cssi/SciSciGPT-SciSciNet huggingface dataset:
Clinical Trial Designs to Evaluate Predictive Biomarkers: What’s Being Estimated?

Predictive biomarkers are used to predict whether a patient is likely to receive benefits from a therapy that outweigh its risks. In practice, a predictive biomarker is measured with a diagnostic assay or test kit. Usually the test has some potential for measuring the biomarker with error. For qualitative tests indicating presence or absence of a biomarker, the probability of misclassification is usually not zero. Study designs to evaluate predictive biomarkers include the biomarker-stratified design, the biomarker-strategy design, the enrichment (or targeted) design, and the discordant risk randomization design. Many authors have reviewed the main strengths and weaknesses of these study designs. However, the estimand being used to evaluate the performance of the predictive biomarker is usually not provided explicitly. In this chapter, we provide explicit formulas for the estimands used in common study designs assuming that the misclassification error of the biomarker test is non-differential to outcome. The estimands are expressed as terms of the biomarker’s predictive capacity (differential in treatment effect between biomarker positive and negative patients when the biomarker is never misclassified) and the test’s predictive accuracy (e.g., positive and negative predictive values of the test for the biomarker). Upon inspection, the estimands reveal not only well-known strengths and weaknesses of the study designs, but other insights. In particular, for the biomarker-stratified design, the estimand is the product of the biomarker predictive capacity and an attenuation factor between 0 and 1 that increases with the test’s predictive accuracy. For other designs, the estimands illuminate important limitations in evaluating the clinical utility of the biomarker test. After presenting the theoretical estimands, we present and discuss estimand values for a hypothetical case study of Procalcitonin (PCT) as a biomarker in Procalcitonin-guided evaluation and management of subjects suspected of lower respiratory tract infection.
Asymptotic Behaviour of Bounded Solutions of Some Functional Equations

Publisher Summary This chapter discusses asymptotic behavior of bounded solutions of some functional equations. It reviews that Volterra equations are of particular interest because they arise naturally in many nonlinear boundary value problems. The questions of existence and boundedness of solutions of Q(x)(t) = f(t) and x’(t) + Q(x)(t) = f(t) are of great interest in themselves, especially in the study of specific equations arising in applications. However, it often happens that once existence and boundedness have been established, a quite different analysis is required for finding more detailed asymptotic properties of the solution. Thus, the Volterra nature of an equation is usually crucial in the study of existence and boundedness on (0, ∞) of solutions x(t). The chapter also discusses the existence and boundedness of solutions as a hypothesis.
Considerations in the use of B6 vitamers in hematologic disorders: I. Red cell transport and metabolism of pyridoxal.

Abstract In order to assess the potential usefulness of pyridoxal (PL) in sickle cell anemia and other hematologic disorders, the in vitro characteristics of the transport and metabolism of pharmacologic levels of this B6 vitamer by normal human red cells were defined. Red cells suspended in phosphate-buffered NaCl rapidly accumulated PL against a concentration gradient until intracellular levels reached 14 µmole/ml. This corresponded to the PL concentration that maximally increased red cell hemoglobin–oxygen affinity. PL uptake was not affected by adenosine triphosphate (ATP) depletion, sulfhydryl reagents, inhibition of the anion transport channel or the addition of pyridoxal 5′-phosphate (PLP). However, when plasma or human serum albumin (5g/dl) was present in the medium, uptake of PL was decreased by 45%. Moreover, when red cells previously loaded with PL were incubated for 1 hr in the presence of plasma or albumin, 75% of their PL content was released and hemoglobin–oxygen affinity returned to normal. Red cell metabolism of PL was also limited, with formation of sufficient PLP to activate the endogenous aspartate amino transferase (GOT) apoenzyme requiring long incubations and high PL concentrations. It is concluded that (1) red cells transport PL primarily by passive diffusion; (2) net red cell accumulation of PL depends on the binding of PL to hemoglobin; (3) PL is not readily metabolized by mature red cells; and (4) plasma proteins, particularly albumin, retard PL uptake and increase its release from hemoglobin binding sites. Thus, the distribution of PL between red cells and plasma reflects the relative binding affinities of hemoglobin (Hb) and albumin for PL. These findings demonstrate that protein binding modifies both the physiologic and pharmacologic effects of PL and suggest that in vivo, PL may have only a transient effect on hemoglobin oxygen affinity and red cell sickling.
Stress-Induced Neuron Remodeling Reveals Differential Interplay Between Neurexin and Environmental Factors in Caenorhabditis elegans

Neurexins are neuronal adhesion molecules important for synapse maturation, function, and plasticity. Neurexins have been genetically associated with neurodevelopmental disorders, including autism spectrum disorders (ASDs) and schizophrenia, but can have variable penetrance and phenotypic severity. Heritability studies indicate that a significant percentage of risk for ASD and schizophrenia includes environmental factors, highlighting a poorly understood interplay between genetic and environmental factors. The singular Caenorhabditis elegans ortholog of human neurexins, nrx-1, controls experience-dependent morphologic remodeling of a GABAergic neuron in adult males. Here, I show remodeling of this neuron’s morphology in response to each of three environmental stressors (nutritional, heat, or genotoxic stress) when applied specifically during sexual maturation. Increased outgrowth of axon-like neurites following adolescent stress is the result of an altered morphologic plasticity in adulthood. Despite remodeling being induced by each of the three stressors, only nutritional stress affects downstream behavior and is dependent on neurexin/nrx-1. Heat or genotoxic stress in adolescence does not alter behavior despite inducing GABAergic neuron remodeling, in a neurexin/nrx-1 independent fashion. Starvation-induced remodeling is also dependent on neuroligin/nlg-1, the canonical binding partner for neurexin/nrx-1, and the transcription factors FOXO/daf-16 and HSF1/hsf-1. hsf-1 and daf-16, in addition, each have unique roles in remodeling induced by heat and UV stress. The differential molecular mechanisms underlying GABAergic neuron remodeling in response to different stressors, and the disparate effects of stressors on downstream behavior, are a paradigm for understanding how genetics, environmental exposures, and plasticity may contribute to brain dysfunction in ASDs and schizophrenia.
Expression of CDX2 in metastatic prostate cancer

The intestinal marker CDX2 has recently been found to stain a small percentage of primary prostate adenocarcinomas, but little is known of its expression in metastatic prostate cancers. We present a case of metastatic prostate adenocarcinoma that stained for CDX2 and highlight the confusion this may create when evaluating a carcinoma of unknown primary.
Democracy and disrespect

The essay takes the widespread complaint that societies today are deeply divided and polarized as a starting point. Affirming that there is no democracy without division, it asks what it means for ...
Electronic consultations with Video Supported PowerPoint versus in-clinic face-to-face, pre-travel consultations: A single-centre, comparative analysis.

Abstract Background Pretravel consultation involves a face-to-face visit with a Travel Medicine expert and includes time consuming educating/counseling. Efficacy of electronic consultations for pretravel is unknown. We compared pretravel education via face-to-face consult to an electronic consultations combined with education via Video Supported PowerPoint for select travelers. Methods We conducted a prospective trial comparing pre-travel education via electronic consultations versus face-to-face consult. Study was conducted from May 2014 through May 2015. Results Pretravel surveys were completed by 100 in electronic consult arm and 94 in face-to-face consult arm; 67/100 (67%) in the electronic consult and 51/94 (54.2%) in the face-to-face group completed post-travel surveys. Both groups had similar baseline demographics. 36.2% of the face-to-face group felt the trip preparation could have effectively been accomplished through electronic consult, while 33% felt that a face-to-face consult was needed; in contrast, a majority (63.3%) of electronic consult group preferred the electronic consult. Pre-travel education effectiveness was similar in both groups. No statistically significant differences in responses were noted in both groups to 5 of the 6 knowledge assessment questions. A higher proportion (76/100; 76%) in the electronic consult group compared to 55.4% (51/94) (p = 0.0018) in face-to-face group chose the correct response regarding management of febrile bloody diarrhea. 53% reported behavior change to prevent travel related illnesses, with no statistically significant differences between the groups. Conclusions electronic consultation with Video Supported PowerPoint pre-travel education is as effective as education via face-to-face consultations and provides a viable alternative to face-to-face consultations in select travelers.
Studying the Intergenerational Transmission of Risk for Depression: Current Status and Future Directions

Studying offspring of depressed mothers is a promising strategy for elucidating factors that contribute to depression onset, given that these offspring are three to six times more likely to develop depression than are their low-risk peers. In this paper we briefly describe representative findings from studies of younger and older offspring of depressed mothers and identify factors that have garnered the most consistent empirical support across development. We discuss what these studies can and cannot tell us about mechanisms that might underlie the intergenerational transmission of risk for depression, regardless of the age of offspring being studied. Finally, in light of limitations of this literature, we offer recommendations for future research.
Socialization, Adaptation, Transnationalism, and the Reproductive Behavior of Sub-Saharan African Migrants in France

Migrants from Sub-Saharan Africa (SSA) move from a region with high fertility to regions with low fertility. Yet very few studies have examined the reproductive behavior of international migrants from SSA. This study examines the roles of origin and destination socialization on the fertility and fertility ideals of SSA migrants in France. The study draws on measures of assimilation to systematically examine the effects of socialization and adaptation as well as transnationalism for the effects of sustained origin ties. Data are from the TEO (“Trajectoires et Origines”) survey conducted in France (2008/2009). Logistic regression is used to examine current fertility (the odds of having a birth in the preceding 5 years), and poisson regression is used to examine cumulative fertility (children ever born) and fertility ideals (reported ideal number of children in a family). Controlling for sociodemographic factors, first-generation SSA migrants have higher fertility than second-generation SSA migrants and non-immigrants. But first- and second-generation SSA migrants have higher fertility ideals than non-immigrants. Among SSA migrants, first- and second-generation migrants do not differ in fertility and fertility ideals when adaptation is accounted for. Most measures of adaptation are negatively associated with actual fertility and fertility ideals. Transnationalism is associated with higher fertility ideals but less so with actual fertility. The study finds some evidence for origin socialization, but the findings are more strongly supportive of adaptation to the host society. Origin socialization appears to have a stronger influence on fertility ideals than actual fertility.
Convection in dilute solutions of /sup 3/He in superfluid /sup 4/He

Thermal convection in dilute solutions of $^{3}\mathrm{He}$ in superfluid $^{4}\mathrm{He}$ has been studied in a novel cell of unity aspect ratio which permits inhomogeneity in the heat flux to be measured. At least three different convecting states have been observed, including a time-dependent state with diminished thermal conductance which can exist very close to the onset of convection.
Abstract B04: Hepatic cholesterol upregulates TAZ in nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide and is rapidly increasing in prevalence owing to the obesity epidemic. Incomplete understanding of the mechanisms of NASH progression, particularly fibrosis, has limited the design of therapeutic strategies. My previous published study indicated that a transcription factor in hepatocytes called TAZ (WWTR1) contributes to steatosis-to-NASH progression. However, the mechanism that induces high TAZ expression in NASH liver remains unknown. The objective of this study is to understand the mechanism of hepatocyte TAZ upregulation in NASH, which may suggest novel therapeutic strategies to prevent NASH and its comorbidities. We hypothesize that hepatic cholesterol upregulates TAZ through PKA-Ca2+-RhoA mediated Hippo pathway inactivation. In vitro, we use liposome to deplete and replete cholesterol in hepatocyte cells and check downstream signaling pathway that includes cholesterol translocation, Ca2+ signaling, RhoA activity, Hippo pathway, and E3 ligase activity. In vivo, we used different concentration cholesterol diet to build the correlation between increased TAZ/liver fibrosis and cholesterol, and AAV8-H1 mediated hepatic-gene silencing to prove the functions of the molecules in the pathway, including AsterB/C, RhoA, and Trcp. My data suggest that hepatic cholesterol accumulation is associated with liver fibrosis and increased TAZ. In addition, cholesterol loading of hepatocytes increases TAZ, and cholesterol depletion decreases TAZ in a proteasome/Trcp-dependent manner. Mechanistically, Hippo pathway kinase-Lats2 inhibits TAZ expression on the post-transcriptional level through TAZ phosphorylation. Moreover, intracellular cholesterol increases cytosolic Ca2+ and activates RhoA signaling, then represses Lats2 activity, so TAZ degradation is inhibited and total protein level increases. Finally, blocking cholesterol translocation from cell membrane to intracellular suppresses the pathway and inhibits TAZ level. We conclude that hepatic cholesterol induces high-level TAZ in NASH through PKA-Ca2+-RhoA mediated Hippo pathway inactivation, and cholesterol transportation plays an important role during this process. These data provide a plausible mechanism underlying liver cholesterol as a risk factor for NASH fibrosis and suggest new therapeutic interventions to block NASH fibrosis and to prevent NASH-associated HCC. Citation Format: Xiaobo Wang, Arun Radhakrishnan, Douglas Covey, Jay Horton, Robert Schwabe, Peter Tontonoz, Kun-Liang Guan, Ira Tabas. Hepatic cholesterol upregulates TAZ in nonalcoholic steatohepatitis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B04.
Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model

Alzheimers disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify an earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Schematic summarizing therapeutic approaches to mitigate the effects of mutant APP through targeting of Cdkn2a, BMI1, USP16 and BMP.
The Public Librarian Low-Morale Experience: A Qualitative Study

Winner of the 2020 Partnership Article Award Recent studies on low morale in academic libraries reveal impacts on workplace health and organizational culture and concerns about leadership training and development. Additionally, established research on library dysfunction and emotional labor in librarianship, along with emerging scholarship on incivility in librarian-patron interactions, highlight a growing area of practice concerns for information professionals. This qualitative study centers public librarians’ experience of low morale. Data validate the development and practice- and health-related outcomes of low morale and illuminate the realities of public library work, organizational culture and behaviours, impact of leadership practices, and the perceptions of the value and role of librarians and the public library in North America.
Designing teaching and reflection experiences to develop candidates’ science teaching self-efficacy

Background: Teacher self-efficacy beliefs are known to be a predictor of future teaching practices and are related to teacher effectiveness and student learning. Science teaching self-efficacy beli...
Counterfactual Graph Learning for Link Prediction.

Learning to predict missing links is important for many graph-based applications. Existing methods were designed to learn the observed association between two sets of variables: (1) the observed graph structure and (2) the existence of link between a pair of nodes. However, the causal relationship between these variables was ignored and we visit the possibility of learning it by simply asking a counterfactual question: "would the link exist or not if the observed graph structure became different?" To answer this question by causal inference, we consider the information of the node pair as context, global graph structural properties as treatment, and link existence as outcome. In this work, we propose a novel link prediction method that enhances graph learning by the counterfactual inference. It creates counterfactual links from the observed ones, and our method learns representations from both of them. Experiments on a number of benchmark datasets show that our proposed method achieves the state-of-the-art performance on link prediction.
Electricity Markets and Power Supply Resilience: an Incisive Review

This paper focuses on the advances in the resilience of electricity systems and energy markets. The objective is to identify how the progress on system resilience may influence market rules while uncovering the gaps in the literature. This review distills three findings. First, significant advances have been achieved both in the design and configuration of power systems for resilience. Second, topological and architectural advances appear isolated from market operations. Third, there is room to integrate self-healing resilience into power systems and bridge the bifurcation between increasing network resilience and having the market adequately value resilience. Evidently, the incidences of disruptions to electricity networks are on the rise, making a change from having a merely reliable electricity network to one that is resilient and adaptive a necessity. This review showcases the qualitative value inherent in processes to enhance adaptive resilience while promoting the requisite signals for power market integration.
Self-care: A concept analysis.

Author(s): Martinez, Nicole; Connelly, Cynthia D; Perez, Alexa; Calero, Patricia | Abstract: ObjectivesThere is extensive literature from various disciplines on self-care, an important aspect of nursing intervention via evaluation and education, but its meaning remains unprecise due to the difficulty integrating the diverse definitions developed over time across disciplines. Therefore, it is vital to clarify the meaning of self-care and formulate the defining attributes, antecedents, and consequences to self-care.MethodsWalker and Avant's concept analysis approach was used to analyze the concept of self-care. A search of the literature was completed using the databases CINAHL, PubMed, and EBSCOhost for years 1975-2020; literature search included peer-review articles, full-text publications, and available in English. A total of 31 articles were reviewed, and saturation was reached.ResultsAn extensive review of the literature revealed salient characteristics that reflected the most frequently used terms associated with the concept. Guided by Walker and Avant's method, three defining attributes emerged as common themes: awareness, self-control, and self-reliance.ConclusionsA clarified definition was identified: the ability to care for oneself through awareness, self-control, and self-reliance in order to achieve, maintain, or promote optimal health and well-being.
Fairness without Imputation: A Decision Tree Approach for Fair Prediction with Missing Values.

We investigate the fairness concerns of training a machine learning model using data with missing values. Even though there are a number of fairness intervention methods in the literature, most of them require a complete training set as input. In practice, data can have missing values, and data missing patterns can depend on group attributes (e.g. gender or race). Simply applying off-the-shelf fair learning algorithms to an imputed dataset may lead to an unfair model. In this paper, we first theoretically analyze different sources of discrimination risks when training with an imputed dataset. Then, we propose an integrated approach based on decision trees that does not require a separate process of imputation and learning. Instead, we train a tree with missing incorporated as attribute (MIA), which does not require explicit imputation, and we optimize a fairness-regularized objective function. We demonstrate that our approach outperforms existing fairness intervention methods applied to an imputed dataset, through several experiments on real-world datasets.
Transcutaneous CO2 Monitoring and Therapeutic Hypothermia

Background: Transcutaneous CO2 (TCM) monitoring is the accepted standard in assessing carbon dioxide pressure (CO2) in the tissue and can be helpful in the management of newborns requiring ventilatory support. Infants with hypoxic ischemic encephalopathy (HIE) are routinely treated with therapeutic hypothermia (TH) to 33.5°C. It is well established that fluctuations in the partial pressure of CO2 in arterial blood (PaCO2) during TH is associated with poor neurodevelopmental outcomes, thus close monitoring of PaCO2 is key to good outcomes. TCM correlation is perfusion dependent. TCM heats the skin at the sensor site to arterialize the sample. The non-invasive device produces a PCO2 value corrected to 37°C (TcPCO2). The TCM is mostly regarded as a reliable noninvasive manner to continuously monitor tissue CO2. Our objective was to determine the accuracy and precision of TcPCO2values in newborns undergoing TH. Methods: We conducted a retrospective chart review of 10 neonates (3F/7M) undergoing TH for HIE requiring respiratory support. The weight of the neonates ranged from 2,230 to 3,810 g. We compared TcPCO2to PaCO2 values (all at 37°C) using a Bland-Altman plot for multiple measurements per patient. A Wilcoxon test for paired samples (non-normally distributed data), and a repeated measures ANOVA (rmANOVA: two types of measurements; five measurements per subject, eight subjects) was also used to aid in the analysis. IRB exempt status was gained through UC Davis. Results: Ninety paired samples were collected in 10 patients with a range of PaCO2 28–94 mm Hg. Median difference was 2 mm Hg higher in TcPCO2 (Wilcoxon test for paired samples P Conclusions: TcPCO2 showed a strong median correlation to PaCO2 values at 37°C but lacked precision. TcPCO2may not be appropriate for estimating PaCO2 in patients undergoing TH. Care should be taken when utilizing TCM in these patients. TCM may prove to be a reliable trending tool but acute changes in values should be confirmed with PaCO2. Given our small sample size (N = 10) and the retrospective nature of our study, more investigation into the usefulness of TCM during TH is warranted. Discrepancy in TcPCO2and PaCO2 values during TH justifies further exploration in transcutaneous monitoring.
Developing a Continuity of Operations Plan

ABSTRACT: This article consists of two parts: the first section covers the genesis of a Continuity of Operations Plan after the Disaster Preparedness Committee received a mandate to develop one to supplant earlier, less complex, and more generic disaster plans. The second section of the article reviews a range of resources consulted by the committee members as they researched pandemic planning issues: journal literature; higher education, health, and library professional associations; company disaster recovery planning; federal government resources; and other libraries' Continuity of Operations plans.
Statistical Tolerance Analysis for Assured Analog Test Coverage

Increasing numbers of analog components in today's systems necessitate system level test composition methods that utilize on-chip capabilities rather than solely relying on costly DFT approaches. We outline a tolerance analysis methodology for test signal propagation to be utilized in hierarchical test generation for analog circuits. A detailed justification of this proposed novel tolerance analysis methodology is undertaken by comparing our results with detailed SPICE Monte-Carlo simulation data on several combinations of analog modules. The results of our experiments confirm the high accuracy and efficiency of the proposed tolerance analysis methodology.
Effects of floating heat spreader in high density BGA packages

In this paper we present the effects of heat spreader on a ball grid array (BGA) package. We have simulated a fast switching CMOS inverter inside a BGA package with power, signal and ground planes. We performed simulations to study the effects of the electrical radiation and signal integrity with different configurations of heat spreader.
Early-stage shipboard power system simulation of operational vignettes for dependability assessment

A principle motivation for the development of early-stage shipboard power system simulation techniques is the need to perform time-domain simulation during the early design stage. In particular, there is a need to understand the performance of a candidate system during challenging situations involving dynamic load profiles and disruptive conditions in order to assess the system dependability. An early-stage simulation technique is applied to simulate the performance of a candidate system for given operational vignettes. Using this early-stage approach allows simulations to be performed very quickly, allowing many vignettes to be considered and the overall system dependability to be assessed.
Databases and Web Sites for Neurogenetics

The goal of neurogenetics is an understanding of the genetic basis of brain structure and function. Neurogenetics deals with multiple areas of investigation, including the genetic basis of neural induction, patterning, cell fate specification, neuron maturation, axonal and dendritic organization, synapse function, neural information processing, and learning and behavior. This appendix provides links to databases and other Web sites used by neurobiologists for discovery of information about genes and cellular networks involved in neural development and neuron function. Special care has been taken to curate sites involving model organisms, since great strides have been made using Drosophila and C. elegans for understanding neural development and function. Published 2019. U.S. Government.
Maternal Effects on Schizophrenia Risk

Local environmental factors impinging on the fetal brain can tip the balance toward mental illness.
Normal lactation and blood growth hormone studies

Abstract Plasma human growth hormone (HGH) was measured by a radioimmunoassay method both in a fasting resting state and during an insulin-induced hypoglycemic episode. There were 35 nonlactating control and 26 lactating nursing women tested in the late postpartum period. No statistically significant differences were demonstrated in either the blood glucose or plasma HGH levels. The significance of these findings is discussed in relation to the control of normal lactation and to the possible presence of a separate prolactin hormone in the human subject.
A Possible New Mechanism Involved in Non-Uniform Field Breakdown in Gaseous Dielectrics

The electrical breakdown of gases under uniform field conditions is fairly well understood [1–3] in terms of the Townsend’s breakdown theory. In most cases involving uniform fields, the breakdown voltage can be estimated via this theory using basic electron impact parameters (including electron attachment cross sections) for molecules in their ground electronic states [1–3].
Expression of DGCR8-dependent microRNAs is indispensable for osteoclastic development and bone-resorbing activity.

Recently, microRNAs (miRs) have been implicated in bone formation and homeostasis. We previously reported that Dicer generated miRs have pivotal roles in differentiation and activity of osteoclasts. However, recent studies have demonstrated that Dicer is implicated in production of endogenous small interfering RNAs, non-canonical miRs, and other small RNAs in mammals. Hence, a challenging question is the extent to which expression of canonical miRs are obligatory for osteoclastic control of bone metabolism. DiGeorge syndrome critical region gene 8 (DGCR8) is exclusively related with expression of miRs by a canonical processing pathway together with the nuclear RNase III enzyme Drosha. Osteoclast-specific deletion of DGCR8 led to impaired osteoclastic development and bone resorption so that bone development was significantly retarded. In culture, the expression levels of osteoclastic phenotype-related genes and proteins were remarkably inhibited during osteoclastogenesis in DGCR8-deficiency. Thus, we have identified that DGCR8-dependent miRs are indispensable for osteoclastic control of bone metabolism.
Gastric toxoplasmosis in a patient with acquired immunodeficiency syndrome. A case report and review of the literature.

Abstract Toxoplasmosis is a common opportunistic pathogen in patients with acquired immunodeficiency syndrome (AIDS). It usually presents with ocular, central nervous system, or pulmonary disease. Gastric toxoplasmosis is uncommon in AIDS patients, especially in the absence of central nervous system manifestations. In the few reported cases, patients have presented with abdominal pain and other digestive complaints that usually are attributed to the more common gastrointestinal manifestations of human immunodeficiency virus infection. We describe a 49-year-old man with AIDS who presented with abdominal pain, diarrhea, dry cough, and systemic symptoms and was diagnosed with toxoplasmosis by a gastric biopsy.
Equilibrium Model for Speciation of Aluminum in Serum

An equilibrium model for the speciation of Al3+ in normal serum has been developed in which 81% of the aluminum is bound to transferrin. The remaining 19% exists primarily as Al(PO4)(OH)-, with minor amounts of citrate and hydroxide species. The model meets several key criteria. The concentration of free aluminum is below the upper limit set by the solubility product of aluminum phosphate. The fraction of low-molecular-mass aluminum species agrees with experimental studies on the fraction of ultrafiltrable aluminum in both normal and uremic serum. Lastly, the model accounts for the relative effectiveness of EDTA, citrate, and desferrioxamine B for binding aluminum in serum by including competition from zinc, magnesium, and calcium for these ligands. Uncertainties in the available thermodynamic database are discussed.
Localization in a Morita context with applications to fixed rings

In the study of a noetherian ring R, there are two related questions that have played a major role in recent years; one is finding prime ideals of R which satisfy the second layer condition, the other is finding the (second layer) link closed sets of prime ideals of R. In particular these properties are necessary to determine the classical sets of prime ideals of R, which allows one to obtain a well behaved Ore localization (see, for example, [24, 8, 91). One aspect of this problem is the transfer of these properties from the prime spectrum of one ring R to the prime spectrum of another, related ring, A. Jategaonkar [S] has shown that, if R is a commutative noetherian ring, then the group ring RG satisfies the second layer condition whenever G is polycyclic-by-finite. This result was then generalized by Bell [2] to strongly group graded rings. More recently Letzter [lo] has studied the relationship between the prime spectrums of the noetherian rings R and S, when S is module finite over R, showing how the second layer condition and links between prime ideals transfer from one ring to the other. Let T be a right noetherian ring and let e be an idempotent element of T, then it is well known that eTe is a right noetherian ring. In Sections 1 and 2 we examine the transfer of the second layer condition between the prime ideals of T and eTe, as well as the transfer of classical sets of prime ideals between these rings. This enables us to study how these properties of Spec(eTe) translate to Spec(( 1 e) T( 1 e)). In particular, under certain hypotheses, we prove that whenever eTe satisfies the second layer condition, then so does (1 e) T( 1 e) (Corollary 2.6). In addition we are able to show that under the same hypotheses, if every prime ideal of eTe belongs to a finite classical set, then so does every prime ideal of (1 -e) T(l -e). Another way to describe the relationship between T and eTe is via a Morita context (see [ 11). Let R and S be rings, let s W, and R V, be bimodules, and let 6: VOs W-+ R, $: WOR V+ S be bimodule 373 OOZI-8693/91 $3.00
Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa.

Abstract Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [ J. Med. Chem. 2003 , 46 , 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (p K a ∼ 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF–VIIa inhibitor.
Characterization of Monomeric and Glutenin Polymeric Proteins of Hard Red Spring Wheats During Grain Development by Multistacking SDS‐PAGE and Capillary Zone Electrophoresis

ABSTRACT Three cultivars of hard red spring (HRS) wheats with identical high molecular weight (HMW) glutenin subunit composition (5+10 type, Glu-D1d) but different dough properties and breadmaking quality were used in this study. The synthesis and accumulation characteristics of different protein fractions during grain development were examined. Samples were collected at three-day intervals from anthesis to maturity between day 10 to day 37. The nonreduced SDS-extractable glutenin aggregates of developing grains were characterized by a multistacking SDS-PAGE procedure to obtain information on the size distribution and polymerization of glutenin aggregates. The HMW to low molecular weight (LMW) glutenin subunit ratio was determined for its relationship to polymerization of the various glutenin aggregates of different molecular sizes. Glutenin proteins were quantified using an imaging densitometer. In addition, albumins and globulins, α- and β-gliadins, γ-gliadins, and ω-gliadins were separated by capillary...
Erik H. Erikson's contribution to ethics

Erik H. Erikson derives his ethical theory from a study of human psycho social development.1 Each human being, he writes, passes through eight critical stages, out of which emerge a set of basic ego strengths that he calls virtues.2 These virtues function in a manner comparable to the way in which instincts operate in the animal kingdom. They provide human be ings with the power to survive and develop and pass on similar strength in rejuvenated form to the next generation.3 Without these virtues man would not survive.
Report on a single-topic conference on “Chronic Viral Hepatitis–Strategies to Improve Effectiveness of Screening and Treatment”†‡

The 2010 Institute of Medicine report on "Hepatitis and Liver Cancer" indicated that lack of knowledge and awareness about chronic hepatitis B (HBV) and C virus (HCV) infections and insufficient understanding about the extent and seriousness of this public health problem impeded current efforts to prevent and control hepatitis B and C. A single-topic conference was held in June 2011 to discuss strategies to improve the effectiveness of screening, care referral, and clinical management of chronic HBV and HCV infections with the ultimate goal of reducing morbidity and mortality from these infections. Various models that have been shown to improve hepatitis screening and effectiveness of hepatitis treatment in the community, including rural settings and populations that have traditionally been excluded due to comorbidities, were presented. Recent advances in laboratory testing, medical management, and new antiviral therapies will not decrease the burden of viral hepatitis if persons at risk for or who are living with viral hepatitis are not aware of the risks, have not been diagnosed, or have no access to care. Systematic changes in our health care delivery system and enhanced coordination of prevention and care services with partnerships between public health leaders and clinicians through education of the public and health care providers and linkage of infected persons with care and treatment services can increase the success of preventing viral hepatitis and the effectiveness of hepatitis treatment in the real world. Implementation of these changes is feasible and will require policy changes, coordination among government agencies, and collaboration between government agencies, health care providers, community organizations, and advocacy groups.
Preferential humoral immune response in prostate cancer to cellular proteins p90 and p62 in a panel of tumor-associated antigens.

BACKGROUND Cytoplasmic p90 autoantigen was recently cloned from a cDNA expression library using serum antibody from a cancer patient. The humoral immune response to p90 in prostate cancer and benign prostatic hyperplasia (BPH) was examined. METHODS An antigenic fragment of recombinant p90 protein and several other tumor-associated antigens (TAAs) were used in ELISA and Western blotting to detect antibodies in sera from patients with prostate cancer, BPH, and other controls. RESULTS Autoantibodies to p90 were detected in 30.8% of 133 prostate cancer patients versus 1.5% in 68 BPH patients. When a selected panel of six TAAs including p90 were used for immunoscreening, the cumulative positive reactions in prostate cancer sera reached 92.5%, significantly higher than in BPH and other control sera. Antibodies to p90 showed the highest frequency in prostate cancer (30.8%), followed by antibodies to p62 (22.6%). CONCLUSIONS A panel of six selected TAAs was shown to have high sensitivity and specificity as immunodiagnostic markers in prostate cancer. © 2004 Wiley-Liss, Inc.
Clinical monitoring of HIV-1 infection in the ERA of antiretroviral resistance testing.

Highly active antiretroviral therapy (HAART) has markedly aided the fight against HIV-1 infection. Protease inhibitors and newer reverse transcriptase inhibitors, such as abacavir and efavirenz, have increased the current anti-HIV repertoire to 14 Food and Drug Administration (FDA)-approved agents. Clinicians combine these drugs into regimens that arrest viral replication and help prevent the emergence of resistant viral strains. In treatment-experienced patients, these combinations are improvised by the best clinicians with attention to many different factors. Newer, more sensitive RNA viral load assays are implemented routinely in clinical practice, helping to reduce viral replication below the current levels of detection. As a result, the rate of HIV-1–related deaths and opportunistic infections in the United States and other developed countries has fallen dramatically over the last several years. 60 Despite these tremendous advances, the battle against HIV-1 infection is far from over. Even the combination regimens for drug-naive patients do not assure a response in all patients involved in clinical trials—10% to 40% of the patients fail to reach undetectable levels or have a rebound in HIV-1 RNA levels in blood. 23 , 27 , 57 , 74 Failure rates are even higher for antiretroviral-experienced patients. 23 , 26 , 27 , 34 , 75 Despite undetectable HIV RNA levels in blood plasma, replication-competent HIV-1 still can be recovered in infected patients from the latent reservoir of resting memory CD4 lymphocytes 21 , 80 ; the half-life of this latent reservoir has been calculated somewhere between 10 and 60 years. 20 , 83 Moreover, residual replication can continue in some infected patients despite the best current therapy. Thus, resistance to even the best regimens may eventually develop, leading to HIV-1 rebound and disease progression. Moreover, patients receiving HAART must adhere vigilantly to a regimen with multiple drug interactions, a large pill burden, and an increasing list of long-term side effects. Although clinicians have clear guidelines outlining the options for initiating antiretroviral therapy and monitoring its effects on HIV-1 infection, there is no consensus about what to do when HAART starts to fail. This article focuses on virologic failure and delineates the causes of treatment failure, in particular, antiretroviral resistance. The molecular basis, basic principles, and different techniques for assaying resistance are addressed with emphasis on the application of these assays to patient care.
Directional solidification and microstructural evolution between diopside and anorthite in the system CaO-MgO-Al2O3-SiO2

Silicate mixtures close to the diopside–anorthite tie line have been unidirectionally solidified by float–zone melting in an arc image furnace and the microstructures examined by optical microscopy, scanning electron microscopy, electron microprobe analysis and from electron backscatter patterns. The structures which evolved have been interpreted by reference to available phase diagram data for the anorthite–diopside eutectic surface within the four–component oxide system, CaO–MgO–Al2O3–SiO2. It is demonstrated how the microstructures and segregation paths can be described in a visually explicit way within the quaternary system. The morphologies of primary diopside, anorthite and the eutectic mixture are described and discussed. In this silicate system the low liquid diffusion rates lead to glass formation at rapid cooling rates and at temperatures close to the freezing point, so that local equilibrium is only partially realized. The consequences are interpreted with reference to the quaternary phase diagram.
Functional equivalence of spatial representations derived from vision and language: Evidence from allocentric judgments

Past research (e.g., J. M. Loomis, Y. Lippa, R. L. Klatzky, & R. G. Golledge, 2002) has indicated that spatial representations derived from spatial language can function equivalently to those derived from perception. The authors tested functional equivalence for reporting spatial relations that were not explicitly stated during learning. Participants learned a spatial layout by visual perception or spatial language and then made allocentric direction and distance judgments. Experiments 1 and 2 indicated allocentric relations could be accurately reported in all modalities, but visually perceived layouts, tested with or without vision, produced faster and less variable directional responses than language. In Experiment 3, when participants were forced to create a spatial image during learning (by spatially updating during a backward translation), functional equivalence of spatial language and visual perception was demonstrated by patterns of latency, systematic error, and variability.
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

Although the immediate receptors (immunophilins) of the immunosuppressants cyclosporin A (CsA) and FK506 are distinct, their similar mechanisms of inhibition of cell signaling suggest that their associated immunophilin complexes interact with a common target. We report here that the complexes cyclophilin-CsA and FKBP-FK506 (but not cyclophilin, FKBP, FKBP-rapamycin, or FKBP-506BD) competitively bind to and inhibit the Ca(2+)- and calmodulin-dependent phosphatase calcineurin, although the binding and inhibition of calcineurin do not require calmodulin. These results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and FK506, respectively, by forming drug-dependent complexes with and altering the activity of calcineurin-calmodulin.
Apocalmodulin Itself Promotes Ion Channel Opening and Ca2+ Regulation

Summary The Ca 2+ -free form of calmodulin (apoCaM) often appears inert, modulating target molecules only upon conversion to its Ca 2+ -bound form. This schema has appeared to govern voltage-gated Ca 2+ channels, where apoCaM has been considered a dormant Ca 2+ sensor, associated with channels but awaiting the binding of Ca 2+ ions before inhibiting channel opening to provide vital feedback inhibition. Using single-molecule measurements of channels and chemical dimerization to elevate apoCaM, we find that apoCaM binding on its own markedly upregulates opening, rivaling the strongest forms of modulation. Upon Ca 2+ binding to this CaM, inhibition may simply reverse the initial upregulation. As RNA-edited and -spliced channel variants show different affinities for apoCaM, the apoCaM-dependent control mechanisms may underlie the functional diversity of these variants and explain an elongation of neuronal action potentials by apoCaM. More broadly, voltage-gated Na channels adopt this same modulatory principle. ApoCaM thus imparts potent and pervasive ion-channel regulation. PaperClip