Non-Uniform Smoothness for Gradient Descent

The analysis of gradient descent-type methods typically relies on the Lipschitz continuity of the objective gradient. This generally requires an expensive hyperparameter tuning process to appropriately calibrate a stepsize for a given problem. In this work we introduce a local first-order smoothness oracle (LFSO) which generalizes the Lipschitz continuous gradients smoothness condition and is applicable to any twice-differentiable function. We show that this oracle can encode all relevant problem information for tuning stepsizes for a suitably modified gradient descent method and give global and local convergence results. We also show that LFSOs in this modified first-order method can yield global linear convergence rates for non-strongly convex problems with extremely flat minima, and thus improve over the lower bound on rates achievable by general (accelerated) first-order methods

Cross-cultural comparison of genetic and cultural transmission of smoking initiation using an extended twin kinship model

Background: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent–offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. Methods: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime ‘ever’ smoking measure was obtained from twins and relatives in the ‘Virginia 30,000’ sample and the ‘Australian 25,000’. Results: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent–offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. Conclusions: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI

Committee Reports

Contains reports from the following committees of the Washington State Bar Association: Administrative Law, Civil Rights, Code Commission, Cooperation with American Bar Association, Federal Legislation, Improvement of Probate Statutes, Law Examiners, Legal Education, Legal Ethics, Legal Institutes, Legislative, Obituary, Selection of Judges, and Unauthorized Practice of Law. Also includes the auditor\u27s report

The Role of Protein Kinase C Epsilon in the Regulation of Endothelial Nitric Oxide Synthase (eNOS) during Oxidative Stress caused by Extracorporeal Shock Wave Lithotripsy (ESWL)

BACKGROUND: Clinical ESWL treatment to ablate kidney stones can cause acute to chronic damage in renal microvasculature leading to decreased renal blood flow and hypertension. Shockwaves can stimulate endothelial cells to release superoxide resulting in decreased nitric oxide (NO) bioavailability and increased oxidative stress, causing vascular endothelial dysfunction in the kidney. When the dihydrobiopterin:tetrahydrobiopterin ratio is increased during oxidative stress such as ESWL, eNOS becomes uncoupled and produces superoxide instead of NO. Superoxide is converted to hydrogen peroxide (H2O2) by superoxide dismutase. Protein kinase C epsilon (PKC-ε) is known to positively regulate endothelial NO synthase (eNOS) activity. In order to establish controls for the effects of PKC-ε activator and inhibitor, the effect of ESWL was tested by the comparison of ESWL-treated rats to those with no ESWL exposure, both with a saline infusion. We hypothesized that the PKC-ε peptide inhibitor (Myr-EAVSLKPT, MW = 1054.6) would decrease ESWL-induced H2O2 release and decreased the attenuation of NO release compared to ESWL-saline control rats. PKC-ε activator (Myr-NDAPIGYD, MW = 1098.5) was expected to show no effect on H2O2 or NO release, displaying a similar trend to ESWL-saline control rats

Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series

Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block. Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel functional roles for genes determining tissue-specific metabolism

The Effects of Modulating Endothelial Nitric Oxide Synthese (eNOS) Activity and Coupling in Extracorporeal Shock Wave Lithotripsy (ESWL)

Introduction: ESWL is a clinical therapy to break down kidney and uretal stones into smaller fragments that are more easily eliminated through the urinary tract. High-energy shock waves are focused on the stone to cause shear stress and cavitation bubbles which synergistically ablate the stones. While ESWL is the preferred treatment for kidney stones over invasive surgeries, the repetitive shock waves necessary to break up the stones may also cause damage to the renal vasculature endothelium and that can lead to chronic hypertension [1]. Previous studies have found that ESWL can cause endothelial dysfunction which is characterized decreased nitric oxide (NO) bioavailability and increased production of reactive oxygen species (ROS) such as superoxide (O2-) [2]. Normally, endothelial nitric oxide synthase (eNOS) is in a coupled state which forms NO in the presence of essential cofactor tetrahydrobiopterin (BH4) and molecular oxygen. Oxidative stress, such as that caused by ESWL-induced ROS, can cause BH4 to be oxidized to dihydrobiopterin (BH2). When the BH2:BH4 ratio is increased, eNOS becomes uncoupled and produces O2- instead of NO [2, 3] (Figure 1). O2- is short-lived and converted to hydrogen peroxide (H2O2) in blood by superoxide dismutase. Protein kinase C epsilon (PKCε) has previously been found to regulate eNOS activity via phosphorylation at serine-1177. Cell-permeable PKCε peptide activator (PKCε+) increases eNOS activity while PKCε inhibitor (PKCε-) reduces eNOS activity [2]. Using a combination of eNOS cofactors BH4 or BH2 with eNOS activity regulators PKCε+ or PKCε-, we can explore the role of modulating eNOS to reduce oxidative stress and endothelial dysfunction caused by ESWL

The Role of Endothelial Nitric Oxide Synthase (eNOS) Uncoupling on Leukocyte-Endothelial Interactions in Rat Mesenteric Postcapillary Venules

BACKGROUND: Endothelial derived nitric oxide (NO) is essential in the regulation of blood pressure and attenuates leukocyte-endothelial interactions associated with vascular injury. Endothelial NO synthase (eNOS) is coupled to L-arginine in the presence of tetrahydrobiopetrin (BH4) to produce NO. However, when BH4 is oxidized to dihydrobiopetrin (BH2) under conditions of oxidative stress, the ratio of BH2 to BH4 is increased causing the uncoupling of eNOS to use molecular oxygen as a substrate, instead of L-arginine, to produce superoxide

Clinical characteristics of familial generalized anxiety disorder

The authors seek to determine whether the clinical characteristics of generalized anxiety disorder (GAD) differ in individuals with a high vs. low familial vulnerability to illness. We identified 486 personally interviewed female twins from a population‐based register who had both an interviewed co‐twin and a lifetime history of GAD using modified DSM‐III‐R criteria which required a one‐month minimum duration of illness. We attempted to predict risk for GAD in the co‐twin from the clinical features of the GAD in the proband twin using the Cox proportional hazard model, controlling for year of birth and zygosity. Only two variables uniquely predicted an increased risk for GAD in the co‐twin: number of GAD symptoms endorsed and comorbidity with bulimia. Variables that did not uniquely predict risk of illness in the co‐twin included age at onset, duration of the longest episode and number of episodes. The familial vulnerability to GAD can be meaningfully indexed by clinical features of the syndrome. These results suggest that if the syndrome of GAD is to be narrowed, it would, from a familial perspective, be more valid to increase the minimum number of required symptoms rather than to increase the minimum duration of illness. Anxiety 1:186–191 (1994/1995). © 1995 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101797/1/3070010407_ftp.pd

The Effects of Dihydrobiopterin and Tetrahydrobiopterin on Hydrogen Peroxide and Nitric Oxide Release During Extracorporeal Shockwave Lithotripsy

Extracorporeal shockwave lithrotripsy (ESWL) is an effective, non-invasive clinical therapy utilized to break up stones in the kidney and urinary tract. A lithotripter generates high-energy acoustic pulses and propagates those shock waves through a lens on a region that focuses on the location of the stone, in turn breaking up the stone. The successive pulses generate shearing forces and cavitation bubbles. Cavitation bubbles are the formation and implosion of liquid free zones. The cavitation bubbles implode rapidly to create their own shockwaves that also put pressure on the stone. After treatment, fragmentation of the stone allows the debris to be cleared by the flow of the urinary tract. The problem is that to break up the kidney stone, it requires many repetitive shock waves that not only hit the kidney stone but also the surrounding tissue. Although lithotripsy provides a safer alternative to invasive treatments for removing harmful stones, ESWL may cause prolonged vasoconstriction after ESWL treatment, reducing renal blood flow, and subsequent endothelial dysfunction, which may cause kidney damage leading to acute to chronic hypertension clinically. ESWL-induced vascular oxidative stress and further endothelial dysfunction may be mediated by reduced levels of endothelial-derived nitric oxide (NO) and/or increased reactive oxygen species. Previous studies have shown that ESWL can induce oxidative stress, which can cause an increase in blood hydrogen peroxide (H2O2) and a decrease in endothelial-derived NO bioavailability release. Under normal conditions, tetrahydrobiopterin (BH4) is the cofactor to promote eNOS coupling, and endothelial-derived NO is produced. When the dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) ratio is increased during oxidative stress, such as ESWL, BH2 promotes eNOS uncoupling and produces superoxide (SO) instead of NO. (1,2) (Figure 1) SO is then later converted to H2O2 by superoxide dismutase. BH4 and BH2 bind to eNOS with equal affinity, therefore the ratio will determine whether eNOS principally produces NO or SO

A review of size and geometrical factors influencing resonant frequencies in metamaterials

Although metamaterials and so-called left-handed media have originated from theoretical considerations, it is only by their practical fabrication and the measurement of their properties that they have gained credibility and can fulfil the potential of their predicted properties. In this review we consider some of the more generally applicable fabrication methods and changes in geometry as they have progressed, exhibiting resonant frequencies ranging from radio waves to the visible optical region