new population of nasal surface macrophages and their susceptibility to PRRSV-1 subtype 1 (LV) and subtype 3 (Lena).

Sialoadhesin (Sn) and CD163 have been recognized as two important mediators for porcine reproductive and respiratory syndrome virus (PRRSV) in host macrophages. Recently, it has been demonstrated that the highly virulent Lena strain has a wider macrophage tropism than the low virulent LV strain in the nasal mucosa. Not only CD163(+)Sn(+) macrophages are infected by Lena but also CD163(+)Sn(-) macrophages. This suggests that an alternative receptor exists for binding and internalization of PRRSV Lena in the CD163(+)Sn(-) macrophages. Further investigation to find the new entry receptor was hampered by the difficulty of isolating these macrophages from the nasal mucosa. In the present study, a new population of CD163(+)Sn(-) cells has been identified that is specifically localized in the nasal lamina propria and can be isolated by an intranasal digestion approach. Isolated nasal cells were characterized using specific cell markers and their susceptibility to two different PRRSV-1 strains (LV and Lena) was tested. Upon digestion, 3.2% (flow cytometry)-6.4% (confocal microscopy) of the nasal cells were identified as CD163(+) and all (99.7%) of these CD163(+) cells were Sn-. These CD163(+)Sn(-) cells, designated as "nasal surface macrophages", showed a 4.9 times higher susceptibility to the Lena strain than to the LV strain. Furthermore, the Lena-inoculated cell cultures showed an upregulation of CD163. These results showed that our new cell isolation system is ideal for the further functional and phenotypical analysis of the new population of nasal surface macrophages and further research on the molecular pathogenesis of PRRSV in the nose

Life at the extreme: Lessons from the genome

© 2012 BioMed Central Ltd. Extremophile plants thrive in places where most plant species cannot survive. Recent developments in high-throughput technologies and comparative genomics are shedding light on the evolutionary mechanisms leading to their adaptation

Epidemiology of depression with psychotic experiences and its association with chronic physical conditions in 47 low- and middle-income countries

BACKGROUND: The co-existence of depression and psychotic experiences (PEs) is associated with more pronounced adverse health outcomes compared to depression alone. However, data on its prevalence and correlates are lacking in the general adult population, and there is no published data on its association with chronic physical conditions. METHOD: Cross-sectional, community-based data from 201 337 adults aged ⩾18 years from 47 low- and middle-income countries from the World Health Survey were analyzed. The presence of past 12-month PE and DSM-IV depression was assessed with the Composite International Diagnostic Interview (CIDI). Information on six chronic medical conditions (chronic back pain, edentulism, arthritis, angina, asthma, diabetes) were obtained by self-report. Multivariable logistic regression analysis was performed. RESULTS: The crude overall prevalence of co-morbid depression/PEs was 2.5% [95% confidence interval (CI) 2.3-2.7%], with the age- and sex-adjusted prevalence ranging from 0.1% (Sri Lanka, Vietnam) to 9.03% (Brazil). Younger age, urban setting, current smoking, alcohol consumption, and anxiety were significant correlates of co-existing depression/PEs. Co-occurring depression/PEs was associated with significantly higher odds for arthritis, angina, and diabetes beyond that of depression alone after adjusting for sociodemographics, anxiety, and country, with odds ratios (depression/PEs v. depression only) being: arthritis 1.30 (95% CI 1.07-1.59, p = 0.0086); angina 1.40 (95% CI 1.18-1.67, p = 0.0002); diabetes 1.65 (95% CI 1.21-2.26, p = 0.0017). CONCLUSIONS: The prevalence of co-existing depression/PEs was non-negligible in most countries. Our study suggests that when depression/PE or a chronic condition (e.g. arthritis, angina, diabetes) is detected, screening for the other may be important to improve clinical outcomes

Health conditions and psychotic experiences: Cross-sectional findings from the American Life Panel

Background: People with psychotic disorders have poor health, but studies have shown that people who have a milder and more prevalent form of psychosis (psychotic experiences) are also at risk for health problems. More research is needed to examine a broad range of health conditions to discover new relations with psychotic experiences. Methods: We analyzed cross-sectional data from the American Life Panel, a nationally representative sample of the United States adult population. Using multivariable logistic regression, we examined the associations between health conditions (categories of conditions, specific conditions, count of conditions) and lifetime psychotic experiences. Results: Approximately 71% of the weighted sample reported at least one health condition, and around 18% reported a lifetime psychotic experience. Using multivariable logistic regression, we found that several health conditions were associated with psychotic experiences, including pain due to other causes, neck pain, other injury, any gastrointestinal/kidney problem, liver diseases/cirrhosis, any nervous/sensory problem, migraine, nerve problem causing numbness/pain, any other disorder, specifically sleep disorder, chronic fatigue syndrome, and chronic pain. Further, the count of specific health conditions and the count of categories were associated with greater odds of psychotic experiences. Conclusion: We found that numerous health conditions were associated with psychotic experiences

Intracellular consequences of SOS1 deficiency during salt stress

A mutation of AtSOS1 (Salt Overly Sensitive 1), a plasma membrane Na+/H+-antiporter in Arabidopsis thaliana, leads to a salt-sensitive phenotype accompanied by the death of root cells under salt stress. Intracellular events and changes in gene expression were compared during a non-lethal salt stress between the wild type and a representative SOS1 mutant, atsos1-1, by confocal microscopy using ion-specific fluorophores and by quantitative RT-PCR. In addition to the higher accumulation of sodium ions, atsos1-1 showed inhibition of endocytosis, abnormalities in vacuolar shape and function, and changes in intracellular pH compared to the wild type in root tip cells under stress. Quantitative RT-PCR revealed a dramatically faster and higher induction of root-specific Ca2+ transporters, including several CAXs and CNGCs, and the drastic down-regulation of genes involved in pH-homeostasis and membrane potential maintenance. Differential regulation of genes for functions in intracellular protein trafficking in atsos1-1 was also observed. The results suggested roles of the SOS1 protein, in addition to its function as a Na+/H+ antiporter, whose disruption affected membrane traffic and vacuolar functions possibly by controlling pH homeostasis in root cells

Genome structures and transcriptomes signify niche adaptation for the multiple-ion-tolerant extremophyte Schrenkiella parvula

Schrenkiella parvula (formerly Thellungiella parvula), a close relative of Arabidopsis (Arabidopsis thaliana) and Brassica crop species, thrives on the shores of Lake Tuz, Turkey, where soils accumulate high concentrations of multiple-ion salts. Despite the stark differences in adaptations to extreme salt stresses, the genomes of S. parvula and Arabidopsis show extensive synteny. S. parvula completes its life cycle in the presence of Na+, K+, Mg2+, Li+, and borate at soil concentrations lethal to Arabidopsis. Genome structural variations, including tandem duplications and translocations of genes, interrupt the colinearity observed throughout the S. parvula and Arabidopsis genomes. Structural variations distinguish homologous gene pairs characterized by divergent promoter sequences and basal-level expression strengths. Comparative RNA sequencing reveals the enrichment of ion-transport functions among genes with higher expression in S. parvula, while pathogen defense-related genes show higher expression in Arabidopsis. Key stress-related ion transporter genes in S. parvula showed increased copy number, higher transcript dosage, and evidence for subfunctionalization. This extremophyte offers a framework to identify the requisite adjustments of genomic architecture and expression control for a set of genes found in most plants in a way to support distinct niche adaptation and lifestyles. © 2014 American Society of Plant Biologists. All rights reserved

The Environment of Birthplace and Self-Reported Mental Health Conditions: Findings from the American Panel of Life

Studies from around the globe have found that urbanicity is associated with greater risk for certain psychiatric disorders, though the association has been less evident in the United States. We analyzed data collected in 2019 from the RAND American Life Panel (n = 2554), which were representative of the general adult population of the United States. Using multivariable logistic regression, we examined the associations between environment of birthplace (large urban, small urban, suburban, rural) and psychiatric disorders, adjusting for sociodemographic characteristics. We found that being born in a large urban area was associated with greater odds of having any psychiatric disorder when compared with being born in a rural area. However, when looking at specific disorders, we found that being born in a large urban area was only significantly associated greater odds of anxiety disorder and post-traumatic stress disorder (PTSD), but was not associated with bipolar disorder, major depressive disorder, attention deficit/hyperactivity disorder, or alcohol/substance use disorder. Being born in a small urban area was marginally associated with anxiety disorder. Future studies should examine why urban birthplace has only been associated with anxiety disorders and PTSD in the United States, and why urbanicity is associated with mood disorders in other parts of the world but not in the United States