Miracle-dz/UniFAR-FTUs huggingface dataset:
Using Pharmacokinetic and Pharmacodynamic Data in Early Decision Making Regarding Drug Development: A Phase I Clinical Trial Evaluating Tyrosine Kinase Inhibitor, AEE788

Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. Experimental design: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. Results: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC50) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC50 in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed. Conclusion: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development. Clin Cancer Res; 18(22); 6364–72. ©2012 AACR.
Reduced Cytosolic Ca2 Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

BackgroundHypothermia is cardioprotective, but it causes Ca2+ loading and reduced function on rewarming. The aim was to associate changes in cytosolic Ca2+ with function in intact hearts before, during, and after cold storage with or without cardioplegia (CP). Methods and ResultsGuinea pig hearts were initially perfused at 37°C with Krebs-Ringer’s (KR) solution (in mmol/L: Ca2+ 2.5, K+ 5, Mg2+ 2.4). One group was perfused with CP solution (Ca2+ 2.5, K+ 18, Mg2+ 7.2) during cooling and storage at 3°C for 4 hours; another was perfused with KR. LV pressure (LVP), dP/dt, O2 consumption, and cardiac efficiency were monitored. Cytosolic phasic [Ca2+] was calculated from indo 1 fluorescence signals obtained at the LV free wall. Cooling with KR increased diastolic and phasic [Ca2+], whereas cooling with CP suppressed phasic [Ca2+] and reduced the rise in diastolic [Ca2+]. Reperfusion with warm KR increased phasic [Ca2+] 86% more after CP at 20 minutes and did not increase diastolic [Ca2+] at 60 minutes, compared with a 20% increase in phasic [Ca2+] after KR. During early and later reperfusion after CP, there was a 126% and 50% better return of LVP than after KR; during later reperfusion, O2 consumption was 23% higher and cardiac efficiency was 38% higher after CP than after KR. ConclusionsCP decreases the rise in cardiac diastolic [Ca2+] observed during cold storage in KR. Decreased diastolic [Ca2+] and increased systolic [Ca2+] after CP improves function on reperfusion because of reduced Ca2+ loading during and immediately after cold CP storage.
[Helminths of the common fox (Vulpes vulpes L.) from the massif central (France) (author's transl)].

Sixty nine wild foxes originating from Auvergne for the period January 1977 to January 1978 have shown intestinal parasites in the proportion of 76,8 per cent. 59,4 per cent are invaded with Cestodes; 72,4 per cent with Nematodes and none with Trematodes. The list of the identified species is following: 1. Cestodes. A) Adults and fertile forms of: Mesocestoides litteratus in 27,5 per cent of the hosts; Taenia crassiceps in 15,9 p.c. ; T. polyacantha in 27,5 p.c. ; Echinococcus multilocularis in 7,2 p.c. ; Amoebotaenia paradoxa in 4,3 p.c. B) Immature forms of : Taenia pisiformis in 2,89 p.c. ; T. ovis in 1,44 p.c. 2. Nematodes. Uncinaria stenocephala in 68,1 per cent of the hosts; Ancylostoma caninum in 1,4 p.c. ; Molineus patens in 1,4 p.c. ; Oxyurid sp. in 1,4 p.c. ; Toxocara canis in 27,5 p.c. and Toxascaris leonina in 33,3 p.c. The composition of the helminth fauna of the foxes in the center countries of France is not different of the European species from the same host, except Amoebotaenia paradoxa, Dilepidid cestode of birds, quite unusual from a carnivorus mammal.
A new approach to I/O performance evaluation: self-scaling I/O benchmarks, predicted I/O performance

Current I/O benchmarks suffer from several chronic problems: they quickly become obsolete, they do not stress the I/O system, and they do not help in understanding I/O system performance. We propose a new approach to I/O performance analysis. First, we propose a self-scaling benchmark that dynamically adjusts aspects of its workload according to the performance characteristic of the system being measured. By doing so, the benchmark automatically scales across current and future systems. The evaluation aids in understanding system performance by reporting how performance varies according to each of fie workload parameters. Second, we propose predicted performance, a technique for using the results from the self-scaling evaluation to quickly estimate the performance for workloads that have not been measured. We show that this technique yields reasonably accurate performance estimates and argue that this method gives a far more accurate comparative performance evaluation than traditional single point benchmarks. We apply our new evaluation technique by measuring a SPARCstation 1+ with one SCSI disk, an HP 730 with one SCSI-II disk, a Sprite LFS DECstation 5000/200 with a three-disk disk array, a Convex C240 minisupercomputer with a four-disk disk array, and a Solbourne 5E/905 fileserver with a two-disk disk array.
Selective Up-Regulation of Phosphodiesterase-4 Cyclic Adenosine 3',5'-Monophosphate (cAMP)-Specific Phosphodiesterase Variants by Elevated cAMP Content in Human Myometrial Cells in Culture.

In human myometrium, the modulation of intracellular cAMP content resulting from agonist-mediated stimulation of the receptor-adenylyl cyclase complex is largely influenced by the rate of cAMP hydrolysis by phosphodiesterase (PDE) isoenzymes. We have previously shown that the PDE4 family contributes to the predominant cAMP-hydrolyzing activity in human myometrium and that elevation of the PDE4B2 messenger RNA steady state level occurs in pregnant myometrial tissue. In the present study, we used a model of human myometrial cells in culture to determine whether an elevated cAMP concentration could influence PDE expression. As in myometrial tissue, high levels of PDE4 activity were detected in these smooth muscle cells. Long term treatment with 8-bromo-cAMP or forskolin resulted in a selective induction of PDE4B and of PDE4D short form messenger RNA variants. Concurrently, an increased immunoreactive signal for the PDE4B- and PDE4D-related isoenzymes was detected. This induction was consistent with an observed significant up-regulation of PDE4 activity. Accordingly, our results demonstrate that in human cultured myometrial cells, cAMP-elevating agents manipulate PDE4 activity through selective induction of synthesis of PDE4B and PDE4D short forms. Such a mechanism might have physiological importance during pregnancy by dampening hormonal stimulation and could thereby be involved in tolerance to the tocolytic effect of beta-adrenoceptor agonists.
Vocal identification of speaker and emotion activates differerent brain regions

REGIONAL cerebral blood flow was measured in six healthy volunteers by positron emission tomography during identification of speaker and emotion from spoken words. The speaker identification task activated several audio-visual multimodal areas, particularly the temporal poles in both hemispheres, which may be involved in connecting vocal attributes with the visual representations of speakers. The emotion identification task activated regions in the cerebellum and the frontal lobe, suggesting a functional relationship between those regions involved in emotion. The results suggest that different anatomical structures contribute to the vocal identification of speaker and emotion.
Starch properties and structure of a wheat mutant high in resistant starch

Starch properties and structure of a wheat mutant (WRS-1) high in resistant starch (RS) was compared to that of the wild type (Sumai No.6). In cooked hot flour and retrograded flour, the amounts of RS in mutant WRS-1 were 7.8 and 9.4 times of wild type (0.5 in hot flour and 0.6 in retrograded flour), respectively, and correspondingly the slower and incomplete starch hydrolysis was also in both types of samples. WRS-1 had a higher λmax of absorbance, blue value (BV), apparent amylose content (AAC), and contained the increased intermediate and long chains with 18≤ degree of polymerization (DP) and decreased short chains with DP≤17. Two types of starch granules, large A in lenticular shape and small B in spherical shape, were observed in both mutant and wild types. However, the starch granules in WRS-1 were relatively larger and some were irregularly-shaped. High content of total starch (TS), decreased contents of lipid (LC) and protein (PC), lower onset temperature (To), peak temperature (Tp), final temperature (Tc), and the enthalpy of gelatinization (ΔHgel) were observed in WRS-1.
A Large PEST-like Sequence Directs the Ubiquitination, Endocytosis, and Vacuolar Degradation of the Yeast a-Factor Receptor

The yeast a-factor receptor (encoded by STE3) is subject to two modes of endocytosis, a ligand-dependent endocytosis as well as a constitutive, ligand-independent mode. Both modes are associated with receptor ubiquitination (Roth, A.F., and N.G. Davis. 1996. J. Cell Biol. 134:661–674) and both depend on sequence elements within the receptor's regulatory, cytoplasmically disposed, COOH-terminal domain (CTD). Here, we concentrate on the Ste3p sequences required for constitutive endocytosis. Constitutive endocytosis is rapid. Receptor is synthesized, delivered to the cell surface, endocytosed, and then delivered to the vacuole where it is degraded, all with a t 1/2 of 15 min. Deletion analysis has defined a 36-residue-long sequence mapping near the COOH-terminal end of the Ste3p CTD that is the minimal sequence required for this rapid turnover. Deletions intruding into this interval block or severely slow the rate of endocytic turnover. Moreover, the same 36-residue sequence directs receptor ubiquitination. Mutants deleted for this sequence show undetectable levels of ubiquitination, and mutants having intermediate endocytosis defects show a correlated reduced level of ubiquitination. Not only necessary for ubiquitination and endocytosis, this sequence also is sufficient. When transplanted to a stable cell surface protein, the plasma membrane ATPase Pma1p, the 36-residue STE3 signal directs both ubiquitination of the PMA1-STE3 fusion protein as well as its endocytosis and consequent vacuolar degradation. Alanine scanning mutagenesis across the 36-residue-long interval highlights its overall complexity—no singular sequence motif or signal is found, instead required sequence elements distribute throughout the entire interval. The high proportion of acidic and hydroxylated amino acid residues in this interval suggests a similarity to PEST sequences—a broad class of sequences which have been shown to direct the ubiquitination and subsequent proteosomal degradation of short-lived nuclear and cytoplasmic proteins. A likely possibility, therefore, is that this sequence, responsible for both endocytosis and ubiquitination, may be first and foremost a ubiquitination signal. Finally, we present evidence suggesting that the true signal in the wild-type receptor extends beyond the 36-residue-long sequence defined as a minimal signal to include contiguous PEST-like sequences which extend another 21 residues to the COOH terminus of Ste3p. Together with sequences identified in two other yeast plasma membrane proteins, the STE3 sequence defines a new class of ubiquitination/endocytosis signal.
Assessing Credit Default using Logistic Regression and Multiple Discriminant Analysis: Empirical Evidence from Bosnia and Herzegovina

This article has an aim to assess credit default prediction on the banking market in Bosnia and Herzegovina nationwide as well as on its constitutional entities (Federation of Bosnia and Herzegovina and Republika Srpska). Ability to classify companies info different predefined groups or finding an appropriate tool which would replace human assessment in classifying companies into good and bad buckets has been one of the main interests on risk management researchers for a long time. We investigated the possibility and accuracy of default prediction using traditional statistical methods logistic regression (logit) and multiple discriminant analysis (MDA) and compared their predictive abilities. The results show that the created models have high predictive ability. For logit models, some variables are more influential on the default prediction than the others. Return on assets (ROA) is statistically significant in all four periods prior to default, having very high regression coefficients, or high impact on the model's ability to predict default. Similar results are obtained for MDA models. It is also found that predictive ability differs between logistic regression and multiple discriminant analysis.
Clinical and Imaging Predictors of Surgical Outcome in Multilevel Cervical Ossification of Posterior Longitudinal Ligament: An Analysis of 184 Patients

Objective To investigate the clinical and imaging predictors of surgical outcomes in patients with ossification of the posterior longitudinal ligament (OPLL). Materials and Methods From May 2010 to April 2012, a total of 200 consecutive patients with cervical OPLL were recruited for this study. Of them, 184 patients (130 men and 54 women) who could be tracked for more than 24 months after surgery were finally included for analysis. Their demographic, clinical and radiological data were collected preoperatively. The recovery ratio in terms of JOA score was used to assess the outcome of the patients preoperatively and at 2 years postoperatively. A JOA recovery rate less than 50% was considered a poor outcome. Results Compared with good outcome group, an older mean age at operation, a longer mean duration of symptoms, a lower mean pre-operativer JOA score, and a higher proportion of diabetics were observed in poor outcome group. Patients in poor outcome group were more likely to present kyphotic cervical alignment, smaller mean transverse area of the spinal cord, and intramedullary signal abnormalities. The result of multivariate stepwise logistic regression showed that a longer duration of symptoms and the presence of T1 hypo-intensity intramedullary changes on MRI were significant risk factors of lower JOA recovery ratios. Conclusion A longer duration of symptom, T1 hypointensity on MRI and a history of minor trauma were highly predictive of a poor outcome for patients undergoing surgical treatment of OPLL. Age at operation, the history of diabetes, the preoperative JOA score, the transverse area of the spinal cord and T2 hyper-intensity on MRI were also associated with the prognosis of OPLL.
Lie algebraic noncommutative gravity

We exploit the Seiberg-Witten map technique to formulate the theory of gravity defined on a Lie algebraic noncommutative space-time. Detailed expressions of the Seiberg-Witten maps for the gauge parameters, gauge potentials, and the field strengths have been worked out. Our results demonstrate that notwithstanding the introduction of more general noncommutative structure there is no first order correction, exactly as happens for a canonical (i.e. constant) noncommutativity.
Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 patients without cirrhosis were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%), and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56), and hepatic steatosis (aOR: 1.78) at the time of initial biopsy were marginally associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/L versus <25% values >100 U/L) were strongly associated with fibrosis progression. Conclusion: Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important noninvasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment. (Hepatology 2014;59:767–775)
Voltage-dependent block of charge movement components by nifedipine in frog skeletal muscle

Potential-dependent inhibition of charge movement components by nifedipine was studied in intact, voltage-clamped, frog skeletal muscle fibers. Available charge was reduced by small shifts in holding potential (from -100 mV to -70 mV) in 2 microM nifedipine, without changes in the capacitance deduced from control (-120 mV to -100 mV) voltage steps made at a fully polarized (-100 mV) holding potential. These voltage-dependent effects did not occur in lower (0-0.5 microM) nifedipine concentrations. The voltage dependence of membrane capacitance at higher (10 microM) nifedipine concentrations was reduced even in fully polarized fibers, but shifting the holding voltage produced no further block. Voltage-dependent inhibition by nifedipine was associated with a fall in available charge, and a reduction in the charge and capacitance-voltage relationships and of late (q gamma) charging transients. It thus separated a membrane-capacitance with a distinct and steep steady-state voltage dependence. Tetracaine (2 mM) reduced voltage-dependent membrane capacitance and nonlinear charge more than did nifedipine. However, nifedipine did not exert voltage- dependent effects on charging currents, membrane capacitance, or inactivation of tetracaine-resistant (q beta) charge. This excludes participation of q beta, or the membrane charge as a whole, from the voltage-dependent effects of nifedipine. Rather, the findings suggest that the charge susceptible to potential-dependent block by nifedipine falls within the tetracaine-sensitive (q gamma) category of intramembrane charge.
Weak phylogenetic effects on ecological niches of Sylvia warblers

To understand the evolution of ecological niches it is important to know whether niche evolution is constrained by phylogeny. We approached this question for Sylvia warblers by testing if closely related species are more similar in 20 ecologically relevant morphological traits than distantly related species. Phylogenetic relatedness was quantified using a molecular phylogeny based on the mitochondrial cytochrome b gene. By Principal Component Analysis (PCA) two major niche axes were extracted. We tested the individual ecomorphological traits and the positions of the species on the PCA axes for phylogenetic effects using Mantel tests. The results demonstrated small but significant phylogenetic effects only for the length of the middle toe, a trait probably correlated with locomotion. In general, however, phylogenetic effects were very weak. This suggests that ecological niches in passerine birds have the potential to evolve rapidly and are not subject to major phylogenetic constraints.
Genome sequencing of environmental Escherichia coli expands understanding of the ecology and speciation of the model bacterial species

Defining bacterial species remains a challenging problem even for the model bacterium Escherichia coli and has major practical consequences for reliable diagnosis of infectious disease agents and regulations for transport and possession of organisms of economic importance. E. coli traditionally is thought to live within the gastrointestinal tract of humans and other warm-blooded animals and not to survive for extended periods outside its host; this understanding is the basis for its widespread use as a fecal contamination indicator. Here, we report the genome sequences of nine environmentally adapted strains that are phenotypically and taxonomically indistinguishable from typical E. coli (commensal or pathogenic). We find, however, that the commensal genomes encode for more functions that are important for fitness in the human gut, do not exchange genetic material with their environmental counterparts, and hence do not evolve according to the recently proposed fragmented speciation model. These findings are consistent with a more stringent and ecologic definition for bacterial species than the current definition and provide means to start replacing traditional approaches of defining distinctive phenotypes for new species with omics-based procedures. They also have important implications for reliable diagnosis and regulation of pathogenic E. coli and for the coliform cell-counting test.
Worries About Labor and Birth: A Population-Based Study of Outcomes for Young Primiparous Women.

BACKGROUND Pregnancy at a young age is a continuing public health concern strongly associated with socioeconomic deprivation, social isolation, and stigma. The objectives were to see whether, compared with women aged 21 or more, women aged 20 years or younger worried more about labor and birth, and had poorer maternal outcomes. Another objective was to investigate the extent to which worries about labor and birth mediated the associations between young age and outcomes. METHODS A secondary analysis of data was conducted relating to 2,598 primiparous women's experience of maternity care in England in 2010. The survey collected data on care in the antenatal, intrapartum, and postnatal periods, and sociodemographic factors. A validated checklist measured worries about labor and birth. RESULTS Compared with women aged 21 or more, women aged 20 years or younger worried more about labor and birth. The pain and duration of labor worried all women and those aged 20 years or younger were particularly worried about the uncertainty of labor onset, cesarean section birth, and about embarrassment. In logistic regression, after adjusting for potential confounders, young age was a significant independent risk factor for worries about pain and distress in labor, and self-reported depression at 1 and 3 months. However, young age was also significantly associated with having a normal vaginal delivery. CONCLUSIONS It may be appropriate to focus support on women experiencing multiple disadvantage, rather than young age alone.