Kinetics and Inhibition Studies of the L205R Mutant of cAMP-Dependent Protein Kinase Involved in Cushing’s Syndrome

Overproduction of cortisol by the hypothalamus–pituitary–adrenal hormone system results in the clinical disorder known as Cushing\u27s syndrome. Genomics studies have identified a key mutation (L205R) in the α‐isoform of the catalytic subunit of cAMP‐dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone‐independent Cushing\u27s syndrome. Here, we conducted kinetics and inhibition studies on the L205R‐PKACα mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (kcat/KM) for each substrate by 12‐fold and 4.5‐fold, respectively. We have also determined the IC50 and Ki for the peptide substrate‐competitive inhibitor PKI(5–24) and the ATP‐competitive inhibitor H89. The L205R mutation had no effect on the potency of H89, but causes a \u3e 250‐fold loss in potency for PKI(5–24). Collectively, these data provide insights for the development of L205R‐PKACα inhibitors as potential therapeutics

LoCoH: nonparameteric kernel methods for constructing home ranges and utilization distributions.

Parametric kernel methods currently dominate the literature regarding the construction of animal home ranges (HRs) and utilization distributions (UDs). These methods frequently fail to capture the kinds of hard boundaries common to many natural systems. Recently a local convex hull (LoCoH) nonparametric kernel method, which generalizes the minimum convex polygon (MCP) method, was shown to be more appropriate than parametric kernel methods for constructing HRs and UDs, because of its ability to identify hard boundaries (e.g., rivers, cliff edges) and convergence to the true distribution as sample size increases. Here we extend the LoCoH in two ways: "fixed sphere-of-influence," or r-LoCoH (kernels constructed from all points within a fixed radius r of each reference point), and an "adaptive sphere-of-influence," or a-LoCoH (kernels constructed from all points within a radius a such that the distances of all points within the radius to the reference point sum to a value less than or equal to a), and compare them to the original "fixed-number-of-points," or k-LoCoH (all kernels constructed from k-1 nearest neighbors of root points). We also compare these nonparametric LoCoH to parametric kernel methods using manufactured data and data collected from GPS collars on African buffalo in the Kruger National Park, South Africa. Our results demonstrate that LoCoH methods are superior to parametric kernel methods in estimating areas used by animals, excluding unused areas (holes) and, generally, in constructing UDs and HRs arising from the movement of animals influenced by hard boundaries and irregular structures (e.g., rocky outcrops). We also demonstrate that a-LoCoH is generally superior to k- and r-LoCoH (with software for all three methods available at http://locoh.cnr.berkeley.edu)

Phase Transitions on Nonamenable Graphs

We survey known results about phase transitions in various models of statistical physics when the underlying space is a nonamenable graph. Most attention is devoted to transitive graphs and trees

Legal Authority and Limitations

The core element for emergency involuntary commitment is dangerousness to oneself or others. Statutes typically also mandate immediate or near immediate petition to the courts, and require immediate or near immediate professional psychiatric review. This chapter reviews the case law associated with civil commitment statutes, both historically and in terms of current issues

Predictors of Juvenile Court Dispositions in a First-Time Offender Population

Scholars and policy makers have long been troubled by the potential for some youth to receive disparate sanctioning as a function of extralegal factors, especially against the backdrop of ethnic/racial minority group overrepresentation in the juvenile justice system as a whole. Beginning in the late 1990s, many states began to adopt a graduated sanctions model in response to the emerging ‘get tough’ zeitgeist of the day. Originally intended by the federal government to reinforce juvenile accountability and to ensure equitable treatment of all youth in custody, some stakeholders began to note concerns about uneven outcomes in the use of graduated sanctioning schemes. Specifically, data across multiple jurisdictions suggested that racial and ethnic minority youth were receiving more restrictive than expected sanctions. The current study in one large urban jurisdiction explored this issue in a group of 2,786 racially and ethnically diverse first-time juvenile male offenders (ages 10-17). Results indicated that race/ethnicity was not a predictor of receiving a more restrictive than expected sanction; however, variables related to offending (offense severity, history of violence), age (older), and parental supervision (inadequate) were significant predictors of such departures

Ethical Issues in Conducting Forensic Evaluations

The role of the forensic mental health professional (MHP) often differs substantially from that of the typical clinician. These differences bear directly on the ethical delivery of services

Scattering statistics of rock outcrops: Model-data comparisons and Bayesian inference using mixture distributions

The probability density function of the acoustic field amplitude scattered by the seafloor was measured in a rocky environment off the coast of Norway using a synthetic aperture sonar system, and is reported here in terms of the probability of false alarm. Interpretation of the measurements focused on finding appropriate class of statistical models (single versus two-component mixture models), and on appropriate models within these two classes. It was found that two-component mixture models performed better than single models. The two mixture models that performed the best (and had a basis in the physics of scattering) were a mixture between two K distributions, and a mixture between a Rayleigh and generalized Pareto distribution. Bayes' theorem was used to estimate the probability density function of the mixture model parameters. It was found that the K-K mixture exhibits significant correlation between its parameters. The mixture between the Rayleigh and generalized Pareto distributions also had significant parameter correlation, but also contained multiple modes. We conclude that the mixture between two K distributions is the most applicable to this dataset.Comment: 15 pages, 7 figures, Accepted to the Journal of the Acoustical Society of Americ

Spasmodic dysphonia may respond to bilateral thalamic deep brain stimulation

Background Spasmodic dysphonia is a primary focal dystonia manifested by loss of control of the vocal muscles during speech secondary to laryngeal muscle spasms. The pathophysiology is not well understood. Deep brain stimulation surgery (DBS) for other focal dystonias has been well reported. Methods We report the first case of bilateral thalamic DBS improving spasmodic dystonia (SD) in a patient with essential tremor.Results This case demonstrates the beneficial of effects of bilateral thalamic DBS for both ET of the hands and AdSD of the vocal cords.Conclusions The potential pathophysiologic mechanisms of this finding are discussed

Load Sharing in Gravel Decked Log Stringer Bridges

Log bridges are an economical alternative to steel and concrete structures for temporary crossings; however, reduced availability of large logs for stringers and the advancing age of existing log bridges increases the importance of structural analysis. Load sharing between the stringers is complicated and can result from load spread due to the gravel deck, cable lashing, and mechanical interlocking and friction between the stringers. This paper describes the development of a finite element model (FEM) for gravel decked log stringer bridges that includes elements capable of transferring vertical loads between the stringers. The FEM was used to interpret load deflection data from two in-situ bridges. The results of this paper suggest the segments of lashing that pass under one stringer and over an adjacent stringer contribute to load sharing between the stringers; however, care must be taken to ensure that the pattern of lashing supports the stringers directly loaded by the live loads