cssi/SciSciGPT-SciSciNet huggingface dataset:
Structure-based design of a T-cell receptor leads to nearly 100-fold improvement in binding affinity for pepMHC.

T-cell receptors (TCRs) are proteins that recognize peptides from foreign proteins bound to the major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This interaction enables the T cells to initiate a cell-mediated immune response to terminate cells displaying the foreign peptide on their MHC. Naturally occurring TCRs have high specificity but low affinity toward the peptide-MHC (pepMHC) complex. This prevents the usage of solubilized TCRs for diagnosis and treatment of viral infections or cancers. Efforts to enhance the binding affinity of several TCRs have been reported in recent years, through randomized libraries and in vitro selection. However, there have been no reported efforts to enhance the affinity via structure-based design, which allows more control and understanding of the mechanism of improvement. Here, we have applied structure-based design to a human TCR to improve its pepMHC binding. Our design method evolved based on iterative steps of prediction, testing, and generating more predictions based on the new data. The final design function, named ZAFFI, has a correlation of 0.77 and average error of 0.35 kcal/mol with the binding free energies of 26 point mutations for this system that we measured by surface plasmon resonance (SPR). Applying the filter that we developed to remove nonbinding predictions, this correlation increases to 0.85, and the average error decreases to 0.3 kcal/mol. Using this algorithm, we predicted and tested several point mutations that improved binding, with one giving over sixfold binding improvement. Four of the point mutations that improved binding were then combined to give a mutant TCR that binds the pepMHC 99 times more strongly than the wild-type TCR. Proteins 2009. © 2008 Wiley-Liss, Inc.
LDPC codes from voltage graphs

Several well-known structure-based constructions of LDPC codes, for example codes based on permutation and circulant matrices and in particular, quasi-cyclic LDPC codes, can be interpreted via algebraic voltage assignments. We explain this connection and show how this idea from topological graph theory can be used to give simple proofs of many known properties of these codes. In addition, the notion of Abelian-inevitable cycle is introduced and the subgraphs giving rise to these cycles are classified. We also indicate how, by using more sophisticated voltage assignments, new classes of good LDPC codes may be obtained.
Phase behavior of hydrogen–light‐hydrocarbon systems

The decreasing solubility of hydrogen in hydrocarbons with decreasing temperature continues down to the freezing point of the hydrocarbons, around −300°F. This behavior is shown to be an enlargement of phenomena exhibited by normal hydrocarbon mixtures. Methods of predicting equilibrium-phase compositions are presented for hydrogen in ligh-hydrocarbon systems. The correlations are satisfactory for binary and certain ternary systems, but are not reliable for complex mixtures.
Climate change in our backyards: the reshuffling of North America's winter bird communities

Much of the recent changes in North American climate have occurred during the winter months, and as result, overwintering birds represent important sentinels of anthropogenic climate change. While there is mounting evidence that bird populations are responding to a warming climate (e.g., poleward shifts) questions remain as to whether these species-specific responses are resulting in community-wide changes. Here, we test the hypothesis that a changing winter climate should favor the formation of winter bird communities dominated by warm-adapted species. To do this, we quantified changes in community composition using a functional index--the Community Temperature Index (CTI)--which measures the balance between low- and high-temperature dwelling species in a community. Using data from Project FeederWatch, an international citizen science program, we quantified spatiotemporal changes in winter bird communities (n = 38 bird species) across eastern North America and tested the influence of changes in winter minimum temperature over a 22-year period. We implemented a jackknife analysis to identify those species most influential in driving changes at the community level and the population dynamics (e.g., extinction or colonization) responsible for these community changes. Since 1990, we found that the winter bird community structure has changed with communities increasingly composed of warm-adapted species. This reshuffling of winter bird communities was strongest in southerly latitudes and driven primarily by local increases in abundance and regional patterns of colonization by southerly birds. CTI tracked patterns of changing winter temperature at different temporal scales ranging from 1 to 35 years. We conclude that a shifting winter climate has provided an opportunity for smaller, southerly distributed species to colonize new regions and promote the formation of unique winter bird assemblages throughout eastern North America.
Multiple Sclerosis Presenting at 4 Years of Age: Clinical and MRI Correlations:

The authors present a patient with multiple sclerosis (MS) whose onset of illness was at 4 years of age. Three separate and distinct episodes of central nervous system (CNS) dysfunction associated with cerebrospinal fluid (CSF) pleocytosis, electroencephalographic (EEG) abnormalities, and extensive CNS white matter demyelination on both computerized tomography (CT) and magnetic resonance imaging (MRI) characterized her clinical course. Two episodes responded well to prednisone therapy.
Correlation length and chirality of the fluctuations in the isotropic phase of nematic and cholesteric liquid crystals

Light-scattering measurements of the correlation length in the isotropic phase of a nematic liquid crystal reveal a temperature dependence following Landau--de Gennes theory for the isotropic phase with a bare correlation length smaller than has been measured in other liquid crystals. Similar measurements in a cholesteric liquid crystal demonstrate that the correlation length in the isotropic phase is larger than typically found in nematics and that the chirality of the fluctuations in the isotropic phase is slightly higher than the chirality of the cholesteric phase. Landau--de Gennes theory of the cholesteric phase describes the chirality in the cholesteric phase well but predicts that the chirality in the isotropic phase is temperature independent, which is not consistent with the data. There is a discontinuity in the chirality at the cholesteric-isotropic transition of about 15%, which is less than the predictions of Landau--de Gennes theory but more than the typical specific volume discontinuity at transitions to the isotropic phase. Except for a mismatch in the discontinuities at the transition, the chirality data resemble the temperature behavior of variables just below a critical point, in spite of the fact that this system is far from a critical point.
A test of the importance of direct and indirect fitness benefits for helping decisions in western bluebirds

In cooperative breeders, the extent to which helpers at the nest adjust their contributions in accordance with direct and indirect (kin-selected) fitness payoffs remains an open question. In a long-term study of the western bluebird, Sialia mexicana, helpers were exclusively male and helped at nests of both parents, a parent and stepparent, or a brother and unrelated female. This natural variation in the context of helping facilitated comparison of observational data on groups in which one type of fitness benefit (current direct, future direct, or indirect) varied, whereas the other two were constant. Helpers reduced their share of provisioning as they got older, so comparisons were restricted to groups with yearling helpers. When potential direct fitness benefits were identical, but relatedness was reduced by half owing to the presence of a stepparent, yearling helpers failed to reduce their share of feeding trips to the nest. The potential for future direct fitness benefits via possible mate and territory inheritance was low, and did not influence the helper’s share of provisioning in a comparison of groups with similar relatedness and opportunities for current direct fitness benefits. Even though cobreeding to gain current direct fitness benefits was infrequent (17% of nests with brother-helpers), it was associated with an increase in the helper’s share of provisioning, suggesting that a helper’s feeding allocation responds positively to increased opportunity for parentage in the nest. The current study demonstrates a useful framework for separating direct and indirect benefits with respect to helping decisions, and indicates that western bluebird helpers adjust their feeding rates in response to the potential for direct fitness benefits in the current nest, not indirect benefits or future direct fitness payoffs. Although past studies of this population showed that indirect benefits play a role in whether or not helpers help, the current study indicates that they do not play a role in how frequently helpers feed at the nest.
Private sector influence in the International Telecommunication Union

Purpose – This paper aims to examine the influence of private corporations in the tripartite structure of the International Telecommunications Union (ITU): Telecommunications Standardization, Radiocommunication, and Telecommunications Development.Design/methodology/approach – This research employs institutional ethnography in conjunction with the case study.Findings – The paper finds that, in the standardization sector, power has been effectively transferred from nation states to the private corporate sector since the approval process now enables standards to be approved by members of the study group that developed them, which is essentially the private sector. In the radiocommunication sector, the private sector continues to conduct much of the requisite technical work, but national governments are ultimately the decision makers and, further, it is difficult to distinguish between treaty and non‐treaty work. In the development sector, the ITU seeks to create an enabling environment for private investment...
Sevrage de l’oxygène

Resume La question du sevrage de l’oxygene reste un probleme difficile et revient a poser trois questions : qu’attendons-nous d’une oxygenotherapie ? (dans quel but ?), quelles sont les cibles de saturation que nous devons viser ? Quel est le mode de surveillance optimale ? Nous essaierons d’envisager ici ces differents points en sachant l’incertitude des reponses que nous pouvons proposer et leur caractere ephemere.
Flow cytometry of fetal adrenal glands with adrenocortical cytomegaly.

Adrenal glands from four autopsied fetuses of 18 to 36 weeks gestation showed varying degrees of cortical cytomegaly. Formalin'fixed, paraffin-embedded sections from these four pairs of glands were studied by flow cytometry to analyze their DNA content and cell cycle parameters. Flow cytometry of Case 1, which had diffuse bilateral cytomegaly, demonstrated a major diploid peak, an increased percentage of tetraploid cells, and a decrease in S phase compared to an age-matched control with no evidence of cytomegaly (Case 2). Cases 3, 4, and 5 showed focal and/or unilateral adrenocortical cytomegaly and were diploid by flow cytometry with no differences in synthetic or tetraploid fractions compared to the control tissues. The focal distribution of the lesions or the limits of resolution of the instrumentation could account for some of these results. However, the findings in Case 1 suggest that the cytomegalic cells are tetraploid in DNA content and may have decreased DNA synthetic activity. A current hypothes...
Dependence of lake ice covers on climatic, geographic and bathymetric variables

Abstract Information on lake ice characteristics is of interest to lake users, natural resource managers and researchers. Lake ice data for 143 North American freshwater lakes were assembled and analyzed. The principal data were observed ice-in dates, observed ice-out dates and observed ice thicknesses. Single variable linear regression and factor analysis were applied to find correlations with air temperature, lake morphometry (mean depth and surface area), latitude and topographic elevation. Strong correlations between lake ice parameters, latitude and mean air temperature were found and quantified. Lake morphometry exhibited consistent but less significant correlation to ice cover. Elevation showed varying degrees of correlation with the dependent variables. Multivariable regression analysis produced equations for ice-in date, ice-out date, ice-cover duration and maximum ice thickness. Despite low standard errors, the best regressions cannot account for the full range of annual variability in the historical records, implying the absence of influential factors from these regression models. Based on sensitivities gleaned from linear regression analysis, the effects of climate change on lake ice characteristics may also be estimated. The following are estimated shifts based on a 1 °C rise in average air temperature: ice-in date occurs ∼5 days later, ice-out date occurs ∼6 days earlier, ice cover duration (ICD) is reduced by ∼11 days, and maximum ice thickness is reduced by ∼7 cm. These values are on the order of those presented in prior studies using other methodologies and lakes.
Droplet-based chemistry on a programmable micro-chip

We describe the manipulation of aqueous droplets in an immiscible, low-permittivity suspending medium. Such droplets may serve as carriers for not only air- and water-borne samples, contaminants, chemical reagents, viral and gene products, and cells, but also the reagents to process and characterise these samples. We present proofs-of-concept for droplet manipulation through dielectrophoresis by: (1) moving droplets on a two-dimensional array of electrodes, (2) achieving dielectrically-activated droplet injection, (3) fusing and reacting droplets, and (4) conducting a basic biological assay through a combination of these steps. A long-term goal of this research is to provide a platform fluidic processor technology that can form the core of versatile, automated, micro-scale devices to perform chemical and biological assays at or near the point of care, which will increase the availability of modern medicine to people who do not have ready access to modern medical institutions, and decrease the cost and delays associated with that lack of access.
Destabilization of CAG Trinucleotide Repeat Tracts by Mismatch Repair Mutations in Yeast

To examine the genetic factors that affect the stability of disease-associated trinucleotide repeats, we have assessed the stability of CAG repeats in yeast strains with mutations in the mismatch repair system. We have found that both pms1 and msh2 mutations destabilize repeat tracts. Destabilization is evidenced both by the increased frequency of repeat length changes and in the pattern of changes that are observed. In wild-type cells repeats are relatively stable when CAG serves as the lagging strand template but relatively unstable when CTG serves as the lagging strand template. Large contractions in repeat length are the most common change. In pms1 and msh2 mutants the relatively stable tracts incur more tract length changes. In addition, many small deletions and some small additions, most often of one repeat unit, are frequent in repeats of the stable orientation. These small changes also are seen as a new class of events that occur in repeats in the unstable orientation. The results show that in yeast the mismatch repair system prevents small changes from occurring but cannot prevent larger changes from occurring.
The β2-Adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-Dependent coupling to phosphatidylinositol 3'-kinase

Recent studies have shown that chronic beta-adrenergic receptor (beta-AR) stimulation alters cardiac myocyte survival in a receptor subtype-specific manner. We examined the effect of selective beta(1)- and beta(2)-AR subtype stimulation on apoptosis induced by hypoxia or H(2)O(2) in rat neonatal cardiac myocytes. Although neither beta(1)- nor beta(2)-AR stimulation had any significant effect on the basal level of apoptosis, selective beta(2)-AR stimulation protected myocytes from apoptosis. beta(2)-AR stimulation markedly increased mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) activation as well as phosphatidylinositol-3'-kinase (PI-3K) activity and Akt/protein kinase B phosphorylation. beta(1)-AR stimulation also markedly increased MAPK/ERK activation but only minimally activated PI-3K and Akt. Pretreatment with pertussis toxin blocked beta(2)-AR-mediated protection from apoptosis as well as the beta(2)-AR-stimulated changes in MAPK/ERK, PI-3K, and Akt/protein kinase B. The selective PI-3K inhibitor, LY 294002, also blocked beta(2)-AR-mediated protection, whereas inhibition of MAPK/ERK activation at an inhibitor concentration that blocked agonist-induced activation but not the basal level of activation had no effect on beta(2)-AR-mediated protection. These findings demonstrate that beta(2)-ARs activate a PI-3K-dependent, pertussis toxin-sensitive signaling pathway in cardiac myocytes that is required for protection from apoptosis-inducing stimuli often associated with ischemic stress.
What Is a Destituent Power

The following essay by Giorgio Agamben is based on a lecture given in central France in the summer of 2013. Responding directly to recent occupations and insurrections—from Cairo and Istanbul to London and New York City—Agamben builds upon his existing work in order to develop and clarify his understanding of the political and, in particular, the notion of destituent power (potenza destituente). In contrast to attempts to affirm a constituent power independent of a relation to constituted power, which for Agamben both reproduce the governmental structure of the exception and represent the apex of metaphysics, destituent power outlines a force that, in its very constitution, deactivates the governmental machine. For Agamben, it is in the sensible elaboration of the belonging together of life and form, being and action, beyond all relation, that the impasse of the present will be overcome. Ultimately, Agamben points not only towards what it means to become Ungovernable, but towards the potential of staying so.
Institutional Review Boards and Professional Counseling Research.

Institutional review boards (IRBs) are responsible for regulating and safeguarding research with human participants in academic institutions in the United States. The authors explore (a) the historical impetus for IRBs, (b) the ethical values and principles as core components of the review process, and (c) the American Counseling Association's (2005) standards for ethical research. In many ways, IRB review and counseling research are complementary, yet some challenges and obstacles unique to counseling research also exist and are elaborated in the article. Implications for counselors initiating research projects and suggestions for implementation are provided.
Simulator training in endoscopic hemostasis.

Endoscopic management of acute gastrointestinal (GI) bleeding is an advanced procedure associated with high morbidity and mortality. The traditional apprentice model of training for such events is often inadequate because of their unpredictable frequency, common occurrence off hours, and high stakes for patient outcome. Hemostasis is the cessation of active bleeding and prevention of rebleeding with an endoscopic intervention. Proficiency in endoscopic management of GI hemorrhage includes proper preparation, a systematic categorization of both the source of bleeding and the technique used to control it, the necessary knowledge base, and technical skills to perform the endoscopic intervention. Various simulation platforms, including virtual reality simulators, in vivo models, and explanted tissue, can be helpful in gaining proficiency in endoscopic hemostasis, although validated criteria for obtaining and maintaining procedural competence in this area are still lacking.
Knockout of p21-activated kinase-1 attenuates exercise-induced cardiac remodelling through altered calcineurin signalling.

Aims Despite its known cardiovascular benefits, the intracellular signalling mechanisms underlying physiological cardiac growth remain poorly understood. Therefore, the purpose of this study was to investigate a novel role of p21-activated kinase-1 (Pak1) in the regulation of exercise-induced cardiac hypertrophy. Methods and results Wild-type (WT) and Pak1 KO mice were subjected to 6 weeks of treadmill endurance exercise training (ex-training). Cardiac function was assessed via echocardiography, in situ haemodynamics, and the pCa–force relations in skinned fibre preparations at baseline and at the end of the training regimen. Post-translational modifications to the sarcomeric proteins and expression levels of calcium-regulating proteins were also assessed following ex-training. Heart weight/tibia length and echocardiography data revealed that there was marked hypertrophy following ex-training in the WT mice, which was not evident in the KO mice. Additionally, following ex-training, WT mice demonstrated an increase in cardiac contractility, myofilament calcium sensitivity, and phosphorylation of cardiac myosin-binding protein C, cardiac TnT, and tropomyosin compared with KO mice. With ex-training in WT mice, there were also increased protein levels of calcineurin and increased phosphorylation of phospholamban. Conclusions Our data suggest that Pak1 is essential for adaptive physiological cardiac remodelling and support previous evidence that demonstrates Pak1 signalling is important for cardiac growth and survival.
Philadelphia Odd Couple - Silas Weir Mitchell - Neurologist-Novelist-Poet and Phillips Brooks - Brahmin Prophet - Sons of 19th Century Rittenhouse Square (P1.288)

OBJECTIVE: To identify intellectual and spiritual influences on Silas Weir Mitchell by Phillips Brooks and how they shaped Mitchell’s career. BACKGROUND: New insights to the life and works of Silas Weir Mitchell are provided by Nancy Cervetti in S. Weir Mitchell, 1829-1914 : Philadelphia9s Literary Physician [ Pennsylvania State University Press 2012 (ISBN-10: 0271054034 | ISBN-13: 9780271054032) ] but in depth review of letters between Mitchell and Phillips Brooks identified a unique relationship between the poet in Mitchell and the lyricist in Brooks who wrote “O Little Town of Bethlehem” three years after a post-Civil War journey to Palestine in 1865. DESIGN/METHODS: Historical review of primary sources - letters, personal papers of S Weir Mitchell and Philips Brooks, family anecdotes and secondary sources - biographies published before 2012. RESULTS: Shortly after S Weir Mitchell return from study in Paris, France Switzerland and Italy, he and Phillips Brooks formed a firm personal friendship when Brooks took over as rector of the Church of the Advent in Philadelphia in 1859. This friendship involved numerous nightly conversations between Mitchell and Brooks as well as Mitchell’s sister, Elizabeth. Mitchell and Brooks traveled in summers to Mount Desert Island, Maine before Mitchell established this as a locus for his literary endeavors. Brooks served as a liaison between Mitchell and Oliver Wendell Holmes among others in Boston. Mysteries surround the intense correspondence between Elizabeth Mitchell and Phillips Brooks and why many of the letters were not published from the post-Civil war period when Brooks left Philadelphia in 1896 to go to Boston as rector of the Trinity Church in Copley Square, much to Elizabeth Mitchell’s lament. Brooks served as a lightning rod for Mitchell’s shibboleths such as the “Rest Cure" and other idiosyncrasies. CONCLUSIONS: Phillips Brooks and Silas Weir Mitchell were a Philadelphia odd couple closely linked by Elizabeth Mitchell, his sister. Their friendship spanned nearly a half-century and affected the intellectual prowess of each. Disclosure: Dr. Brooks has received personal compensation for activities with Biogen Idec, Avanir Pharmaceuticals, Acorda Therapeutics, Cytokinetics, Synapse, and the National Institute of Neurological Disorders and Stroke. Dr. Brooks has received research support from Biogen Idec, Avanir Pharmaceuticals, Cytokinetics, Neuraltus Pharmaceuticals, GlaxoSmithKline, Inc., and the National Institute of Neurological Disorders and Stroke.
Hub Network Location

The ‘hub-and-spoke’ network is an important design for a variety of transportation and communications systems. Critical to the hub-based model is the idea that flows between origins and destinations passing through intermediate switching points along the journey. Flows pass from origins via spokes to hub(s), and from hub to hub, and finally from hub to destination. Hubs can therefore be viewed as switching points for interactions. The location of these hubs has become an active area of research for geographers and others interested in the operational planning of diverse areas such as telecommunications, logistics, and passenger transportation. While there are many variants on the conceptual problem, they can be usefully broken down depending on their approaches to three key questions: do nodes connect to ‘single’ or to ‘multiple’ hubs; is the hub-to-hub subnetwork fully connected; and, are nodes permitted to be connected to each other directly, bypassing the use of hubs? A full suite of techniques from mathematical programming has been devoted to designing efficient solutions for such networks, under a variety of connection protocols. Important insights include the contrast between hub location and classical facility location, and extensive algorithmic work that has extended the theoretical models to practical cases.
Development of a Testing System for Piezoelectric Wafer Active Sensors Exposed to Extreme Temperatures

Piezoelectric Wafer Active Sensors (PWAS) are a viable option for monitoring the structural integrity of pressure vessels and piping systems. They are inexpensive, small and unobtrusive sensors which can be permanently attached to structures for long term monitoring without interfering with operations, such as operating in areas with limited head space. PWAS are used to inspect the structure through several methods which include; pitch catch or pulse echo wave propagation, and electromechanical impedance spectroscopy. Since the PWAS could be exposed to a range of environmental and/or operating conditions while attached to the structure, the change in the properties and electromechanical characteristics of the sensor must be known at a given condition. Accordingly, there is a need for a testing system which can measure the PWAS properties while exposing the sensor to a wide range of temperatures.The focus in this paper is on elevated temperatures, but the same methodology could be used for low temperature or environmental testing. The requirements which were imposed on the design include: providing an electrical connection from each electrode to the exterior of an industrial oven; allow the sensor to expand and contract both in plane and out of plane; withstand an extended duration at elevated temperatures; the equipment must not influence the measured quantities. The challenges include how to place the sensor in an oven and make electrical contact while allowing free motion, how to implement wiring and electrical connections at elevated temperatures, how to allow the thermal expansion of components and account for thermal mismatching, and how to maintain electrical isolation of the two electrodes. This paper discusses how these requirements were met and challenges overcome, as well as experimental validation of the system.Copyright © 2015 by ASME
Chapter 6 Bimetallic Catalysts for Co Activation

Publisher Summary Bimetallic catalysts play an important role in many industrial catalytic processes and represent an area of intense research interest. Bimetallic systems give an opportunity to investigate geometrical versus electronic or ligand effects in catalysis. Studies of these effects can help to elucidate the key factors controlling the activity and more importantly, the selectivity of metal catalysts. For the designer of catalysts, adding a second metal component allows to systematically alter the size or electronic structure of catalytic surface ensembles. One could envision modifications of the adsorption characteristics, of the surface coverage with reactive intermediates, and consequently of the selectivity. The presence of a second metal component can make its influence felt in terms of changes in reducibility of the catalyst. Furthermore, the second metal component can in certain cases alter the deactivation behavior, a fact that has proven to be beneficial in bimetallic reforming catalysts. This chapter focuses on the modification of surface sites by addition of a second metal component and on the direct conversion of synthesis gas over organometallic clusters or cluster-derived catalysts that are not entirely subject to the Anderson-Schultz-Flory polymerization kinetics. The chapter reviews the methanation process, Fischer-Tropsch catalysts modified by addition of a second metal component, and bimetallic catalysts derived from organometallic clusters. It seeks to present an overview of supported bimetallic CO activation catalysts and to highlight major trends and fundamental principles.
Contemporary Review of Treatment Options for Peyronie's Disease

Peyronie's disease (PD) is a penile wound-healing disorder resulting in fibrotic plaque in the tunica albuginea, likely resulting from micro trauma. Due to variable disease presentations, a myriad of proposed treatment options, physician misconceptions about the disorder, and severe psychological distress in afflicted patients, PD can be a difficult to manage entity. This review seeks to provide a current and comprehensive overview of oral, topical, intralesional, mechanical, and surgical therapies for PD.
Practical Advancements in Digestive Physiology and Futuristic Research Needs in Poultry

Abstract While predicting future needs is risky, it is very likely that the human population will increase substantially in the next twenty years. Agricultural production is declining or stabilizing in many areas, so competition for food resources will increase. Poultry and livestock will be competing with humans. Producers may be forced to use poorer quality feed ingredients for animals than are currently in use. Research on the practical use of ingredients such as cellulose, uric acid, and chitin should be undertaken.
Parallel Electrophoretic Analysis of Segmented Samples On Chip for High-Throughput Determination of Enzyme Activities

Capillary electrophoresis (CE) on microfabricated structures has achieved impressive sample throughput by combining fast separation speed and parallel operations. One obstacle to further increasing throughput has been lack of methods for loading and injecting individual samples at a rate that matches analysis speed. To address this issue, we have developed a microfluidic device in which samples stored as nanoliter volume plugs segmented by a fluorocarbon oil are introduced sequentially to an array of three electrophoresis channels. A microfluidic interface consisting of patterned surface chemistry and geometric restriction was used to extract samples from each segmented flow channel and transfer to the respective electrophoresis channel for separation. Fluorescence detection was achieved by imaging the chip using a fluorescence microscope equipped with a charge-coupled device. Characterization of the system shows that injection volume is controlled by sample plug volume, flow rate during introduction, and voltage applied to the electrophoresis channel. The system was tested for a GTPase assay. Peak area ratios of enzyme product and internal standard had 6% relative standard deviations. Cross-contamination between peaks was 7%. Throughput of 120 samples in 10 min was achieved. Further development of the system may allow application to high-throughput applications such as drug screening.
Dramatic Behavioral Differences of the Copolymerization Reactions of 1,4-Cyclohexadiene and 1,3-Cyclohexadiene Oxides with Carbon Dioxide

The copolymerization of 1,3-cyclohexadiene oxide (1,2-epoxy-3-cyclohexene) with CO2 in the presence of the binary catalyst (salen)CoX or (salen)CrX and onium salts was shown to selectively afford the completely alternating copolymer poly(1,3-cyclohexadiene carbonate) in good yield. In the process catalyzed by the cobalt(III) system, the reaction was 100% selective for copolymer, whereas employing the higher temperature chromium(III) catalyst, the reaction yielded in addition to copolymer a significant quantity of the cis-1,3-cyclohexadiene carbonate. Importantly, no corresponding trans-1,3-cyclohexadiene carbonate was produced. The reactivity of 1,3-cyclohexadiene oxide in coupling reactions with CO2 was strikingly greater than that of 1,4-cyclohexadiene oxide under either catalytic conditions. Authentic samples of the cis-cyclic carbonate and trans-cyclic carbonate were synthesized from epoxide and CO2 using ZnCl2/PPNI catalyzed and trans-diol/ethyl chloroformate routes, respectively. trans-1,3-Cyclohexa...
Understanding the Mechanisms of Desistance at the Intersection of Race, Gender, and Neighborhood Context

Objectives:This study tests theorized mechanisms of desistance, and whether the process of desistance is conditioned by social structural position.Methods:We investigate how marriage promotes desistance from crime among urban African American males raised in the Woodlawn community, a disadvantaged neighborhood in Chicago. Using hierarchical linear modeling, we test the resiliency of the marriage effect by observing offending trajectories following marital dissolution; is the marriage effect conditional upon staying married, indicating situational effects? or does the effect persist when marriage is taken away, indicating enduring effects? Further, we test if the process of desistance is conditional upon contextual disadvantage.Results:While initial findings show an increase in violent and property offending upon divorce, further analysis shows evidence that this effect differs by neighborhood structural context; the increase in offending upon divorce is apparent only for African American men who experienc...
Selective ligands for lysophosphatidic acid receptor subtypes: gaining control over the endothelial differentiation gene family.

In this issue of Molecular Pharmacology , [Heise et al. (2001)][1]report their results with derivatives of N -acyl ethanolamide phosphate that display subtype-selective agonist and antagonist properties for the endothelial differentiation gene (EDG) family of lysophosphatidic acid (LPA) receptors ([
Effects of invasive plant patch size and distance on the pollination and reproduction of native boreal plants

In pollinator-limited ecosystems in the earliest stages of the invasion process, the effects of invasive plants on the pollination and reproduction of co-flowering native plants may be particularly sensitive to the distance between native and non-native plants. Our study tests how the distance from invasive plant patches affects the pollination and reproduction of two native boreal shrubs. We established circular sites with plots of flowering Vaccinium vitis-idaea L. and Rhododendron groenlandicum (Oeder) Kron and Judd spanning from 1 to 40 m from the site center. In 2011 and 2012, we added flowering non-native Melilotus albus Medik. to the center of sites in small patches (40 individuals) or large patches (120 individuals) and left other sites as controls. In some cases, the effects of M. albus were uniform across the 40 m distance, such as the change in V. vitis-idaea seed production when large patches of M. albus were added. In other cases, relationships with distance were found, and changes in percent...
Effects of anandamide administration on components of reward processing during free choice

Previous research has implicated the positive modulation of anandamide, an endocannabinoid neurotransmitter, on feeding behavior. Anandamide is particularly noteworthy as it acts as an endogenous ligand of the CB1 receptor, the same receptor that is activated by tetrahydrocannabinol, the primary psychoactive component in Cannabis sativa. Cannabis legalization in North America has presented with a need to study endocannabinoid agonists and their effects on behavior. Much has yet to be determined in terms of the role of the endocannabinoid system in decision-making scenarios. The research presented here tested the hypothesis that anandamide would augment motivation and reward processing via appetitive and consummatory measures during an operant, foraging task. A three-box design was used in order to provide the animals with a free choice, exploratory foraging environment. Discrimination, preference, and incentive contrast were analyzed as discrete measures of decision-making in the three-box paradigm. Anandamide administration (1mg/kg) was found to significantly increase motivation for the optimal foraging outcome and alter basic processing of reward information involved in discrimination and relative valuation. The positive effects of anandamide on eating behavior and motivation have implications toward possible treatment modalities for patient populations presenting with disorders of motivation. These findings suggest the need for continued investigation of the endocannabinoid system as a central component of motivated behavior.
Numerical Modeling of a Caisson Foundation Retrofitted with Helical Piles

While the nonlinear finite element analysis methods have been commonly used for the performance assessment of existing structures, their use for the retrofit design of concrete foundations has remained limited. One reason for this is the sophisticated modeling process which requires knowledge, experience, and caution. This study demonstrates the applicability and benefit of the nonlinear finite element modeling for the performance-based structural retrofit design of caisson foundations. The foundation system investigated supports a self-supporting telecommunication tower located in Canada. The addition of new antennas and the change in the design standards requires the caisson foundations of this tower to be retrofitted with new cap beams and helical piles to resist significant additional tensile forces. A two-stage analysis and design process is conducted with the help of a continuum-type finite element analysis method, treating reinforced concrete as an orthotropic material and employing the constitutive relations of the Disturbed Stress Field Model. General modeling guidelines and the points for caution are discussed for the retrofit design of caisson foundations using nonlinear analysis methods.
Cryopreserved embryos: a response to "forced parenthood" and the role of intent.

Assisted reproductive technologies (ART) are changing the legal defi nitions of parenthood. The severing of genetic ties from gestational ones and from the social aspect of parenting has resulted in courts having to revise traditional definitions of mother and father. This has led to a legal construct known as "intended parenthood," in which biological ties are sometimes subordinated in determining the relative parental rights and obligations of the parties. In the case of cryopreserved embryos, courts have used this "intended parenthood" doctrine in a different context, as they search for principles to guide them in making disposition of embryos upon divorce. In these cases, the courts are using the intended parenthood doctrine not to form parent-child relationships, but to deny them. Pertinent provisions of The Uniform Parentage Act also employ this intentional parenthood doctrine, using it to deprive children born of gametes or embryos of a legal father after a divorce, unless he has expressly consented to his own parental status. Among the consequences to these children who have no legal father will be the inability of the child to look to the father for financial support and other economic benefits. It is the position of this author that this is a misuse of the intended parent doctrine and is against both the grain of existing law and of sound social policy.
Skeletal muscle from aged American Quarter Horses shows impairments in mitochondrial biogenesis and expression of autophagy markers

Aging is associated with decreased mitochondrial content and function in skeletal muscle, possibly due to compromised biogenesis and autophagic removal of dysfunctional mitochondria. The aim of this study was to compare markers of mitochondrial content and biogenesis and of autophagy between skeletal muscle from young and aged American Quarter Horses. Citrate synthase protein and mtDNA copy number were decreased in triceps brachii (TB) muscle (P<0.05) from aged horses, suggesting an age-related decline in mitochondrial content. Concomitantly, mRNA expression of PGC-1α and TFAM, regulators of mitochondrial biogenesis, was lower in aged compared to young TB (P<0.05). Expression of autophagy markers suggested an age-associated decline of autophagy. The autophagosomal cargo protein SQSTM/p62 accumulated with age in both muscles (P<0.05). Expression of Autophagy-related protein Atg5 (P<0.05) and the autophagosome-bound form of Microtubule-associated protein light chain 3 (LC3-II; P<0.05) were lower in aged compared to young TB. While LC3 transcript level was elevated in aged compared to young GM (P<0.001), protein expression of LC3-II was unaffected. Gene expression of Lysosomal Membrane-Associated Protein 2 (LAMP2) was not affected by age in either muscle. However, LAMP2 protein expression declined with age (P<0.05), suggesting a decline in autophagosome-lysosome fusion. Taken together, our data indicate that equine skeletal muscle mitochondrial content and biogenesis were impaired with age. Further, autophagosome formation and lysosomal degradation were negatively affected in aged TB and GM, respectively. Future research needs to explore whether interventions targeting these cellular processes can prolong health and performance of aging American Quarter Horses.
A specialized fungal parasite (Massospora cicadina) hijacks the sexual signals of periodical cicadas (Hemiptera: Cicadidae: Magicicada).

Male periodical cicadas (Magicicada spp.) infected with conidiospore-producing (“Stage I”) infections of the entomopathogenic fungus Massospora cicadina exhibit precisely timed wing-flick signaling behavior normally seen only in sexually receptive female cicadas. Male wing-flicks attract copulation attempts from conspecific males in the chorus; close contact apparently spreads the infective conidiospores. In contrast, males with “Stage II” infections that produce resting spores that wait for the next cicada generation do not produce female-specific signals. We propose that these complex fungus-induced behavioral changes, which resemble apparently independently derived changes in other cicada-Massospora systems, represent a fungus “extended phenotype” that hijacks cicadas, turning them into vehicles for fungus transmission at the expense of the cicadas’ own interests.
Efficacy of dacarbazine imidazole carboxamide and mitomycin C combination therapy in patients with adenocarcinoma of the colon refractory to 5-fluorouracil therapy.

Therapy for metastatic cancer of the colon is a major problem for the medical oncologist. This tumor is refractory to most chemotherapeutic maneuvers. Moertel has noted that the median survival in this group is only 7 months, with a median survival of 5 months in patients with liver metastasis [13]. 5-Fluorouracil (5-FU), the standard agent for this disease, has a response rate of 20% at best [3], and the response rate falls to 10% if stringent criteria for hepatic response are applied [4]. combinations.
Opportunities to Improve Detection and Treatment of Depression Among Patients With Breast Cancer Treated in an Integrated Delivery System.

Abstract Context Patients with cancer commonly experience depression. If not addressed, depression can lead to reduced quality of life and survival. Objective Given the introduction of national initiatives to improve management of psychiatric symptoms among patients with cancer, we examined patterns of depression detection and treatment over time, and with respect to patient characteristics. Methods This cross-sectional study linked data from the Pathways Study, a prospective cohort study of women diagnosed with breast cancer at Kaiser Permanente Northern California between 2005 and 2013, with data from Kaiser Permanente Northern California's electronic medical record. Pathways participants eligible for this analysis had no known prior depression but reported depressive symptoms at baseline. We used modified Poisson regression to assess the association of cancer diagnosis year and other patient characteristics with receipt of a documented clinician response to depressive symptoms (depression diagnosis, mental health referral, or antidepressant prescription). Results Of the 725 women in our sample, 34% received a clinician response to depression. We observed no statistically significant association of breast cancer diagnosis year with clinician response. Characteristics associated with clinician response included Asian race (adjusted risk ratio, Asian vs. white: 0.44, 95% CI: 0.29–0.68) and depression severity (adjusted risk ratio, mild-moderate vs. severe depression: 1.45, 95% CI: 1.11–1.88). Conclusion Most patients in our sample did not receive a clinician response to their study-reported depression, and rates of response do not appear to have improved over time. Asian women, and those with less severe depression, appeared to be at increased risk of having unmet mental health care needs.
Synthetic ionophores as non-resistant antibiotic adjuvants

Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores (‘hydraphiles’) that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C14 hydraphile (BC14H) shows high efficacy as an antimicrobial. BC14H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC14H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BCnHs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC14H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus. BC14H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants.