Miracle-dz/UniFAR-FTUs huggingface dataset:
γ-Secretase Substrate Selectivity Can Be Modulated Directly via Interaction with a Nucleotide-binding Site*

γ-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid β-protein (Aβ) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of γ-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified γ-secretase to selectively block cleavage of APP- but not Notch-based substrates. Moreover, ATP activated the generation of the APP intracellular domain and Aβ, but not the generation of the Notch intracellular domain by the purified protease complex, and was a direct competitor of the APP-selective inhibitors, as were other nucleotides. In accord, purified γ-secretase bound specifically to an ATP-linked resin. Finally, a photoactivable ATP analog specifically labeled presenilin 1-C-terminal fragments in purified γ-secretase preparations; the labeling was blocked by ATP itself and APP-selective γ-secretase inhibitors. We concluded that a nucleotide-binding site exists within γ-secretase, and certain compounds that bind to this site can specifically modulate the generation of Aβ while sparing Notch. Drugs targeting the γ-secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease.
Detection and Differentiation of Entamoeba histolytica and Entamoeba dispar Isolates in Clinical Samples by PCR and Enzyme-Linked Immunosorbent Assay

ABSTRACT Differential diagnosis of Entamoeba histolytica (pathogenic) and Entamoeba dispar (nonpathogenic), which are two morphologically identical species of amebae, is essential both for treatment decision and public health knowledge. The study reported here was designed to choose a reference differentiation technique. Stool samples (n = 95) were tested by microscopy, TechLab enzyme-linked immunosorbent assays (ELISAs), and an in-house PCR. The target for the PCR amplification was a small region (135 bp) of the SSU rRNA selected to increase the sensitivity of the test. Sixty-eight specimens tested positive by PCR: 2 for E. histolytica and 66 for E. dispar. For detection of E. dispar, ELISA performance was lower than that of microscopy in this reference context, while PCR was much more sensitive than microscopy. Given the low proportion of E. histolytica cases, test performance for this species is difficult to assess. However, for differentiation, PCR performed well on simulated samples, while ELISA gave a discordant result for one of the two samples PCR positive for E. histolytica during the study. This report also confirms that E. dispar infection is significantly higher among travelers and underlines the possibility of acquiring E. histolytica infection in regions that are not areas of endemicity. Because of its lower sensitivity, the interest of ELISA for Entamoeba detection and differentiation in stools seems questionable in nontropical regions. On the other hand, results suggest that PCR should be useful as a reference test for sensitive differentiation of both species and to contribute to physicians' decision in treatment of E. histolytica- or E. dispar-infected patients.
Bmc Musculoskeletal Disorders Characteristics of Children with Hip Displacement in Cerebral Palsy

Background: Hip dislocation in children with cerebral palsy (CP) is a common and severe problem. The dislocation can be avoided, by screening and preventive treatment of children with hips at risk. The aim of this study was to analyse the characteristics of children with CP who develop hip displacement, in order to optimise a hip surveillance programme.
Plasma levels of α-tocopherol, γ-tocopherol and selenium in patients with prostate cancer in Nigeria

Background: Evidence suggests that essential trace metals and vitamins play crucial roles in slowing down the initiation and progression stages of many cancers, but the plausible role of selenium and vitamin E, especially the gamma-tocopherol (γ-tocopherol), against prostate cancer is yet to be ascertained. Aim: To compare levels of selenium, alpha-tocopherol (α-tocopherol) and γ-tocopherol between prostate cancer (PCa) and benign prostatic hyperplasia (BPH) patients. Methods: Twenty (20) prostate cancer (PCa) patients and 25 patients with benign prostatic hyperplasia (BPH) recruited from Urology Clinic of the Department of Surgery, University College Hospital (UCH), Ibadan acted as case and control subjects, respectively. Informed consent was obtained from all participants. The plasma levels of selenium, α-tocopherol and γ-tocopherol were determined by Atomic Absorption Spectrophotometer (AAS) and High Performance Liquid Chromatography (HPLC), respectively. Results: γ-tocopherol levels were significantly higher in BPH patients (control) when compared with PCa patients. Selenium and α-tocopherol levels were lower in PCa patients, but not significant. Conclusion: Plasma low level of γ-tocopherol in PCa patients was statistically significant. This may be a risk factor among adult Nigerian men for the development of prostate cancer. Increased plasma level of -tocopherol through diet or supplementation may reduce the risk and progression of prostate cancer. Key words: Prostate cancer, benign prostatic hyperplasia, γ-tocopherol, α-tocopherol, selenium, trace metals.
Towards Reversible Computation in Erlang

In a reversible language, any forward computation can be undone by a finite sequence of backward steps. Reversible computing has been studied in the context of different programming languages and formalisms, where it has been used for debugging and for enforcing fault-tolerance, among others. In this paper, we consider a subset of Erlang, a concurrent language based on the actor model. We formally introduce a reversible semantics for this language. To the best of our knowledge, this is the first attempt to define a reversible semantics for Erlang.
Developing questionnaires for educational research: AMEE Guide No. 87

Abstract In this AMEE Guide, we consider the design and development of self-administered surveys, commonly called questionnaires. Questionnaires are widely employed in medical education research. Unfortunately, the processes used to develop such questionnaires vary in quality and lack consistent, rigorous standards. Consequently, the quality of the questionnaires used in medical education research is highly variable. To address this problem, this AMEE Guide presents a systematic, seven-step process for designing high-quality questionnaires, with particular emphasis on developing survey scales. These seven steps do not address all aspects of survey design, nor do they represent the only way to develop a high-quality questionnaire. Instead, these steps synthesize multiple survey design techniques and organize them into a cohesive process for questionnaire developers of all levels. Addressing each of these steps systematically will improve the probabilities that survey designers will accurately measure what they intend to measure.
Effects of Halothane and Isoflurane on the Intracellular Ca2+ Transient in Ferret Cardiac Muscle

Background Halothane and isoflurane depress myocardial contractility by decreasing transsarcolemmal Ca2+ influx and Ca2+ release from the sarcoplasmic reticulum. Decreases in Ca2+ sensitivity of the contractile proteins have been shown in skinned cardiac fibers, but the relative importance of this effect in intact living myocardium is unknown. The aims of this study were to assess whether halothane and isoflurane decrease myofibrillar Ca2+ sensitivity in intact, living cardiac fibers and to quantify the relative importance of changes in myofibrillar Ca2+ sensitivity versus changes in myoplasmic Ca2+ availability caused by these anesthetics. Methods The effects of halothane and isoflurane (0–1.5 times the minimum alveolar concentration (MAC) in three equal increments) on isometric and isotonic variables of contractility and on the intracellular calcium transient were assessed in isolated ferret right ventricular papillary muscle microinjected with the Ca2+-regulated photoprotein aequorin. The intracellular calcium transient was analyzed in the context of a multicompartment model of intracellular Ca2+ buffers in mammalian ventricular myocardium. Results Halothane and isoflurane decreased contractility, time-to-peak force, time to half-isometric relaxation, and intracellular Ca2+ transient in a reversible, concentration-dependent manner. Halothane, but not isoflurane, slowed the increase and the decrease of the intracellular Ca2+ transient. Increasing extracellular Ca2+ in the presence of anesthetic to produce peak force equal to control values increased intracellular Ca2+ to values higher than control values. Conclusions Halothane decreases myoplasmic Ca2+ availability more than isoflurane; halothane and isoflurane decrease myofibrillar Ca2+ sensitivity to the same extent; in halothane at 0.5 MAC and isoflurane at 1.0 MAC, the decrease in Ca2+ sensitivity is already fully apparent; halothane decreases intracellular Ca2+ availability more than myofibrillar Ca2+ sensitivity; and isoflurane decreases myoplasmic Ca2+ availability and Ca2+ sensitivity to the same extent, except at 1.5 times the MAC, which decreases Ca2+ availability more.
Making the Best of a Bad Situation: Proactive Coping with Racial Discrimination

Proactive coping with racial discrimination takes three forms: self-focused coping, situation-focused coping, and avoidance. Overall, African Americans used self-focused coping more than situation-focused coping or physical avoidance, though there were interesting differences between retrospective recall of racial discrimination and daily reports. Relative to reports during the diary week, when recalling how they typically dealt with racial discrimination, African Americans overestimated their use of situation-focused strategies and underestimated their use of self-focused strategies. For both retrospective and daily reports, proactive coping was positively related to primary appraisals of harm but unrelated to secondary appraisals of resources. African American identification, but not stigma consciousness or optimism, was uniquely associated with proactive coping. We discuss the potential benefits and limitations of proactive coping with racial discrimination.
Multimodality imaging of cortical and white matter abnormalities in Sturge-Weber syndrome.

BACKGROUND AND PURPOSE Impaired cortical venous outflow and abnormal deep venous collaterals are common in Sturge-Weber syndrome (SWS), but their relation to brain metabolism and function is poorly understood. In this study, advanced MR imaging techniques, such as susceptibility-weighted imaging (SWI) and diffusion tensor imaging (DTI), were applied in conjunction with positron-emission tomography (PET), to assess cortical and white matter structural abnormalities and their relation to cortical glucose metabolism and cognitive functions in children with unilateral SWS. MATERIALS AND METHODS Thirteen children (age, 1.5-10.3 years) with unilateral SWS underwent MR imaging with SWI and DTI, glucose metabolism PET, and comprehensive neuropsychologic assessment prospectively. The MR imaging and PET images were coregistered and cortical regions showing decreased glucose metabolism were compared with locations of SWI signal intensity abnormalities, changes in white matter water diffusion, and cognitive functions. RESULTS SWI detected both cortical abnormalities (n=8) and deep transmedullary veins (n=9), including those in young children with no cortical SWI signal intensity changes. These veins were often located under cortex adjacent to hypometabolic regions. DTI showed abnormal water diffusion both under hypometabolic cortex and in adjacent white matter with collateral veins. Cognitive dysfunction was associated with abnormal water diffusion in the posterior white matter. CONCLUSIONS Transmedullary venous collaterals can be detected early by SWI and persist in white matter adjacent to damaged cortex in children with SWS. Microstructural white matter damage extends beyond cortical abnormalities and may contribute to cognitive impairment. SWI and DTI can be incorporated into clinical MR imaging acquisitions to objectively assess microstructural abnormalities at different stages of SWS.
A meta-analytic examination of the potential correlates and consequences of workload

Over the last four decades, occupational stress researchers have given considerable attention to the potential correlates and consequences of workload. In the current study, we use meta-analysis (overall k = 336) to quantitatively review the workload literature. In analyses of hypothesized correlates, we found that social support was negatively associated (ρ = −.20 for supervisor support; ρ = –.11 for co-worker support) and that trait negative affectivity (ρ = .22), role ambiguity (ρ = .28), role conflict (ρ = .44) and work-family conflict (ρ = .44 for work-to-family conflict; ρ = .20 for family-to-work conflict) were each positively associated with workload. Analyses examining hypothesized outcome variables suggest that workload is negatively associated with several indices of psychological and physical well-being (ρs were generally in the –.20s and –.30s), and affective organizational commitment (ρ = –.11), and is positively associated with turnover intention (ρ = .16) and absenteeism (ρ = .07).
Pharmacological classical conditioning in humans

Two groups, each with five healthy male volunteers, received pairings of a distinct environment, the laboratory, with administrations of the muscle relaxant carisoprodol (CSP group), or pairings of the same environment with administrations of an inactive agent (control group). The control group received carisoprodol at home. This procedure was in effect in three sessions, each spaced 1 week apart. The CSP group received an inactive agent in the fourth session, and the control group received carisoprodol. The administration procedure was hypothesized to constitute a conditioned stimulus (CS) in the CSP group. The results showed that carisoprodol decreased blink reflex amplitude and duration. However, increased blink reflex amplitude was seen in the CSP group when the inactive agent was administered, which is opposite to the effect of carisoprodol. This indicates that a drug‐antagonistic conditioned response was elicited by the CS in the CSP group. Moreover, blink reflex amplitude was increased in the CSP group compared to the control group when carisoprodol was administered, indicating that the antagonistic conditioned response decreased the effect of carisoprodol. The results suggest a role for antagonistic conditioned responses in human drug tolerance. © 1997 John Wiley & Sons, Ltd.
Cells of origin of entorhinal cortical afferents to the hippocampus and fascia dentata of the rat

The pathway from the entorhinal cortical region to the hippocampal formation has previously been shown to be comprised of two sub‐systems, one of which projects predominantly to the ipsilateral fascia dentata and regio inferior of the hippocampus proper, and a second which projects bilaterally to regio superior. The goal of the present investigation was to determine if these two pathways might originate from different cell populations within the entorhinal area. The cells of origin of these entorhinal pathways were identified by retrograde labeling with horseradish peroxidase (HRP).
Psychological maltreatment: Toward an operational definition

Abstract Despite consensus on the existence and importance of psychological maltreatment, there is far less agreement on how it should be defined. This article reviews the current definitions, proposes a theoretical clarification of the concept, and describes its relevance for the field of developmental psychopathology. We conceptualize psychological maltreatment as the interaction between maltreating parent behaviors and the special vulnerabilities of a child, particularly his or her developmental level. Also, we restrict the definition of psychological maltreatment to verbal and nonverbal parent communication; parental acts that involve physical or sexual contact are excluded. This effort strives to minimize the redundancy with the definitions of other forms of maltreatment and facilitate research into the effects of all forms of victimization.
Illegal Media File Sharing: The Impact of Cultural and Demographic Factors

The purpose of this article is to examine the ethics and economics behind the illegal file-sharing phenomena. A model of media evasion that adjusts for demographics, locus of control, and cultural aspects is developed to examine individual behavior. Using an expanded survey instrument at three universities (a private Midwest Christian liberal arts school, a public Division II university, and a public historically black college), data are collected on both student attitudes toward and actual propensity to illegally download music and other forms of multimedia. With a total sample of 302 individuals, logistic regression results indicate that age and internal locus of control tendencies are positively associated with moral attitudes, while age is the only demographic variable that is negatively associated with reduced illegal behavior. The cultural/religious results indicate that (1) self-reported religiosity has no effect on a person's attitude toward the morality of file sharing, and (2) frequency of attending religious services (“religious intensity”), particularly among those who indicate they are of the Christian faith, has a significantly positive effect on a person's attitude toward the morality of file sharing, but (3) neither of these two factors have a significant effect on actual illegal behavior.
Should the diagnosis of Attention-Deficit/ Hyperactivity disorder be considered in children with Pervasive Developmental Disorder?

Objective: To assess the overlap between Pervasive Developmental Disorder (PDD) and Attention-Deficit/Hyperactivity Disorder (ADHD) in a consecutive sample of referred youth. We hypothesized that children with PDD plus ADHD-like symptoms would have a symptom profile similar to ADHD children. Method: Subjects were consecutively referred children meeting DSM-III-R criteria for PDD with (PDD+ADHD, N = 50) and without (PDD, N= 10) ADHD-like symptoms and ADHD without PDD (ADHD, N= 105). All subjects were comprehensively assessed with structured diagnostic interviews. Results: Clinical characteristics of PDD were similar in those PDD children who did and who did not have ADHD, and ADHD features were very similar in ADHD children with and without PDD. Conclusion: These results suggest that children with PDD with concomitant symptoms of inattention, hyperactivity and impulsivity may have true comorbid ADHD. If confirmed, these findings challenge the exclusionary criteria for the diagnosis of ADHD in PDD youth.
Are the Monday Blues Ail in the Mind? The Role of Expectancy in the Subjective Experience of Mood1

The role of expectations based on the Monday-blues stereotype was explored in self-reports of mood throughout the week. Participants (N= 66) were allocated to 3 matched groups. Expectations were manipulated in 2 experimental groups: 1 in support of Monday blues and 1 against them. All participants completed the Positive and Negative Affect Schedule (PANAS) daily for 2 weeks, and ranked the days of the week in terms of mood after completion. While there were no effects on negative affect, the pro-blues group reported lower positive affect on Monday. All 3 groups recalled Monday as the worst day in terms of mood. This suggests that expectations have subtle effects on the experience of Monday blues, and highlights the discrepancies between prospective and retrospective self-reports.
State Changes Rapidly Modulate Cortical Neuronal Responsiveness

The responsiveness of cortical neurons is strongly and rapidly influenced by changes in the level of local network activity. In rodent somatosensory cortex, increases in network activity increase neuronal responsiveness to the intracellular injection of brief conductance stimuli but paradoxically decrease responsiveness to brief whisker deflections. However, whisker stimulation frequently evokes long-lasting changes in the level of local circuit activity. The ability of stimuli to successfully evoke prolonged increases in circuit activity is associated with both an increase in the amount of conductance evoked by a whisker stimulus and an increase in action potential responsiveness to whisker stimulation. In addition, brief whisker stimuli presented during periods of high network activity evoke postsynaptic potentials containing a greater proportion of inhibition, consistent with an increased efficiency in the activation of inhibitory mechanisms during the Up state. In contrast, during prolonged and variable whisker stimulation, increased network activity is associated with an increase in overall responsiveness, dynamic range, output gain, and correlation between action potential response and speed of whisker movement. We conclude that stimulus-evoked or spontaneous alterations in cortical state can influence neuronal responsiveness in a complex manner, resulting in large changes in which, and how, sensory stimuli are represented.
Sphingosine 1-Phosphate Stimulates Cell Migration through a Gi-coupled Cell Surface Receptor

Sphingosine 1-phosphate (SPP) has been shown to inhibit chemotaxis of a variety of cells, in some cases through intracellular actions, while in others through receptor-mediated effects. Surprisingly, we found that low concentrations of SPP (10–100 nm) increased chemotaxis of HEK293 cells overexpressing the G protein-coupled SPP receptor EDG-1. In agreement with previous findings in human breast cancer cells (Wang, F., Nohara, K., Olivera, O., Thompson, E. W., and Spiegel, S. (1999) Exp. Cell Res. 247, 17–28), SPP, at micromolar concentrations, inhibited chemotaxis of both vector- and EDG-1-overexpressing HEK293 cells. Nanomolar concentrations of SPP also induced a marked increase in chemotaxis of human umbilical vein endothelial cells (HUVEC) and bovine aortic endothelial cells (BAEC), which express the SPP receptors EDG-1 and EDG-3, while higher concentrations of SPP were less effective. Treatment with pertussis toxin, which ADP-ribosylates and inactivates Gi-coupled receptors, blocked SPP-induced chemotaxis. Checkerboard analysis indicated that SPP stimulates both chemotaxis and chemokinesis. Taken together, these data suggest that SPP stimulates cell migration by binding to EDG-1. Similar to SPP, sphinganine 1-phosphate (dihydro-SPP), which also binds to this family of SPP receptors, enhanced chemotaxis; whereas, another structurally related lysophospholipid, lysophosphatidic acid, did not compete with SPP for binding nor did it have significant effects on chemotaxis of endothelial cells. Furthermore, SPP increased proliferation of HUVEC and BAEC in a pertussis toxin-sensitive manner. SPP and dihydro-SPP also stimulated tube formation of BAEC grown on collagen gels (in vitro angiogenesis), and potentiated tube formation induced by basic fibroblast growth factor. Pertussis toxin treatment blocked SPP-, but not bFGF-stimulated in vitro angiogenesis. Our results suggest that SPP may play a role in angiogenesis through binding to endothelial cell Gi-coupled SPP receptors.