cssi/SciSciGPT-SciSciNet huggingface dataset:
HMG I/Y regulates long-range enhancer-dependent transcription on DNA and chromatin by changes in DNA topology

The nature of nuclear structures that are required to confer transcriptional regulation by distal enhancers is unknown. We show that long-range enhancer-dependent β-globin transcription is achieved in vitro upon addition of the DNA architectural protein HMG I/Y to affinity-enriched holo RNA polymerase II complexes. In this system, HMG I/Y represses promoter activity in the absence of an associated enhancer and strongly activates transcription in the presence of a distal enhancer. Importantly, nucleosome formation is neither necessary for long-range enhancer regulation in vitro nor sufficient without the addition of HMG I/Y. Thus, the modulation of DNA structure by HMG I/Y is a critical regulator of long-range enhancer function on both DNA and chromatin-assembled genes. Electron microscopic analysis reveals that HMG I/Y binds cooperatively to preferred DNA sites to generate distinct looped structures in the presence or absence of the β-globin enhancer. The formation of DNA topologies that enable distal enhancers to strongly regulate gene expression is an intrinsic property of HMG I/Y and naked DNA.
Almost all steinhaus graphs have diameter 2

A Steinhaus graph is a graph with n vertices whose adjacency matrix (ai, j) satisfies the condition that ai, j aa--1, j--1 + ai--1, j (mod 2) for each 1 < i < j ≤ n. It is clear that a Steinhaus graph is determined by its first row. In [3] Bringham and Dutton conjecture that almost all Steinhaus graphs have diameter 2. That is, as n approaches infinity, the ratio of the number of Steinhaus graphs with n vertices having diameter 2 to the total number of Steinhaus graphs approaches 1. Here we prove Bringham and Dutton's conjecture.
Effect of low dose‐rate prostate brachytherapy on the sexual health of men with optimal sexual function before treatment: analysis at ≥ 7 years of follow‐up

OBJECTIVE To evaluate the effect of low-dose rate prostate brachytherapy on the sexual health of men with ≥ 7 years of prospective evaluation and optimum sexual function before treatment. PATIENTS AND METHODS In all, 223 patients with T1b to T3a prostate cancer and a median (range) age of 66 (50–82) years were treated with permanent seed implantation from November 1990 to March 1998. They were followed for a median (range) of 8.2 (7–14.1) years using prospective quality-of-life measures. Erectile function (EF) was assessed using a physician-assigned score and beginning in June 2000; the validated International Index of EF (IIEF-5) was used as a complementary method to quantify late EF. No adjustment was made to differentiate sexual function with or with no pharmacological intervention for EF. Pearson’s chi-square test and Student’s t-test were used to compare the groups. RESULTS Of the 223 men, 131 (59%) had optimal EF before their brachytherapy; of these, 51 (40%) at the last follow-up evaluation were using either a phosphodiesterase type 5 inhibitor (44, 86%), yohimbine (two, 4%) or alprostadil (five, 10%). The age at implantation was highly predictive of current EF; 23 of 25 (92%) men aged 50–59 years had a current EF of ≥ 2; those aged 60–69 and 70–78 years had an EF of ≥2 in 48/75 (64%) and 18/31 (58%) (P = 0.01). A current IIEF-5 score of ≥ 16 also correlated highly with age at implant, i.e. 50–59, 16/25 (64%); 60–69, 20/75 (27%) and 70–78 years, 6/31 (19%) (P < 0.001). CONCLUSION Patients aged <60 years and with optimal EF before low-dose rate prostate brachytherapy have a very high probability of long-term EF.
Neuroimmune interactions in guinea pig stomach and small intestine

Enteric neuroimmune interactions in gastrointestinal hypersensitivity responses involve antigen detection by mast cells, mast cell degranulation, release of chemical mediators, and modulatory actio...
Design of incentive programs for accelerating penetration of energy-efficient appliances

Abstract Incentives are policy tools that sway purchase, retail stocking, and production decisions toward energy-efficient products. Incentives complement mandatory standards and labeling policies by accelerating market penetration of products that are more energy efficient than required by existing standards and by preparing the market for more stringent future mandatory requirements. Incentives can be directed at different points in the appliance׳s supply chain; one point may be more effective than another depending on the technology׳s maturity and market penetration. This paper seeks to inform future policy and program design by categorizing the main elements of incentive programs from around the world. We identify advantages and disadvantages of program designs through a qualitative overview of incentive programs worldwide. We find that financial incentive programs have greater impact when they target highly efficient technologies with a small market share, and that program designs depend on the market barriers addressed, the target equipment, and the local market context. No program design is inherently superior to another. The key to successful program design and implementation is a thorough understanding of the market and identification of the most important local obstacles to the penetration of energy-efficient technologies.
Lost in menuspace: user interactions with complex medical devices

The advent of fast-acting drugs has made the infusion pump the most pervasive electronic medical device in the acute care (hospital) environment. Despite the importance of its correct operation, incident reports in the US Food and Drug Administration (FDA) database implicate interface programming as a significant aspect of adverse outcomes. This article describes a study of infusion pump-programming performance by experienced healthcare professionals in a major urban teaching hospital. Early findings indicate that practitioner experience with device programming does not increase proficiency. This suggests that a complex menu structure ("menuspace") makes programming difficult and inefficient in ways that impede practitioner development of mental models that are sufficient for reliable device operation. This causes operators to become disoriented in the interface structure, or "lost in menuspace." We relate these findings to the current study of the USFDA adverse events reports and indicate directions for further research.
HUMAN EVOLUTIONARY PSYCHOLOGY: PARDON OUR DUST1

The study of human psychology and behavior from an evolutionary perspective is a work in progress, more like a construction site than a finished product. Whatever sets us apart as a species took place at most over the last few million years. The major evolutionary principles that guide the study of animal psychology and behavior must surely apply to us to some degree. In addition, the factors most often cited as alternatives to "biological" explanations, such as "culture," are themselves probably best understood from an evolutionary perspective. Just as Dobzhansky (1973) said that "nothing in biology makes sense except in the light of evolution," perhaps one day it will be said that "nothing in the human behavioral and social sciences makes sense except in the light of evolution.'" Alas, that day is still a gleam in the architect's eye. The current construction site looks more like naked scaffolding and pits in the ground. Why is progress so slow? At least three major factors can be identified: (1) Some of the scientific methods employed on other species are unavailable for humans for obvious ethical reasons; (2) Speculating about human nature is a notoriously touchy subject, not only for religious believers and postmodernists, but also for many psychologists and evolutionary biologists; and (3) Even those who have become enthusiastic about the project have difficulty agreeing with each other. In particular, the school of thought currently associated with the term "evolutionary psychology" (e.g., Barkow et al. 1992; Buss 1999; Cosmides and Tooby 2003; Gaulin and McBurney 2001) remains controversial among the larger community of scientists and scholars working on human psychology and behavior from an evolutionary perspective (Heyes and Huber 2000; Scher and Rauscher 2002). Human Evolutionary Psychology was written with the third factor in mind. Barrett, Dunbar, and Lycett (hereafter BDL) recount in the preface (p. xii) that "We had been teaching undergraduate courses in evolutionary psychology for nearly a decade and were frustrated by the fact that there was nothing we could use as a textbook that was sufficiently broad to cover all our interests." What they originally intended as "a gentle introduction to the literature" turned into an attempted synthesis of "a surprisingly fractionated field-not to say one that had become seriously misunderstood by both the popular press and academics in other fields (including evolutionary psychology's own parent disciplines, psychology and biology)." The result is a large volume that could serve
Climate variation is filtered differently among lakes to influence growth of juvenile sockeye salmon in an Alaskan watershed

The physical landscape filters regional climate variation such that the environmental conditions an organism experiences are unique to the characteristics of local habitat features. While it has become apparent that populations may show watershed-specific responses to changing climate within a geographic region, the population dynamics of Pacific salmon Oncorhynchus spp. suggest that within watershed climate filtering is also important. Growth provides an integrated measure of habitat quality capturing the overall response of individuals to climate as filtered by their habitat and their response to the biological interactions in the ecosystem. We used two different long-term datasets, scales from returning adults and juvenile length measurements, to assess the response of sockeye salmon O. nerka growth during their juvenile life phase to single and integrated measures of climate within a watershed between 1950 and 2010. Scale growth showed evidence for differences among stocks rearing in different lake habitats within the same Alaska Peninsula watershed. These lakes have substantially different morphometry and showed opposite responses to changes in spring and fall air temperatures. Juvenile length data were also available for one of these stocks and indicated that density effects were relatively weak in contrast to the effects of temperature. While direct measures of juvenile length and measures derived from adult scales showed some similarity in their trends over time, they indicated opposite effects of air temperature. Throughout the range of Pacific salmon, climate change is altering freshwater ecosystems through changes to temperature, precipitation and associated variables. These data suggest that sockeye salmon populations are experiencing climate filtering at a sub-watershed scale. Maintaining connected, heterogeneous landscapes will therefore likely be important for providing productive habitat for sockeye salmon across a range of climate conditions that they are going to experience under new climate regimes.
The relationship between police belief systems and attitudes toward police practices

This article develops the proposition that both ideological and traditional belief systems are present in the occupation of policing. Police professionalism is conceptualized as an explicit, articulated ideology that has emerged to challenge the commonsense beliefs associated with craftsmanship, the world-view of traditional police agencies. The relationship between these world-views and three attitudes toward three traditional police practices—antipathy toward due process, the code of secrecy, and the tendency to resolve citizen confrontations with “street justice”—were assessed. Endorsement of a craftsmanship world-view was associated with favorable attitudes toward each of these practices. Also, endorsement of a professionalism world-view had little effect on the relationships between craftsmanship and attitudes toward these three police practices.
Decentralized tracking of indistinguishable targets using low-resolution sensors

This paper addresses the problem of using a distributed team of tracking robots to maintain proximity to a collection of unpredictably moving targets. Each tracker is equipped with short range communication hardware and a low resolution sensor that can detect the presence of targets, but not their precise locations, their identities, nor even the number of targets within the sensing range. We present methods for set-membership-based filtering that exploit specific structures in the information space for this problem. We also describe an active algorithm that allows the tracker team to follow the targets in a coordinated way, in spite of the incomplete information and intermittent communication links. A simulation of this algorithm shows that the passive filtering algorithm maintains an accurate representation of each tracker's knowledge, and that the active tracking algorithm is able to leverage this information to achieve accurate, robust target tracking.
Comparative study of maximum likelihood detection for two multi-rate DS/CDMA systems

Multi-rate communication systems are considered for the transmission of direct-sequence code-division multiple-access wireless signals. Performance for jointly optimal detection is studied in the context of multi-code access and variable spreading length access. Prior results for dual-rate systems are extended to multi-rate systems and the effects of correlation between high-rate users in the multi-code scenario are explored. Comparison of the two multirate systems is done via the calculation of asymptotic multi-user performance measures and appropriate bounds.
Macroeconomic Fluctuations and Mortality in Postwar Japan

Recent research has shown that after long-term declining trends are excluded, mortality rates in industrial countries tend to rise in economic expansions and fall in economic recessions. In the present work, co-movements between economic fluctuations and mortality changes in postwar Japan are investigated by analyzing time series of mortality rates and eight economic indicators. To eliminate spurious associations attributable to trends, series are detrended either via Hodrick-Prescott filtering or through differencing. As previously found in other industrial economies, general mortality and age-specifi death rates in Japan tend to increase in expansions and drop in recessions, for both males and females. The effect, which is slightly stronger for males, is particularly noticeable in those aged 45–64. Deaths attributed to heart disease, pneumonia, accidents, liver disease, and senility—making up about 41% of total mortality—tend to fluctuate procyclically, increasing in expansions. Suicides, as well as deaths attributable to diabetes and hypertensive disease, make up about 4% of total mortality and fluctuate countercyclically, increasing in recessions. Deaths attributed to other causes, making up about half of total deaths, don’t show a clearly defined relationship with the fluctuations of the economy.
Rapid purging of genetic load in a metapopulation and consequences for range expansion in an invasive plant

Invasive species often display high fitness despite bottlenecks and inbreeding during establishment. We address this paradox through simulations and experiments that assess the potential for purging of genetic load during range expansion. Success of invaders often depends on the production of vigorous inbred offspring allowing for rapid population growth after colonization. Substantial genetic load of outbreeding species reduces the fitness of offspring as inbreeding ensues during the establishment of populations. In our simulations, sustained selfing or outcrossing within isolated populations did little to remove deleterious mutations. Conversely, inbreeding combined with periodic gene flow resulted in efficient purging and accelerated rates of range expansion. Purging efficiency was dependent on initial genetic diversity levels, in line with predictions that multiple introductions facilitate invasion and the evolution of more aggressive invaders. Simulation predictions were tested using the invasive species Brachypodium sylvaticum. Homozygous populations on B. sylvaticum’s range periphery displayed lower inbreeding depression compared to heterozygous populations near introduction sites. Empirical tests with B. sylvaticum demonstrate that purging of genetic load is a plausible scenario promoting range expansion during invasion.
Household Water Insecurity in the Global North: A Study of Rural and Periurban Settlements on the Texas–Mexico Border

This article examines household-level characteristics that predict water insecurity in low-income rural and periurban communities on the Texas–Mexico border. We employ two logistic regression models (binary and ordered) to identify household characteristics that are more likely to result in water insecurity. Our analyses yielded unexpected findings: Whereas socioeconomic factors are weak predictors, immigration status of household members is a significant variable that contributes to household water insecurity. Policymakers need to pay more attention to marginalized communities as “universal” water access still leaves populations without adequate, reliable, and affordable water in the Global North.
Evidence for nuclear molecular orbital effects in the C 13 + C 13 → C 12 + C 14 transfer reaction

Detailed measurements of the angular distribution for the $^{13}\mathrm{C}$+$^{13}\mathrm{C}$\ensuremath{\rightarrow}$^{12}\mathrm{C}$+$^{14}\mathrm{C}$ single neutron transfer reaction as a function of bombarding energy from just above the Coulomb barrier to approximately four times the barrier energy are reported. The distorted-wave Born approximation for the transfer process does not reproduce the strong oscillations observed in both the experimental angular distributions and excitation functions, while analyses using a two-pole model for the transfer amplitude indicate significant multistep contributions. We show that the cross section in the 90\ifmmode^\circ\else\textdegree\fi{} region in the center of mass is characteristic of an increased collision delay time and of an effective $Q$ value 1 MeV smaller than the asymptotic observable $Q$ value. Angular distributions calculated using the dynamic two-center shell model of Konnecke et al. also succeed in reproducing the salient features of the data. The present experiment provides evidence for the occurrence of single-particle nuclear molecular behavior in a heavy-ion neutron transfer reaction. Data for the elastic scattering of $^{13}\mathrm{C}$+$^{13}\mathrm{C}$ are also presented and analyzed. We conclude that the elastic scattering excitation functions are consistent with the occurrence of orbiting in the dynamic interaction.NUCLEAR REACTIONS $^{13}\mathrm{C}$($^{13}\mathrm{C}$,$^{12}\mathrm{C}$)$^{14}\mathrm{C}$ and $^{13}\mathrm{C}$($^{13}\mathrm{C}$,$^{14}\mathrm{C}$)$^{12}\mathrm{C}$, measured $\ensuremath{\sigma}(E;\ensuremath{\theta})$, $E(\mathrm{lab})=16.0\ensuremath{-}50.0$ MeV, $\ensuremath{\theta}(\mathrm{lab})=17.8\ifmmode^\circ\else\textdegree\fi{}\ensuremath{-}51.4\ifmmode^\circ\else\textdegree\fi{}$, comparison with DWBA calculations, analysis using two-pole model, interpreted as evidence for reduced effective $Q$ value in the surface region and an increase in the collision delay time compared to values expected for a single step process; $^{13}\mathrm{C}$($^{13}\mathrm{C}$,$^{13}\mathrm{C}$)$^{13}\mathrm{C}$, measured $\ensuremath{\sigma}(E)$, $\ensuremath{\theta}(\mathrm{lab})=25\ifmmode^\circ\else\textdegree\fi{}, 30\ifmmode^\circ\else\textdegree\fi{}, 35\ifmmode^\circ\else\textdegree\fi{}, 40\ifmmode^\circ\else\textdegree\fi{}, 45\ifmmode^\circ\else\textdegree\fi{}$, $E(\mathrm{lab})=14.5\ensuremath{-}71.0$ MeV, optical model calculations, analysis using one pole model, gross structure oscillations interpreted as a geometrical effect.
Non-ionizing radiation generated by nanosecond pulsed electric fields (nsPEFS) induce apoptosis in cancer in vivo

Summary form only given. Over the last several years pulse power technology has developed into a novel and innovative time domain nanotechnology as a new modality to treat cancer. The technology treats cancer in the absence of drugs by generating non-ionizing radiation with nanosecond pulsed electric fields (nsPEFs or nanopulses) that are high in power (gigawatts) and low in energy (millijoules). They can induce apoptosis and cause loss of vascular viability contributing to infarctive tumor death in a temperature-independent manner. NsPEFs have effects distinct from conventional electroporation (EP) used in irreversible EP and electrochemotherapy with bleomycin. Nanopulses affect intracellular structures and functions while having unique, non-EP effects on plasma membranes. Unlike cancer therapies that induce necrosis through lethal cryotherapy or hyperthermia, such as radiofrequency ablation, nanopulses convey intense, high power, non-thermal electric fields to the tumor mass, sparing adjacent tissues and resulting in the elimination of tumors. NsPEFs induced apoptosis in all tumor cells tested in vitro. In addition, nsPEFs induced apoptosis in fibrosarcoma tumors and significantly reduced tumor size. Apoptosis is a form of programmed cell death that is altruistic cell suicide that eliminates cells that are senescent, damaged, diseased or not needed such that surrounding cells are spared the damage by inflammation. During apoptosis cells undergo an orchestrated disassembly of cell structure and function by proteases called caspases. The apoptotic cells are phagocytized by other cells such that the cell raw materials can be recycled. Apoptosis is the antithesis of death by necrosis, where cell membrane integrity fails and cells leak their contents into the surrounding environment leading to inflammation, pain and scarring. Indicators of apoptosis in fibrosarcoma tumors included caspase activation and DNA fragmentation (degradation). The use of nsPEFs as a non-thermal, non-ionizing radiation modality without chemotherapeutic agents will provide a basis for future clinical studies to treat cancers. The application of nsPEFs is safe and relatively inexpensive. Unlike chemotherapy it does not have systemic side effects and unlike surgery it is minimally invasive and leaves no scars. The therapeutic application of nsPEFs can provide an inexpensive, non-invasive, new, novel, and effective method to the arsenal for cancer treatment strategies.
In situ biomineralization and particle deposition distinctively mediate biofilm susceptibility to chlorine.

Microbial biofilms and mineral precipitation commonly co-occur in engineered water systems, such as cooling towers and water purification systems, and both decrease process performance. Microbial biofilms are extremely challenging to control and eradicate. We previously showed that in situ biomineralization and the precipitation and deposition of abiotic particles occur simultaneously in biofilms under oversaturated conditions. Both processes could potentially alter the essential properties of biofilms, including susceptibility to biocides. However, the specific interactions between mineral formation and biofilm processes remain poorly understood. Here we show that the susceptibility of biofilms to chlorination depends specifically on internal transport processes mediated by biomineralization and the accumulation of abiotic mineral deposits. Using injections of the fluorescent tracer Cy5, we show that Pseudomonas aeruginosa biofilms are more permeable to solutes after in situ calcite biomineralization and are less permeable after the deposition of abiotically precipitated calcite particles. We further show that biofilms are more susceptible to chlorine killing after biomineralization and less susceptible after particle deposition. Based on these observations, we found a strong correlation between enhanced solute transport and chlorine killing in biofilms, indicating that biomineralization and particle deposition regulate biofilm susceptibility by altering biocide penetration into the biofilm. The distinct effects of in situ biomineralization and particle deposition on biocide killing highlight the importance of understanding the mechanisms and patterns of biomineralization and scale formation to achieve successful biofilm control.
A method for the determination of genetic sex in the fathead minnow, Pimephales promelas, to support testing of endocrine-active chemicals.

Certain endocrine-active toxicants have been reported to completely sex reverse both male and female individuals in amphibian, avian, fish, invertebrate, and reptile species, resulting in a phenotype indistinguishable from unaffected individuals. Detection of low-level sex reversal often requires large numbers of organisms to achieve the necessary statistical power, especially in those species with predominantly genetic sex determination and cryptic/homomorphic sex chromosomes. Here we describe a method for determining the genetic sex in the commonly used ecotoxicological model, the fathead minnow (Pimephales promelas). Analysis of amplified fragment length polymorphisms (AFLP) in a spawn of minnows resulted in detection of 10 sex-linked AFLPs, which were isolated and sequenced. No recombination events were observed with any sex-linked AFLP in the animals examined (n = 112). A polymerase chain reaction (PCR) method was then developed that determined the presence of one of these sex-linked polymorphisms fo...
Magnetic and Electronic Transport Properties of Single Crystal La0.64Pb0.36MnO3

We studied the magnetic and electronic transport properties of a single crystal sample of La0.64Pb0.36MnO3 in the temperature range 5 K to 350 K and magnetic field up to 5.5 T. A magnetic transition is found at 210 K. The single crystal sample is ferromagnetic below the transition temperature (Tc) and becomes paramagnetic at temperatures T > Tc. Magnetization measurements along three different orthorhombic crystal axes show no significant difference. The magnetoresistance approaches a maximum value of about -60% at Tc in 5 T magnetic field strength and has qualitatively different field dependence below and above Tc. The scaling behavior between resistivity and magnetic moment is examined for temperatures both below and above the transition. A low temperature (T<15 K) dp / dT < 0 effect is attributed to possible quantum tunneling of carriers between neighbouring distortions.
Pro: Higher serum bicarbonate in dialysis patients is protective

Chronic metabolic acidosis is common in dialysis patients. Bicarbonate administration via the dialysate helps maintain the acid-base balance in these patients. Serum bicarbonate level in dialysis patients is determined by several factors that include dietary protein intake, nutritional status and dialysis prescription, etc. Additionally, a meaningful interpretation of serum bicarbonate in dialysis patients requires an understanding of complexities involving its measurement. Both very low as well very high levels of serum bicarbonate have been associated with adverse outcomes in observational studies. However, recent observational data, when adjusted for the confounding effects of nutritional status, do not associate higher predialysis serum bicarbonate with adverse consequences. At this time, there are no prospective studies available that have examined the association of serum bicarbonate with hard outcomes in dialysis patients. The ideal level of serum bicarbonate in dialysis patients is therefore unknown. This article examines the available data with regard to the benefits of higher predialysis serum bicarbonate.
Postwar Agricultural Problems in the Great Plains Area

THE extent and the nature of the postwar agricultural problems of the Great Plains area, in large measure, still are to be determined. These problems are dependent upon national policies and programs as well as upon existing and probable conditions within the area. The national policies to be followed are none too clear as yet, and some of them still to be determined. These policies will have material effects on conditions within the area and result in problems of varying types and degrees of severity. Existing federal legislation guarantees support prices for most of the more important farm products at 90 per cent or more of parity until January 1, 1949, or possibly longer. It is possible that some degree of production control may accompany this program of support prices. Marketing quotas may be used in the case of certain farm products. The use of marketing quotas to any great extent would necessarily involve some type of production control program. Many proposals have been made to revise the formula used in determining parity prices. Most of these proposals would result in higher parity prices than now prevail for many farm products. It is probable that any program which revises parity prices upward would, in the long run, accentuate the adjustment problems of the Great Plains area. This area is more concerned with the scope of the markets available for its products than markets of limited scope for limited quantities of the products which can be produced within the area.
More than one-half of a decade of experience with venlafaxine dual serotonin-norepinephrine reuptake inhibitor

There are many telling reasons to assemble a special issue of Depression and Anxiety at this time on venlafaxine, the dual serotonin-norepinephrine reuptake inhibitor, that is currently approved in the United States for the treatment of major depression and generalized anxiety disorder. First, there has been increasing evidence largely compiled by Bech and his colleagues in Denmark that antidepressants that inhibit both norepinephrine and serotonin reuptake (SNRI) are more effective in severe and refractory depression than those that inhibit uptake of a single monoamine neurotransmitter. In addition, patients with major depression treated with dual reuptake inhibitors may achieve remission more frequently than those treated with single monoamine reuptake inhibitors. This is not a trivial point in view of the considerable morbidity associated with chronic depression. There is now convincing data not only of the potential suicide risk in partially treated depressed patients, but the emerging data base that suggests that depression is associated with a significantly increased risk for both the development of, and poor outcome after, both myocardial infarction and stroke. The present volume reviews in a comprehensive fashion the neurobiology of depression with a focus on the pathophysiologic involvement of serotonergic and noradrenergic systems, as well as the preclinical and clinical neuropharmacology of venlafaxine. Much emphasis is paid to summarize in a succinct manner the pharmacokinetics and drug–drug interaction profile of this agent, as well as its efficacy in the treatment of depression, severe depression, refractory depression, as well as geriatric depression. Moreover, particular consideration is given to the growing awareness of the remarkably high comorbidity of mood and anxiety disorders, and the efficacy of venlafaxine in these states. The use of venlafaxine in generalized anxiety disorder as well as in other psychiatric conditions is adequately reviewed, as is the use of this dual reuptake inhibitor in children and adolescents. Finally, the importance of measures of quality of life in assessing treatment response in mood and anxiety disorders is described, as well as pharmacoeconomic studies which seek to determine the cost utility of antidepressant treatment in this common and devastating set of conditions. There is little doubt that the introduction of venlafaxine has had a remarkable impact on clinical practice. I Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
Abstract 199: Distinctive Roles of Linker Histone H1 Variants in the Hypertrophic Response of Cardiomyocytes

Heart failure results when cardiac output is insufficient to meet physiological requirements and is often preceded by development of cardiomyocyte hypertrophy. As cardiac myocytes respond to hypertrophic stresses they re-express developmentally important genes, normally senescent in the adult. The chromatin structural events underlying this “fetal gene program” are unknown. We previously showed by proteomics that histones, components of the chromatin protein functional unit, the nucleosome, are altered during hypertrophic and failing phases of pressure overload in mouse: linker histone variants H1.2 and H1.5 decreased in hypertrophied myocardium while H1.0 increased during the transition to failure. The linker histone H1 family influences higher order chromatin structure and gene expression, although the role of this family in the heart is unknown. To assess the role of linker histones in hypertrophy, neonatal rat ventricular cardiomyocytes (NRVMs) were transfected with siRNAs individually targeting six H1 variants. Loss of H1.3 and H1.4 respectively induced a significant 26.1% (76 of 90) and 13.5% (80 of 94) increase in cell size area (µm2). A role of H1 in the hypertrophic response is evidenced by its influence on myosin heavy chain (MHC) mRNA expression. Knock-down of individual H1 variants significantly altered the MHC isoform ratio: loss of H1.3 increased α-MHC levels 1.5 fold and decreased β-MHC 1.6 fold while H1.5 depletion decreased α-MHC 2.5 fold. Both H1.3 and H1.4 knock-down increased atrial natriuretic factor (ANF) 1.3 fold while H1.5 loss decreased ANF 6.2 fold shown by qRT-PCR. Treatment with hypertrophy-inducing agents Isoproterenol (1μM), Endothelin (2nM) or Phenylephrine (10μM), reduced H1 mRNA levels however with subtle effects on protein abundance. To evaluate whether H1 loss shifted NRVM nuclei from a predominantly heterochromatic toward euchromatic state favoring gene accessibility we examined distinct histone markers of chromatin states. Histone H1.5 knock-down significantly decreased H3K9Me3 levels, a silencing mark associated with heterochromatin, 1.7 fold. Therefore we conclude that variants package distinctive regions of the genome and that H1.3 and H1.4 controls genes involved in the hypertrophic response.
An updated systematic review and meta-analysis of early outcomes after left atrial appendage occlusion.

Background Left atrial appendage occlusion (LAAO) is a promising intervention for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Early outcomes following LAAO have been published in many studies with variable results. Objective This updated meta-analysis aims to provide a summary of the early outcomes of LAAO. Methods Medline/Pubmed, Ovid Journals, Clinical trials, Abstract meetings, Cochrane databases were searched from January 1st, 1999 to November 30th, 2016. Results This meta-analysis included 49 studies involving 12 415 patients. The median age was 73.5 years (IQR 72-75 years) and 43% were males. Hypertension and diabetes were present in 36% and 15% of the population, respectively. There was a prior history of stroke and congestive heart failure in 14% and 18% of the population, respectively. The median CHADS2 score was 2.9 (IQR 2.6-3.3) and the median HASBLED score was 3.3 (IQR 3-4). LAAO implantation was successful in 96.3% of patients (95.40-97.08, I2 = 76.1%). The pooled proportion of all-cause mortality was 0.28% (0.19-0.38, I2 = 0%). The pooled proportion of all-cause stroke was 0.31% (0.22-0.42, I2 = 9.4%), major bleeding requiring transfusion was 1.71% (1.13-2.41, I2 = 73.2%), and pericardial effusion was 3.25% (2.46-4.14, I2 = 79%). Sub analysis of randomized clinical trials comparing LAAO devices to warfarin showed lower mortality (P = 0.03) with similar bleeding risk (P = 0.20) with LAAO. Conclusions This meta-analysis concludes that LAAO occlusion is a safe and effective stroke prevention strategy in patients with NVAF.
Nutritional Guidelines, Energy Balance, and Weight Control Issues for the Mature Physically Active Woman

After completing this chapter, you should have an understanding of the following: • Energy balance and weight control. • Dietary guidelines for the mature woman. • Important nutrients, vitamins, and minerals for physically active women.
Multivariate Life Testing in Variably Scaled Environments

This paper examines modeling and inference questions for experiments in which different subsets of a set of k possibly dependent components are tested in r different environments. In each environment, the failure times of the set of components on test is assumed to be governed by a particular type of multivariate exponential (MVE) distribution. For any given component tested in several environments, it is assumed that its marginal failure rate varies from one environment to another via a change of scale between the environments, resulting in a joint MVE model which links in a natural way the applicable MVE distributions describing component behavior in each fixed environment. This study thus extends the work of Proschan and Sullo (1976) to multiple environments and the work of Kvam and Samaniego (1993) to dependent data. The problem of estimating model parameters via the method of maximum likelihood is examined in detail. First, necessary and sufficient conditions for the identifiability of model parameters are established. We then treat the derivation of the MLE via a numerically-augmented application of the EM algorithm. The feasibility of the estimation method is demonstrated in an example in which the likelihood ratio test of the hypothesis of equal component failure rates within any given environment is carried out.
Effects of mutagenesis of murine hepatitis virus nsp1 and nsp14 on replication in culture

For nsp1, the fact that the carboxy-terminal but not the amino-terminal half of the protein can be deleted suggests that there may be specific and distinct domains within the protein or that the entire protein is dispensable but that the RNA encoding the amino-terminal half of nsp1 cannot be deleted. The identification of specific required residues support the conclusion that it is the portion of the protein that is required for replication. The results of mutagenesis of the nsp14 coding region and flanking cleavage sites also provided important new insights into this protein and its requirements. Our previous study raised the question as to the essential nature of nsp14 in replication. The results of this study show that putative active site residues cannot be substituted without loss of replication in culture. Interestingly, mutagenesis of Tyr414 showed that while this residue can tolerate a number of substitutions, it was intolerant of Lysine or deletion. The results suggest that nsp14 is required for replication. However, whatever functions nsp14 serves appear to be retained by noncleaved or partially processed nsp14, since abolition of either the amino-terminal or carboxy-terminal cleavage site allowed recovery of viable virus.
Sleep Changes Induced by 4 and 6 Days of Experimental Alcoholization and Withdrawal in Humans

The delineation of five somewhat sequential stages of sleep which occurred rhythmically in approximately 90 minute cycles in normal adults generated considerable interest in those who saw in it the possibility for investigating the nature of these stages of sleep and their relation to normal and pathological states.
Structurally Abnormal X Chromosomes

The wide range of aneuploidy displayed by the human X chromosome is matched by a greater variety of structural abnormalities than is found in any of the autosomes. In cells with one normal and one abnormal X chromosome, consisting of X chromosomal material, the abnormal X is practically always inactivated. This naturally diminishes the effect of the abnormal X. The sizes of the Barr bodies reflect the sizes of the abnormal X chromosomes. They range from considerably smaller than normal for partly deleted chromosomes to very large ones for chromosomes consisting of two long arms of the X or even of two almost intact X chromosomes.
Distributions of Visible and Invisible Segments

In the present chapter we develop formulae for the distributions of the length of visible and invisible (shadowed) segments of the target curve C in the plane. We will focus attention on trapezoidal fields, in which the strip S is bounded by two parallel lines U and W, and the target curve C is a straight line parallel to S. As before, the distances of U, W, and C from O are u, w and r, respectively, where 0 x U , and, as before, $$x_L^* = {x_L} - b\frac{r}{u}{(1 + {(\frac{{{x_L}}}{r})^2})^{1/2}}$$ $$x_U^* = {x_U} - b\frac{r}{u}{(1 + {(\frac{{{x_U}}}{r})^2})^{1/2}}$$ .
Lakota Female Scholarship: A Collective Case Study on Transcending Indigenous Educational Pathways and Persistence at the Graduate Level

This study explored the perspectives of seven Lakota females who graduated from Oglala Lakota College (OLC) master’s degree in Lakota Leadership and Management or Lakota Leadership and Management with an emphasis in Education Administration programs. Education histories, cultural identification, and college experiences were evaluated to investigate what incentives, not only influenced but propelled the women through the world of academia. The research was qualitative in nature, thus giving a thorough examination of each student perspective. The qualitative research was conducted through a collective case study. Four themes identified through in the findings were: financial support, high female influence, cultural identification, and formal versus informal supports.
Mutation analysis of causative genes in a case of congenital hypotrichosis

Objective To identify the genetic cause of a case of congenital hypotrichosis by a next-generation sequencing technology. Methods A 9-year and 3-month-old girl presented with few villous hairs at birth, which grew slowly. Skin examination showed sparse, thin, soft, woolly and light-yellow hairs, small amount of hairs on the top of the head and a less amount of hairs around the head, hairline recession and broadened forehead. No abnormality was found by ophthalmic examination. No similar aberrant phenotype was observed in the patient′s parents or her younger sister. Her parents were non-consanguineous marriage. Peripheral venous blood samples were obtained from the patient, her mother and younger sister. Genomic DNA was extracted and then analyzed by a next-generation sequencing technology. The suspected pathogenic mutations were validated by Sanger sequencing and subjected to bioinformatics analysis. Results Two mutations were identified in the CDH3 gene in the patient, including a c.1057G > T (p.D353Y) heterozygous mutation in exon 5 and a c.1767delC (p.I589Ifs) heterozygous mutation in exon 10. They were both novel mutations, and their pathogenicity was predicted by softwares. Sanger sequencing indicated that the c.1057G > T (p.D353Y) heterozygous mutation was inherited from the patient′s mother, and gene transfer analysis revealed that the c.1767delC (p.I589Ifs) heterozygous mutation was inherited from the patient′s father. Conclusion The c.1057G > T (p.D353Y) and c.1767delC (p.I589Ifs) heterozygous mutations may cause hypotrichosis and juvenile macular dystrophy in the patient, so careful observation and comprehensive ophthalmic examination should be performed on time for early diagnosis and treatment of eye symptoms. Key words: Hypotrichosis; Mutation; DNA mutational analysis; CDH3 gene
Community factors associated with local RSV epidemic patterns:a spatiotemporal modeling study

ABSTRACT Background Respiratory syncytial virus (RSV) causes a large burden of morbidity in infants, young children, and the elderly. The timing of RSV seasonal epidemics exhibits strong spatial patterns within the United States. Spatial variability in the timing of RSV epidemics provides an opportunity to probe the factors driving transmission of the virus. Methods We evaluated competing hypotheses about the associations between RSV epidemic timing at the ZIP-code level and household size, population density, school district boundaries, commuting patterns, and geographic proximity. We used hierarchical Bayesian models with monthly ZIP-code level hospitalization data from New York, New Jersey, and Connecticut between July 1997 and June 2014 to investigate these hypotheses. Results Early epidemic timing across ZIP codes was associated with large household sizes and high population density, and nearby ZIP codes shared similar epidemic timing. Variations in epidemic timing attributed to commuting patterns or school district boundaries are negligible. Conclusion Our results suggest RSV epidemics take off faster in areas with more household crowding and higher population density, and that epidemic spread follows a spatial diffusion process based on geographic proximity. With several vaccines against RSV under development, it is important to understand the drivers of RSV transmission and disease in order to maximize population protection of a vaccine program. Our findings can inform more effective control measures against RSV, such as vaccine programs and household infection control, and guide future studies on the transmission dynamics of RSV.
Long-term follow up of systemic rituximab therapy as first-line and salvage therapy for idiopathic orbital inflammation and review of the literature.

Purpose: To report long-term outcomes of systemic rituximab therapy for idiopathic orbital inflammation (IOI) as both primary and salvage therapy and to review the English literature. Methods: A re...
Hot-melt extrusion based sustained release ibrutinib delivery system: An inhibitor of Bruton's Tyrosine Kinase (BTK).

Abstract Ibrutinib (IB) is the first Bruton s tyrosine kinase (BTK) inhibitor classified as BCS class-II, with multiple polymorphic forms. Development of its amorphous solid dispersion (ASD) is an effective approach to overcome drug’s poor solubility and concerns regarding metastable polymorphic forms. In this work, Hot Melt Extrusion (HME) was used to develop robust ASD of ibrutinib and copovidone at different ratios. The ASDs were blended with a swellable crosslinked super-disintegrant and compressed into a sustained-release (SR) matrix. ASDs representing drug loadings of 20%, 40%, and 60% showed broad, amorphous “halos” and absence of an endotherm as revealed by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Using dynamic oscillatory rheology, storage modulus, and viscosities versus temperature confirmed formation of a homogeneous dispersion with a manifestation of plasticizing effect of API. Micro-dissolution testing of ASDs in fasted state simulated intestinal fluid (FaSSIF) demonstrated >70% drug release compared to the saturation solubility of crystalline IB. Results of USP dissolution testing of SR tablets exhibited a desirable sustained delivery up to six hours with >88% drug release versus 34% release from tablets containing crystalline ibrutinib. Co-existence of ASD within the hydrating matrix provided unhindered drug release and release duration.
I'm All Ears: A Population-Based Analysis of Consumer Product Foreign Bodies of the Ear.

OBJECTIVES The purpose of this study was to assess the nationwide incidence of ear foreign body (FB) presentations to the emergency department (ED) and analyze the most common FB consumer products encountered. METHODS The National Electronic Injury Surveillance System (NEISS) was evaluated for ED visits that included "ear foreign bodies" from 2010 through 2019. The most frequent foreign bodies were identified and organized by demographics. RESULTS A total of 20,545 ear FB cases were found, with an estimated 608,860 ED visits nationwide. Female patients (56%) were more likely to have jewelry and first aid equipment FBs. Males between the ages of 5 and 15 years were significantly (P < 0.05) more likely to have paper products, pens/pencils, and desk supplies in their ears. CONCLUSION Ear FBs represent a substantial proportion of healthcare expenditures. Although children are the most commonly affected individuals, all ages require further education and preventive measures.