cssi/SciSciGPT-SciSciNet huggingface dataset:
Distinct roles for dystroglycan, (β)1 integrin and perlecan in cell surface laminin organization

Dystroglycan (DG) is a cell surface receptor for several extracellular matrix (ECM) molecules including laminins, agrin and perlecan. Recent data indicate that DG function is required for the formation of basement membranes in early development and the organization of laminin on the cell surface. Here we show that DG-mediated laminin clustering on mouse embryonic stem (ES) cells is a dynamic process in which clusters are consolidated over time into increasingly more complex structures. Utilizing various null-mutant ES cell lines, we define roles for other molecules in this process. In (β)1 integrin-deficient ES cells, laminin-1 binds to the cell surface, but fails to organize into more morphologically complex structures. This result indicates that (β)1 integrin function is required after DG function in the cell surface-mediated laminin assembly process. In perlecan-deficient ES cells, the formation of complex laminin-1 structures is defective, implicating perlecan in the laminin matrix assembly process. Moreover, laminin and perlecan reciprocally modulate the organization of the other on the cell surface. Taken together, the data support a model whereby DG serves as a receptor essential for the initial binding of laminin on the cell surface, whereas (β)1 integrins and perlecan are required for laminin matrix assembly processes after it binds to the cell.
Proteomic Analysis of Bovine Brain G Protein γ Subunit Processing Heterogeneity

We characterized the variable processing of the G protein γ subunit isoforms associated with bovine brain G proteins, a primary mediator of cellular communication. Gγ subunits were isolated from purified brain G proteins and characterized by Edman sequencing, by MALDI MS, by chemical and/or enzymatic fragmentation assayed by MALDI MS, and by MS/MS fragmentation and sequencing. Multiple forms of six different Gγ isoforms were detected. Significant variation in processing was found at both the amino termini and particularly the carboxyl termini of the proteins. All Gγ isoforms contain a carboxyl-terminal CAAX motif for prenylation, carboxyl-terminal proteolysis, and carboxymethylation. Characterization of these proteins indicates significant variability in the normal processing of all of these steps in the prenylation reaction, including a new variation of prenyl processing resulting from cysteinylation of the carboxyl terminus. These results have multiple implications for intracellular signaling mechanisms by G proteins, for the role of prenyl processing variation in cell signaling, and for the site of action and consequences of drugs that target the prenylation modification.
Solitude Experiences: Varieties, Settings, and Individual Differences

Solitude may be positive or negative, depending on situational and personal factors. From prior research, nine types of solitude were identified. Based on data from a questionnaire study of undergraduate participants, factor analysis suggests that these nine types can be reduced to three dimensions, two positive and one negative. These are, respectively, Inner-Directed Solitude (characterized by self-discovery and inner peace), Outer-Directed Solitude (characterized by intimacy and spirituality), and Loneliness. Personality and value correlates, as well as situational correlates, of the various types of solitude also were explored.
A reproducing kernel Hilbert space framework for pairwise time series distances

A good distance measure for time series needs to properly incorporate the temporal structure, and should be applicable to sequences with unequal lengths. In this paper, we propose a distance measure as a principled solution to the two requirements. Unlike the conventional feature vector representation, our approach represents each time series with a summarizing smooth curve in a reproducing kernel Hilbert space (RKHS), and therefore translate the distance between time series into distances between curves. Moreover we propose to learn the kernel of this RKHS from a population of time series with discrete observations using Gaussian process-based non-parametric mixed-effect models. Experiments on two vastly different real-world problems show that the proposed distance measure leads to improved classification accuracy over the conventional distance measures.
The difficult doctor-patient relationship: Somatization, personality and psychopathology

The difficult doctor-patient relationship and “difficult patients” have been the subject of considerable anecdotal study. Reliable methods for identification of difficult patients have not been available for the empirical study of their prevalence and characteristics. We developed the Difficult Doctor-Patient Relationship Questionnaire (DDPRQ), composed of 30 Likert items, completed by physicians after encounters with patients. Adult patients and their providers in an academic, municipal hospital clinic participated in the instrument development (n = 92), reliability (n = 224), and assessment of patient characteristics phases (n = 113) of the study. The DDPRQ was shown to be a reliable, practical instrument. Factor analysis revealed 5 dimensions with face validity. The DDPRQ classified 10.3–20.6% of patient encounters as “difficult” depending on the sample. Demographic characteristics, provider characteristics and most medical diagnoses were not associated with DDPRQ score. In contrast, difficult patients were characterized by psychosomatic symptoms, at least mild personality disorder, and Axis I (major) psychopathology, and most had more than one of these characteristics. The need to identify and understand these components of difficult patient behavior and to include the doctor-patient relationship in strategies for managing the difficult patient is discussed.
Sex Differences in Diabetes and Risk of Incident Coronary Artery Disease in Healthy Young and Middle-Aged Adults

Objective Controversy exists about the coronary artery disease (CAD) risk conveyed by diabetes in young and middle-aged women. We investigated gender differences in CAD by diabetes-status among healthy individuals with different underlying risks of heart disease. Research Design/Methods We examined subjects aged<60 years without CAD at enrollment in the high-risk GeneSTAR Study (n=1448;follow-up∼12years), Multi-Ethnic Study of Atherosclerosis (n=3072;follow-up∼7years) and NHANES III Mortality Follow-up Study (n=6997;follow-up∼15years). Diabetes was defined by report, hypoglycemics use, and/or fasting glucose≥126 mg/dl. The outcome was any CAD event during follow-up (fatal CAD in NHANES). Results In the absence of diabetes, CAD rates were lower among women in GeneSTAR, MESA, and NHANES (4.27, 1.66, 0.40/1000 person-years,respectively) versus men (11.22, 5.64, 0.88/1000 person-years); log-rank p-value 0.05. Adjusting for demographics, diabetes was associated with a significant four-to-five-fold higher CAD rate among women in each cohort, without differences in men. In meta-analyses of three cohorts, additionally adjusted for body-mass index,smoking,hypertension,HDL and non-HDL cholesterol,anti-hypertensive and cholesterol-lowering medication use, the hazard ratio(HR) of CAD in men versus women among non-diabetes was 2.43(1.76-3.35) and diabetes 0.89(0.43-1.83), p=0.013 interaction by diabetes-status. Conclusions Though young and middle-aged women are less likely to develop CAD in the absence of diabetes, the presence of diabetes equalizes the risk by gender. Our findings support aggressive CAD prevention strategies in women with diabetes, and at similar levels to those that exist in men.
Src tyrosine kinase as a therapeutic target in ovarian cancer and multidrug-resistant ovarian cancer

A235 Background: We have reported previously that inhibition of Src tyrosine kinase sensitizes drug-sensitive and drug-resistant ovarian cancer cells to both paclitaxel and cisplatin. Here we demonstrate that the potent, orally available Src inhibitor, AZD0530, sensitizes ovarian cancer cells to paclitaxel by inhibiting two potent survival signals; an IGF1-Src-STAT1 pathway, and the inhibitor of apoptosis protein survivin. Methods and Results: Gene array technology identified increased IGF1 and STAT1 expression in paclitaxel-resistant ovarian cancer cells compared with sensitive cells. Exogenous IGF1 in drug-sensitive cells activated STAT1 and inhibited paclitaxel- and cisplatin-induced apoptosis. STAT1 knockdown resensitized resistant cells to paclitaxel, whereas STAT1 overexpression was protective of paclitaxel-sensitive cells. Co-treatment of drug-resistant cells with AZD0530 in the presence or absence of IGF1 and/or paclitaxel disrupted a Src-STAT1 interaction, was associated with redistribution of STAT1 to the cytoplasm, and reversed the pro-survival effects of IGF1. Thus, increased IGF1 signaling utilizing a Src-STAT1 pathway appears to promote and maintain paclitaxel resistance in ovarian cancer cells. This effect can be reversed through Src inhibition. Inhibition of either Src or PI3-kinase was associated with a loss of survivin expression in drug-resistant ovarian cancer cells. This appears to be the result of decreased survivin protein stability, as inhibition of the 26S proteasome rescues survivin expression in the presence of Src/PI3-kinase inhibition. Knockdown of survivin expression with siRNA is associated with increased low-molecular-weight activated caspase-3 in response to paclitaxel. Furthermore, survivin knockdown is associated with multipolar spindle formation and mitotic arrest in drug-resistant ovarian cancer cells treated with paclitaxel. This occurs in a manner similar to that induced by Src inhibition with AZD0530, suggesting this effect of Src inhibition may be due to loss of survivin. In a mouse model of drug-resistant ovarian cancer, mice receiving combination treatment with AZD0530 plus paclitaxel showed an increase in overall survival compared with mice receiving paclitaxel alone (median 127 days versus 99 days, respectively). There appeared to be no increased morbidity in mice receiving combination therapy versus paclitaxel alone. Conclusion: These data demonstrate that Src may be a viable target in the treatment of ovarian cancer, and warrant further investigation into the possible therapeutic benefit of Src inhibitor AZD0530 in this disease.
Compressive ulnar neuropathies at the elbow: I. Etiology and diagnosis.

Ulnar nerve compression at the elbow can occur at any of five sites that begin proximally at the arcade of Struthers and end distally where the nerve exits the flexor carpi ulnaris muscle in the forearm. Compression occurs most commonly at two sites-the epicondylar groove and the point where the nerve passes between the two heads of the flexor carpi ulnaris muscle (i.e., the true cubital tunnel). The differential diagnosis of ulnar neuropathies at the elbow includes lesions that cause additional proximal or distal nerve compression and systemic metabolic disorders. A complete history and a thorough physical examination are essential first steps in establishing a correct diagnosis. Electrodiagnostic studies may be useful, especially when the site of compression cannot be determined by physical examination, when compression may be at multiple levels, and when there are systemic and metabolic problems.
Disparities in Temporal and Geographic Patterns of Declining Heart Disease Mortality by Race and Sex in the United States, 1973–2010

Background Examining small‐area differences in the strength of declining heart disease mortality by race and sex provides important context for current racial and geographic disparities and identifies localities that could benefit from targeted interventions. We identified and described temporal trends in declining county‐level heart disease mortality by race, sex, and geography between 1973 and 2010. Methods and Results Using a Bayesian hierarchical model, we estimated age‐adjusted mortality with diseases of the heart listed as the underlying cause for 3099 counties. County‐level percentage declines were calculated by race and sex for 3 time periods (1973–1985, 1986–1997, 1998–2010). Strong declines were statistically faster or no different than the total national decline in that time period. We observed county‐level race–sex disparities in heart disease mortality trends. Continual (from 1973 to 2010) strong declines occurred in 73.2%, 44.6%, 15.5%, and 17.3% of counties for white men, white women, black men, and black women, respectively. Delayed (1998–2010) strong declines occurred in 15.4%, 42.0%, 75.5%, and 76.6% of counties for white men, white women, black men, and black women, respectively. Counties with the weakest patterns of decline were concentrated in the South. Conclusions Since 1973, heart disease mortality has declined substantially for these race–sex groups. Patterns of decline differed by race and geography, reflecting potential disparities in national and local drivers of these declines. Better understanding of racial and geographic disparities in the diffusion of heart disease prevention and treatment may allow us to find clues to progress toward racial and geographic equity in heart disease mortality.
Preliminary Design of a Crewed Mission to Asteroid Apophis in 2029-2036

A crewed mission to a near-Earth object (NEO) as early as 2025 was announced by President Obama on April 15th, 2010 at the Kennedy Space Center in Florida. This was announced as part of NASA’s new space exploration plan after announcing plans to cancel the Constellation program. The extensive requirements of such a mission would help NASA to evaluate the performance of future space systems prior to sending a crewed mission to Mars. Apophis, an asteroid of particular interest due to its once high impact probability, would be a logical choice for a manned mission in the near future. This mission could provide a valuable NEO research opportunity to determine the composition of Apophis. This data that would be extremely useful if Apophis were to pass through the gravitational keyhole in 2029, which would then require a deflection mission. This paper focuses on mission design as well as the system architecture that would be required for this mission to Apophis. The primary mission will be a 180 day mission in the 2028-2029 range during the Earth-Apophis close encounter on April 13th, 2029. In an effort to reduce mission requirements mission analysis for missions up to 1 year will be performed as well. In this paper a crewed mission will be designed for a fictional scenario where Apophis has gone through the 2029 keyhole, which puts it on a resonant orbit that will collide with the earth on April 13th, 2036. This work provides baseline mission requirements and optimum launch windows and trajectories for the crewed mission to Apophis, as well as possible mission architecture that allow such missions.
Hyperbolic geometry on a hyperboloid

(1993). Hyperbolic Geometry on a Hyperboloid. The American Mathematical Monthly: Vol. 100, No. 5, pp. 442-455.
Granulocytic adherence in chronic alcoholism.

Granulocytic adherence was measured in blood samples from 40 chronic alcoholic subjects soon after withdrawal from ethanol and from 40 nonalcoholic control subjects. Mean granulocytic adherence (76.5%) and mean neutrophil counts (5,095/cu mm) were higher for alcoholic than for nonalcoholic subjects (mean granulocytic adherence, 64.4%; mean neutrophil count, 3,956/cu mm). For the alcoholic subjects, mean granulocytic adherence was highest (87.9%) during the period from 12 to 48 hours after the last alcohol consumption, the same period in which the neutrophil count was lowest. Mean granulocytic adherence for alcoholic subjects who had received hydroxyzine alone (65.5%), diazepam alone (73.5%), or both of these drugs (76.0%) within 12 hours of testing were lower than the mean granulocytic adherence (83.8%) for the group receiving neither of these drugs. Mean granulocytic adherence was lower ( P < .001) in the group whose alcoholism was of less than five years’ duration (62.7%) than in the group whose alcoholism was of more than five years’ duration (80.7%), although this difference may have been partly due to a greater proportion of the former group’s having been given diazepam and/or hydroxyzine. The authors conclude that although ethanol may inhibit granulocytic adherence acutely, during periods of abstinence from alcohol, granulocytic adherence may rebound to above normal levels. The resultant increase in margination of neutrophils may be partly responsible for the temporary neutropenia seen in some alcoholic patients at the time of admission to the hospital.
Molecular Dynamics Simulation of Amorphous Hydroxypropyl-Methylcellulose Acetate Succinate (HPMCAS): Polymer Model Development, Water Distribution, and Plasticization

Molecular models for HPMCAS polymer have been developed for molecular dynamics (MD) simulation that attempt to mimic the complex substitution patterns in HPMCAS observed experimentally. These molecular models were utilized to create amorphous HPMCAS solids by cooling of the polymeric melts at different water contents to explore the influence of water on molecular mobility, which plays a critical role in stability and drug release from HPMCAS-based solid matrices. The densities found for the simulated amorphous HPMCAS were 1.295, 1.287, and 1.276 g/cm(3) at 0.7, 5.7, and 13.2% w/w water, indicating swelling of the polymer with increasing water content. These densities compare favorably with the experimental density of 1.285 g/cm(3) for commercial HPMCAS-(AQOAT AS-MF) supporting the present HPMCAS models as a realistic representation of amorphous HPMCAS solids. Water molecules were observed to be mostly isolated from each other at a low water content (0.7% w/w), while clusters or strands of water were pervasive and broadly distributed in size at 13.2% w/w water. The average number of first-shell water molecules (n(w)) increased from 0.17 to 3.5, though the latter is still far below that (8.9) expected for the onset of a separate water phase. Increasing water content from 0.7 to 13.2% w/w was found to reduce the T(g) by ~81 K, similar to experimental observations. Plasticization with increasing water content resulted in increasing polymer mobility and water diffusivity. From 0.7 to 13.2% w/w water, the apparent water diffusivity increased from 1.1 × 10(-9) to 7.0 × 10(-8) cm(2)/s, though non-Einsteinian behavior persisted at all water contents explored. This and the water trajectories in the polymers suggest that water diffusion at 0.7% w/w water follows a "hopping" mechanism. At a higher water content (13.2% w/w) water diffusion follows dual diffusive processes: (1) fast water motions within water clusters; and (2) slower diffusion through the more rigid polymer matrix.
Implicit Time Marching Methods for Large-Scale High-Accuracy Simulations of Compressible Flows

This study describes a methodology that combines the implicit time marching with the GMRES method when the spatial derivatives are discretized with the uniformly high order WENO schemes for the simulation of complex shock-containing flows. While the GMRES method are proved to be an efficient parallel method for non-symmetric, nonlinear equation systems, its stability and convergence rate depend on the condition number (or the eigenvalues) of the Jacobian matrix. The adaptively weighting procedure of the WENO schemes achieves high orders of accuracy for compressible flow, but often leads to large variations of the condition number (or the eigenvalues) of the Jacobian matrix. New developments are proposed in this study to improve the accuracy, stability and convergence rate of the implicit time integration with the GMRES method and WENO schemes.
Large built-in electric fields due to flexoelectricity in compositionally graded ferroelectric thin films

We investigate the origin of large built-in electric fields that have been reported in compositionally graded ferroelectric thin films using PbZr${}_{1\ensuremath{-}x}$Ti${}_{x}$O${}_{3}$ ($0.2lxl0.8$) as a model system. We show that the built-in electric fields that cause a voltage offset in the hysteresis loops are dependent on strain relaxation (through misfit dislocation formation) and the accompanying polarization distribution within the material. Using a Ginzburg-Landau-Devonshire phenomenological formalism that includes the effects of compositional gradients, mechanical strain relaxation, and flexoelectricity, we demonstrate that the flexoelectric coupling between the out-of-plane polarization and the gradient of the epitaxial strain throughout the thickness of the film, not other inhomogeneities (i.e., composition or polarization), is directly responsible for the observed voltage offsets. This work demonstrates the importance of flexoelectricity in influencing the properties of ferroelectric thin films and provides a powerful mechanism to control their properties.
Value of Privacy, Security, and Accountability

Anthology Introduction: In bringing together leading scholars to address the tensions between privacy, security, and accountability, this anthology is intended to address the thorny value propositions of an increasingly interconnected and monitored society. Our hope is that by clarifying the moral, legal, and social foundations of privacy, security, and accountability, we can move towards determining the appropriate balance between these contested values. Advances in information technology development have introduced concerns and considerations that simply weren’t on the minds of most people as little as twenty years ago. The capabilities, opportunities, and anxieties being articulated by the authors in this collection are novel, ethically complex, and badly in need of sustained inquiry. We begin by providing an overview of the values under study.
Role of Bile Acid–Regulated Nuclear Receptor FXR and G Protein–Coupled Receptor TGR5 in Regulation of Cardiorenal Syndrome (Cardiovascular Disease and Chronic Kidney Disease)

It is well known that chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease. In fact, studies have shown that cardiovascular event rates and all-cause mortality increase as a function of CKD as determined by decrease in estimated glomerular filtration rate and presence of microalbuminuria.1,2 In recent years, the term cardiorenal syndrome (CRS) has been proposed to define the relationship between cardiac disease and renal disease. Ronco et al has defined CRS as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other.3–6 CRS Type 1: acute CRS is defined as sudden worsening of cardiac function (acute cardiogenic shock or acutely decompensated heart failure), leading to acute kidney injury. CRS Type 2: chronic CRS is defined as chronic abnormalities in cardiac function (chronic congestive heart failure) causing progressive and potentially permanent CKD. CRS Type 3: acute renocardiac syndrome is defined as sudden worsening of kidney function (acute kidney injury or acute glomerulonephritis) causing acute cardiac disorder (heart failure, arrhythmia, or ischemia). CRS Type 4: chronic renocardiac syndrome is defined as CKD contributing to decreased cardiac function, cardiac hypertrophy, and increased risk of adverse cardiovascular events. CRS Type 5: secondary CRS is defined as systemic condition (obesity, diabetes mellitus, sepsis) causing simultaneous cardiac and renal dysfunction. In this review, I will be discussing mainly the type 5 CRS associated with obesity and diabetes mellitus and models of atherosclerosis and vascular calcification. In addition to discussing renal disease, I will also be discussing vascular disease because vascular dysfunction is a well-characterized complication of renal disease, and vascular dysfunction is also a leading cause of cardiac disease. Our work early on determined an important role for altered renal lipid …
Update on Computed Tomography Myocardial Perfusion Imaging

Purpose of Review Computed tomography (CT) coronary angiography is a well-validated non-invasive technique for accurate and expedient diagnosis of coronary artery disease (CAD). However, a limitation of coronary CT angiography (CCTA) is its limited capability to identify physiologically significant stenoses, which may eventuate the need for further functional testing. Stress CT myocardial perfusion imaging (CT-MPI) is an emerging technique that has the ability to identify flow-limiting stenoses.
Analysis of Relationships between Temperament Type and Talent Identification, Tactical Position as well as Technical Specialty in Basketball Players

The growth factors of elite basketball players are various. The identification of sports talent should start first to shorten the way to become a talent. In identifying a sports talent not only the index of shape and function, physical fitness and specific skill should be considered, but also the psychological quality of an athlete. And the temperament type is one of the most important psychological qualities essential for an athlete. There is a close relation between the psychological identification of an athlete and his/her effective training to become a sports talent. In this paper the temperament types of basketball players were studied. The distribution characteristics of their temperament types, the differences of some technical indexes in basketball players of different temperament type were studied. And the relationships between technical specialty and tactical position etc. were further discussed as well. The purpose is to provide beneficial reference for the psychological identification of basketball players and effective training of the players' technical specialty and technical style.
The blood pressure effects of calcium supplementation in humans of known sodium responsiveness.

We examined the interactions between sodium and calcium responsiveness of blood pressure by studying the effects of calcium supplementation in 46 normotensive and hypertensive subjects who had been previously characterized as salt sensitive or salt resistant on the basis of their blood pressure responses to rapid sodium and extracellular volume expansion and contraction. The calcium supplementation study utilized a placebo-controlled, double-blind, randomized crossover design. Subjects received calcium carbonate supplementation (1.5 g/day) for 8 weeks or matching placebo, with 2-week placebo lead-in and crossover periods. For the entire group, no significant blood pressure changes were seen with calcium supplementation. When the subjects were separated on the basis of race or prior salt sensitivity, significant differences were seen. Blacks and salt sensitive subjects exhibited a significant (P < .05) blood pressure decrease when compared to their counterparts. Calcium sensitive subjects had significantly (P < .02) lower levels of plasma renin activity than those not demonstrating a decrease in blood pressure with added calcium. When urinary calcium excretion of subjects previously defined as salt sensitive or salt resistant were compared, the former had significantly (P < .001) higher calcium excretion values at baseline as well as during the placebo and calcium supplementation periods than did the latter. There were no known differences in dietary calcium intake to account for the striking urinary findings. These observations confirm the heterogeneity of blood pressure response to calcium supplementation and demonstrate congruity between sodium and calcium responsiveness of blood pressure in normal and hypertensive humans.(ABSTRACT TRUNCATED AT 250 WORDS)
Antisense Oligonucleotides: Treatment Strategies and Cellular Internalization.

The clinical application of antisense oligonucleotides (ASOs) is becoming more of a reality as several drugs have been approved for the treatment of human disorders and many others are in various phases in development and clinical trials. ASOs are short DNA/RNA oligos which are heavily modified to increase their stability in biological fluids and retain the properties of creating RNA-RNA and DNA-RNA duplexes that knock-down or correct genetic expression. This review outlines several strategies that ASOs utilize for the treatment of various congenital diseases and syndromes that develop with aging. In addition, we discuss some of the mechanisms for specific non-targeted ASO internalization within cells.
Identifying Risk: Concurrent Overlap of the Antarctic Krill Fishery with Krill-Dependent Predators in the Scotia Sea

Mitigating direct and indirect interactions between marine predators and fisheries is a motivating factor for ecosystem-based fisheries management (EBFM), especially where predators and fisheries compete for a shared resource. One difficulty in advancing EBFM is parameterizing clear functional responses of predators to indices of prey availability. Alternative characterizations of fishery-predator interactions may therefore benefit the implementation of EBFM. Telemetry data identify foraging areas used by predators and, therefore, represent critical information to mitigate potential competition between predators and fisheries. We analyzed six years (2009-2014) of telemetry data collected at Cape Shirreff, Livingston Island and Admiralty Bay, King George Island, Antarctica, on three species of Pygoscelid penguins and female Antarctic fur seals. In this region, all four species are primarily dependent on Antarctic krill. The tracking data demonstrate local movements near breeding colonies during the austral summer and dispersal from breeding colonies during the winter. We then assessed overlap between predators and the Antarctic krill fishery on a suite of spatiotemporal scales to examine how different data aggregations affect the extent and location of overlap. Concurrent overlap was observed on all spatiotemporal scales considered throughout the Antarctic Peninsula and South Orkney Islands region, including near tagging locations and in distant areas where recent fishing activity has concentrated. Overlap occurred at depths where mean krill densities were relatively high. Our results demonstrate that direct overlap of krill-dependent predators with the krill fishery on small spatiotemporal scales is relatively common throughout the Antarctic Peninsula region. As the krill fishery continues to develop and efforts to implement ecosystem-based management mature, indices of overlap may provide a useful metric for indicating where the risks of fishing are highest. A precautionary approach to allocating krill catches in space would be to avoid large increases in catch where overlap on small spatiotemporal scales is common.
Bortezomib Down-Regulates HLA Class I and Enhances Natural Killer Cell Mediated Lysis of Myeloma.

Abstract Introduction: Immunotherapy with Natural Killer (NK) cells may eradicate residual chemotherapy-resistant myeloma (MM) after a state of minimal residual disease has been achieved by autologous stem cell supported high-dose chemotherapy. NK cell activity is regulated by Killer Immunoglobulin-Like Receptors (KIRs). The principal inhibitory ligands of KIRs are HLA Class I molecules (-C and -Bw4) expressed by target cells. NK cells lyse tumor cells that do not display such inhibitory KIR-ligands (KIR-L), such as the K562 cell line. The proteasome is responsible for the generation of peptides that bind to and stabilize Class I molecules at the cell surface. We hypothesized that treatment of MM cells with the proteasome inhibitor bortezomib results in the down-regulation of Class I and thereby sensitizes MM to NK cell mediated lysis. Methods: MM cell lines and primary MM cells were treated with concentrations of bortezomib easily achievable in vivo. The objectives were to determine a) the optimal concentration of bortezomib to down-regulate Class I, b) the time to maximum down-regulation of Class I, and c) a bortezomib concentration that increases NK-mediated MM killing without affecting NK cell function. Results: We found that down-regulation of Class I post-bortezomib treatment of the MM cell line, JJN3, and primary MM cells was dose and time dependent. Bortezomib at 10–20nM down-regulated HLA-class I by 63% compared to untreated control cells with maximal down-regulation at 24hrs (Fig.1a). Bortezomib treatment of primary MM cells greatly increased sensitivity to NK cell-mediated lysis, compared to controls (6% vs. 61%) at an E:T ratio of 20:1 (Fig.1b). These bortezomib concentrations did not affect NK cell function. Conclusions: We observed that bortezomib down-regulates Class I and enhances the sensitivity of MM to NK cell-mediated lysis. Our findings have clear therapeutic implications for MM and other NK cell-sensitive malignancies. Download : Download high-res image (87KB) Download : Download full-size image Download : Download high-res image (87KB) Download : Download full-size image
Miniature spectral imaging device for wide-field quantitative functional imaging of the morphological landscape of breast tumor margins.

We have developed a portable, breast margin assessment probe leveraging diffuse optical spectroscopy to quantify the morphological landscape of breast tumor margins during breast conserving surgery. The approach presented here leverages a custom-made 16-channel annular photodiode imaging array (arranged in a 4×4 grid), a raster-scanning imaging platform with precision pressure control, and compressive sensing with an optimized set of eight wavelengths in the visible spectral range. A scalable Monte-Carlo-based inverse model is used to generate optical property [μs′(λ) and μa(λ)] measures for each of the 16 simultaneously captured diffuse reflectance spectra. Subpixel sampling (0.75 mm) is achieved through incremental x, y raster scanning of the imaging probe, providing detailed optical parameter maps of breast margins over a 2×2 cm2 area in ∼9 min. The morphological landscape of a tumor margin is characterized using optical surrogates for the fat to fibroglandular content ratio, which has demonstrated diagnostic utility in delineating tissue subtypes in the breast.
Thermomechanical Concepts and Modeling for Stability Physics in Liquid-Propellant Rocket Engines

Thermomechanical concepts and modeling are used to describe the response of inert and reactive gases to transient, spatially resolved thermal energy deposition. The ultimate goal is to establish th...
Design of Integrated Care and Expansion of Health Insurance for the Underserved and Medically Indigent Population

The US health-care system fails to deliver integrated care through community health centers. The Medicaid crisis encountered by every state is pervasive and has adversely affected emergency departments’ operation and function. The proposed managed care plan for Medicaid beneficiaries is an attempt to develop fundamental principles of reengineering or restructuring the community-based delivery system with applications of health information technology (HIT). This chapter illustrates important integrated care principles for restructuring community health centers to serve the underserved population in the United States. We present a schema for employing health-care information technologies in the design of a community-based delivery system. Based on the best practices of community health centers, we analyze the factors influencing their effectiveness and efficiency. The principles of an integrated care management plan are formulated. Expected outcomes of the HIT-based delivery system are discussed.
Quantitative and Structural Assessment of Histone Methyllysine Analogue Engagement by Cognate Binding Proteins Reveals Affinity Decrements Relative to Those of Native Counterparts

Methyllysine analogues (MLAs), furnished by aminoethylation of engineered cysteine residues, are widely used surrogates of histone methyllysine and are considered to be effective proxies for studying these epigenetic marks in vitro. Here we report the first structure of a trimethyllysine MLA histone in complex with a protein binding partner, quantify the thermodynamic distinctions between MLAs and their native methyllysine counterparts, and demonstrate that these differences can compromise qualitative interpretations of binding at the nucleosome level. Quantitative measurements with two methyllysine binding protein modules reveal substantial affinity losses for the MLA peptides versus the corresponding native methyllysine species in both cases, although the thermodynamic underpinnings are distinct. MLA and methyllysine adopt distinct conformational geometries when in complex with the BPTF PHD finger, a well-established H3K4me3 binding partner. In this case, an ∼13-fold Kd difference at the peptide level translates to nucleosomal affinities for MLA analogues that fall outside of the detectable range in a pull-down format, whereas the methyllysine species installed by native chemical ligation demonstrates robust binding. Thus, despite their facile production and commercial availability, there is a significant caveat of potentially altered binding affinity when MLAs are used in place of native methyllysine residues.
Time delay definitions and characterization in the pacific DC intertie wide area damping controller

When large generation and load centers are separated by long transmission lines, the propensity for complex inter-area oscillations increases. These oscillations are deleterious to utility systems since they may cause damage to equipment or restrictions on power flows. To improve small-signal stability in the utility grid, new methods of control have been introduced that utilize local and remote feedback of phasor measurement unit signals to compute a control action. A key consideration in the implementation of these controls is thus the network and control delays associated with these signals since excessive control delay may degrade performance. This work focuses on the recently installed Pacific DC Intertie wide area damping controller prototype system located at the Celilo Converter Station. Network and control delays are defined and quantified through experiments done to commission the system, and the results are discussed in the context of the controller's expected performance.
Novel regulations of the angiotensin II receptor type 1 by calmodulin

The angiotensin II receptor type 1 (AT1R) mediates many Ca2+-dependent actions of angiotensin II (AngII). Calmodulin (CaM) is a key transducer of Ca2+ signals in cells. Two locations on the receptor's submembrane domains (SMD) 3 and 4 are known to interact with CaM. However, the binding sites for CaM, biochemical properties of the interactions, and their functional impact are not fully understood. Using a FRET-based screening method, we identified a new binding site for CaM on SMD2 (a.a. 125-141), in addition to SMD3 and the juxtamembranous region of SMD4 (SMD4JM, a.a., 309-327). Simultaneous measurements of CaM binding and free Ca2+ show that the interactions are Ca2+-dependent, with disparate Kd and EC50(Ca2+) values within the physiological range of cytoplasmic Ca2+. Full interaction between CaM and SMD3 requires the entire domain (a.a. 215-242) and has an EC50(Ca2+) value in the range of resting cytoplasmic Ca2+, suggesting AT1R-CaM interaction can occur in resting conditions in cells. AngII induces robust ERK1/2 phosphorylation in primary vascular smooth muscle cells. This effect is suppressed by AT1R inhibitor losartan and virtually abolished by CaM antagonist W-7. AngII-induced ERK1/2 phosphorylation is suppressed in cells expressing mutant AT1R with reduced CaM binding at each identified binding domain. AngII triggers transient Ca2+ signals in cells expressing wild-type AT1R. These signals are reduced in cells expressing mutant AT1R with reduced CaM binding at SMD3 or SMD4JM, but are very slow-rising, low amplitude signal in cells expressing AT1R with reduced CaM binding at SMD2. The data indicate that CaM interactions with AT1R can occur at various domains, with different affinities, at different physiological Ca2+ levels, and are important for AT1R-mediated signaling.
The State, Midwives, Expectant Mothers, and Childbirth Reforms from the Meiji Through to the Early Shōwa Period (1868–1930s)

This chapter explores the expansion of modern bio-power in biological reproduction and maternal health from the late 1880s through to the early twentieth century. The key to this process was the spread of “modern” and “hygienic” childbirth practice. This transition involved the restructuring and introduction of medical and other types of institution and practice after the 1868 Meiji Restoration, setting in motion and promoting the modern medicalization of bodies. Building upon the modern health bureaucracy and medical system, the government sought to improve maternal and infant health by producing trained midwives, the so-called “new midwives” [shin sanba] or “modern midwives” [kindai sanba], educated in modern Western medicine. The government and organized medicine intensified their supervision of mothers and reproduction by way of trained and licensed midwives.
Thiols as antioxidant drugs

Drugs containing the thiol moiety (or those metabolized to thiol-containing species) play important and diverse roles in biological systems. Thiols are highly sensitive to the redox environment and form stable disulfide bonds upon oxidation. Thiol drugs exhibit mucolytic and antiurolithic activity, as well as the ability to chelate heavy metals such as lead and mercury. In addition, thiol drugs have untapped potential as primary and adjuvant therapies in a wide variety of oxidative stress-related conditions. Thiol drugs bolster GSH levels following acetaminophen overdose, protect tissues against free radical attack after ionizing radiation exposure, and may mitigate lens protein disruption in cataract. Moving forward, chemical alterations or drug delivery strategies may further improve the effectiveness of thiol drugs by increasing bioavailability while reducing systemic side-effects. This presentation will highlight research on the effects of thiol drugs in conditions with therapeutically exploitable redox dysregulation, including heavy metal toxicity, radiation poisoning, acetaminophen toxicity, cataracts and others.
Streamlining building energy efficiency assessment through integration of uncertainty analysis and full scale energy simulations

Abstract Asset Score is a standardized rating system and tool for assessing a building's energy-related systems in the United States. The web-based tool models building energy use under standard operating conditions to rate the energy efficiency of the as-built building systems and enable level comparisons of building assets. With basic characteristics entered by users, the tool creates simplified EnergyPlus building models to support the rating analysis. However, even with a reduced set of model inputs, data collection remains a challenge and the commercial building market demands a more simplified entry point to the rating system. This paper discusses a hybrid method that combines regression models with real-time simulations to allow users to enter as few as seven building parameters to quickly assess the building energy performance prior to a full-scale analysis. Built upon large-scale building stock simulations, a random forest approach was used to develop a set of regression models for various building use types. The majority of the Asset Score tool inputs were sampled extensively and fed into the regression models. These were combined with inferred inputs and user-defined uncertainty levels to create a distribution of possible energy use intensities for the building and its Preview score. With additional user inputs, the regression model can be transferred to an energy model for a full-scale energy simulation. The streamlined Asset Score Preview assessment provides an easy entry point to a full Asset Score assessment. It also enables users who manage a large number of buildings to screen and prioritize buildings that can benefit most from a more detailed evaluation and possible energy efficiency upgrades without intensive data collection.
Terrorism, Secession, and the United States: An Indigenous Perspective

Previous chapters of this book have laid the groundwork for the analyses of the natures and moral justification of terrorism and secession, respectively. The neutral conditions of what amounts to terrorism have been set forth and defended, along with the rather demanding (on terrorists) conditions of morally justified terrorism. Prior to that “secession” was defined and a Territorialist Rights-Based (Indigenous) Theory of Secession was articulated and defended. Now it is important to ask if there exist conditions which, morally speaking, might justify terrorism against and/or secession from the United States, and if so, why? In this regard, we want to know if (1′)-(6) of morally justified terrorism (set forth and defended in Chapter 5) might be satisfied concerning the U.S. government and/or its citizens. Yet we also want to know whether the conditions that would justify, on moral grounds, secession can be satisfied in the case of Native Americans in the U.S. Along the way, it is helpful to know whether or not secession and terrorism might be morally justified in the case of the U.S. It is to these complex issues that I now turn, beginning with secession and the U.S.
Message Passing Algorithms for Semiring-Based and Valued Constraint Satisfaction Problems

Local consistency algorithms, like arc consistency (AC) algorithms, are polynomial-time algorithms that prune the search space of constraint satisfaction problems (CSPs). In this paper, we present connections between message passing algorithms and AC for semiring-based CSPs (SCSPs) and valued CSPs (VCSPs), two well-established frameworks that generalize CSPs. Message passing algorithms are well known distributed search algorithms for solving many combinatorial problems in artificial intelligence, probabilistic reasoning, and information theory. However, the relationship between message passing algorithms and SCSPs or VCSPs still remains understudied. Towards this end, we propose the best-O message passing (BOMP) algorithm for SCSPs and VCSPs. We prove that, unlike other standard message passing algorithms which are in general not guaranteed to converge, the BOMP algorithm guarantees convergence for SCSPs and specific subclasses of VCSPs. We also theoretically study the relationship between the BOMP algorithm and AC on SCSPs, and empirically study the quality of the solutions produced by the BOMP algorithm for VCSPs.
Thermal environment sensor array: Part 2 applying the data to assess grow-finish pig housing

Current thermal environment (TE) assessment techniques for controlling livestock and poultry facilities often solely use dry-bulb temperature (Tdb) and occasionally relative humidity (RH) as assessment parameters. The TE sensor array (TESA; Part 1) provides the opportunity to simultaneously quantify Tdb, RH, airspeed, and black globe temperature, but there are no existing methods incorporating these additional TE parameters to accurately assess the TE based on the thermal demands of the animal. Hence, the goal of Part 2 of this series was to develop a technique for evaluating the TE as a function of mean body temperature difference from thermally comfortable (ΔTb) using body mass, Tdb, RH, and airspeed inputs. Multiple regression analysis of the simulated data from the mechanistic thermal balance model for group-housed growing pigs was used to develop the Housed Swine Heat Stress Index (HS2I), which scales impact of the TE from 0 (thermally comfortable) to 10 (severe heat stress). Further, a wetted skin adjustment parameter was included to enable analysing TE with sprinklers. Simulated and predicted ΔTb agreed well without wetted skin (R2 = 0.98; RMSE = 0.061 °C) and with wetted skin (R2 = 0.97; RMSE = 0.054 °C). The HS2I was applied to assess the spatiotemporal TE data collected by TESA in the commercial grow-finish facility presented in Part 1. HS2I can be used to evaluate the potential impact of the TE in existing facilities and as a design tool to explore different ventilation and cooling strategies.