Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Studies Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN 8054 , a Small-Molecule Inhibitor of Aurora A Kinase

The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure–effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues. Cancer Res; 71(3); 675–85. 2010 AACR.
Parenting behaviours and children’s development from infancy to early childhood: changes, continuities and contributions

This study investigated trajectories of parenting behaviours and children’s development from infancy to early childhood, associations between parenting behaviours and children’s development and how these associations vary according to socioeconomic indicators. Mothers and children were examined from an ongoing longitudinal study of families resident in the geographic area of Avon in the UK. Using growth curve modelling, four waves of data were examined when the children were 6–42 months old. Findings suggest that timing is an important factor in the relationship between parenting and children’s development. The positive association between mother–child interactions and children’s development was evident 12 months later, whereas engagement in outside activities had both concurrent and later positive associations with children’s development. Maternal education was also highlighted as a significant moderator suggesting that interactive parenting may have a protective role for children whose mothers have lower education.
Human Leukocyte Antigen C*12:02:02 and Killer Immunoglobulin-Like Receptor 2DL5 are Distinctly Associated with Ankylosing Spondylitis in the Taiwanese

Human leukocyte antigen (HLA) class I ligands and Killer immunoglobulin-like receptors (KIRs) regulate the cytolytic activity of natural killer (NK) cells and certain T cells. We examined their genetic predisposition to disease susceptibility and clinical phenotypes in Taiwanese ankylosing spondylitis (AS) patients. KIR genotyping and Human Leucocyte Antigen C (HLA-C) sequencing were performed in 653 Taiwanese AS patients and 952 healthy controls. KIR genotype distributions and HLA-C allele frequencies were compared in patients and controls and among patients with and without HLA-B27 positivity, early age onset and spinal syndesmophytes. HLA-C alleles were functionally characterized using 3D structural modelling with peptide simulation. This study discovered that the HLA-C*12:02:02 allele (43.42% vs. 3.31%; p < 0.00001 odds ratio (OR), 16.88; 95% confidence intervals (CI): 11.27–25.28) confers a strong risk for Taiwanese AS development. The 3D modelling results identified four unique amino acid polymorphisms, Ala73, Trp156, Arg219 and Met304, that may affect the function of the HLA-C*12:02:02 allele. KIR2DL5 (p = 0.0047; pFDR = 0.0423) and the KIR Bx haplotype (p = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; p = 0.0044; pFDR = 0.1998) appeared to be a risk factor for it. KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect (AS 5.97% vs. normal 11.66%; p = 0.002; pFDR = 0.0127, OR, 0.48 95% CI: 0.33–0.70); in contrast, KIR 2DS4/1D combined with the HLA-C1C1 homozygous genotype (AS 45.33% vs. normal 35.92%; p = 0.002; pFDR = 0.0127, OR, 1.48 95% CI: 1.21–1.81) represented a risk factor for AS development. Our data suggested that interactions between KIRs and their cognate HLA-C ligands may contribute to the pathogenesis of AS.
Microvascular disease: what does the UKPDS tell us about diabetic nephropathy?

The UK Prospective Diabetes Study is the largest study in Type 2 diabetes with pre‐specified renal outcomes. The study showed that the natural history of nephropathy in newly diagnosed Type 2 diabetic patients was similar to that described previously in those with Type 1 diabetes. Around 2% per annum progress from normo‐ to micro‐albuminuria [urinary albumin concentration (UAC) > 50 mg/l] and a further 2% from microalbuminuria to clinical grade proteinuria (UAC > 300 mg/l). Mortality rates for those with nephropathy are high, increasing from 1.4% per annum (normoalbuminuria) to 4.6% per annum (clinical grade proteinuria), and to 19.2% per annum for those with renal impairment.
Prevalence and seasonal variation of human intestinal parasites in patients attending hospital with abdominal symptoms in northern Jordan.

This study was carried out to determine the prevalence of intestinal parasites and their seasonal variation in northern Jordan. A total of 21 906 stool samples were collected over a period of 4 years (2009- 2013) from 5 government hospitals in 3 cities. Samples were processed and examined microscopically and by concentration methods. Parasitic infection was found in 9611 samples (44%). Giardia lamblia was the most prevalent parasite (41%) followed by Entamoeba histolytica (31%) and Ent. coli (13%); the least prevalent parasites were Ascaris lumbricoides (1%), Hymenolepis nana, Taenia sp. , and Chilomastix mesnili (all < 1%). The prevalence of different parasites varied according to season, on average the summer months showed the highest incidence of parasitic infection (62%) compared with the winter months (16%). Giardia lamblia and Ent. histolytica were most prevalent in the summer months.
Alien Invasions and the Game of Hide and Seek in Patagonia

The introduction, establishment and spread of alien species is a major threat to biodiversity and the provision of ecosystem services for human wellbeing. In order to reduce further loss of biodiversity and maintain productive and sustainable ecosystems, understanding the ecological mechanisms underlying species invasions and avoiding potentially harmful effects on native communities is urgently needed, but largely lacking. We here demonstrate, by means of hydroacoustics and advanced spatial modelling, how native fish species as a result of previous exposure to native predators may successfully respond to invasive novel predators through a complicated game of hide and seek, minimizing spatio-temporal overlap with predators, and potentially facilitating coexistence between native prey species (Galaxiids) and introduced novel predators (Salmonids) in a deep Andean lake, Patagonia.
Families of Young Children with Developmental Disabilities: A Model of the Parenting Process

Parents of children with developmental disabilities (DD) experience a wide variety of conditions and influences that may affect the parenting process. Researchers have long recognized that child characteristics in particular influence parental behaviors and have demonstrated the reciprocal nature of the parent-child relationship. The main purpose of this study was to identify some of the primary mechanisms by which young children with DD influence their parents’ behaviors. 10 couples (10 mothers, 10 fathers) raising young (birth to five years old) children with DD (e.g., hearing loss, autism, hypothyroidism) participated in the study. Following grounded theory methods, parents were interviewed using face-to-face audio-recorded semistructured interviews that focused on their parenting behaviors and their experiences raising a child with DD. Parents described multiple categories related to the parenting process that highlighted the bidirectional influences between parents and children. The central categories that emerged from the analysis in relation to the overall parenting process were: life history (family of origin influences, other life experiences), child effects (characteristics of the disability, other child characteristics), formal social support (empowerment, homework, differentiating services), informal social support (family support, partner support, other parents), worry and stress (child’s future, child’s safety and wellbeing), and parenting behaviors (seeking normalcy, regulation, support). These categories are proposed to interrelate in a model illustrating the process by which parents and children with DD reciprocally influence one another. Limitations of this study are identified and implications of this model for future research and practice are discussed.
Stability and interactions of the amino‐terminal domain of ClpB from Escherichia coli

ClpB is a member of a multichaperone system in Escherichia coli (with DnaK, DnaJ, and GrpE) that reactivates aggregated proteins. The sequence of ClpB contains two ATP‐binding regions that are enclosed between the N‐ and C‐terminal extensions. Whereas it has been found that the N‐terminal region of ClpB is essential for the chaperone activity, the structure of this region is not known, and its biochemical properties have not been studied. We expressed and purified the N‐terminal fragment of ClpB (residues 1–147). Circular dichroism of the isolated N‐terminal region showed a high content of α‐helical structure. Differential scanning calorimetry showed that the N‐terminal region of ClpB is thermodynamically stable and contains a single folding domain. The N‐terminal domain is monomeric, as determined by gel‐filtration chromatography, and the elution profile of the N‐terminal domain does not change in the presence of the N‐terminally truncated ClpB (ClpBΔN). This indicates that the N‐terminal domain does not form strong contacts with ClpBΔN. Consistently, addition of the separated N‐terminal domain does not reverse an inhibition of ATPase activity of ClpBΔN in the presence of casein. As shown by ELISA measurements, full‐length ClpB and ClpBΔN bind protein substrates (casein, inactivated luciferase) with similar affinity. We also found that the isolated N‐terminal domain of ClpB interacts with heat‐inactivated luciferase. Taken together, our results indicate that the N‐terminal fragment of ClpB forms a distinct domain that is not strongly associated with the ClpB core and is not required for ClpB interactions with other proteins, but may be involved in recognition of protein substrates.
Learning to Transduce with Unbounded Memory

Recently, strong results have been demonstrated by Deep Recurrent Neural Networks on natural language transduction problems. In this paper we explore the representational power of these models using synthetic grammars designed to exhibit phenomena similar to those found in real transduction problems such as machine translation. These experiments lead us to propose new memory-based recurrent networks that implement continuously differentiable analogues of traditional data structures such as Stacks, Queues, and DeQues. We show that these architectures exhibit superior generalisation performance to Deep RNNs and are often able to learn the underlying generating algorithms in our transduction experiments.
EXTRACTION OF THE MELODY PITCH CONTOUR FROM POLYPHONIC AUDIO

MIREX 2005 is the second evaluation of algorithms related to music information retrieval (MIR). This document describes our submission to the MIREX audio melody extraction contest addressing the task of identifying the melody pitch contour from polyphonic musical audio. We use mainly a data-driven approach – implementing standard audio signal processing techniques like Fourier analysis, instantaneous frequency estimation and sinusoidal extraction. Nevertheless, some high level knowledge is applied. Examples of such knowledge include perceptually motivated methods (psychoacoustics, auditory stream segregation) as well as basic voice-leading principles. The result of the Mirex 2005 evaluation proves that our algorithm performs best in respect of runtime and overall accuracy, a measure which combines voicing detection (discrimination between melody and non-melody parts) and pitch estimation.
Isolation and Characterization of Batatasin III and 3,4'- Dihydroxy-5-methoxybibenzyl: A Pair of Positional Isomers from Sunipia scariosa

Purpose : To isolate and characterize chemical compounds of biological importance from the whole plant of Sunipia scariosa. Methods : The whole plant of Sunipia scariosa was extracted with methanol (MeOH) and chromatographed on silica gel and sephadex LH-20 to afford the pure isolates. High perfomance liquild chromatography (HPLC) was used for further purification of the isolated compounds. Characterization of the isolated compounds was achieved by 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Results : Batatasin III (3,3’-dihydroxy-5-methoxybibenzyl) and 3,4’-dihydroxy-5-methoxybibenzyl, a pair of positional isomers, were isolated from the whole plant of Sunipia scariosa. The yields of the two isomers were 60 and 40 %, respectively, from the mixture of two compounds. Conclusion : Batatasin III and 3,4’-dihydroxy-5-methoxybibenzyl, a pair of positional isomers were successfully isolated from the whole plant of Sunipia scariosa for the first time. Keywords : Sunipia scariosa, Batatasin III, 3,4’-Dihydroxy-5-methoxybibenzyl, Isomers
Symbolic Filtering: Selectively Permeable Evangelical Boundaries in an Age of Religious Pluralism

Since Peter Berger's (1967, The Sacred Canopy: Elements of a Sociological Theory of Religion, Garden City, NY: Doublday) early work on the sacred canopy, scholars have debated the effects of increased diversity on religious belief and vitality. Smith (1998, American Evangelicalism: Embattled and Thriving, Chicago: University of Chicago Press), in particular, has suggested that subcultures like American evangelicalism can thrive in a religiously pluralistic environment by both engaging with the world while remaining symbolically distinct from it. This article builds on this work as well as recent scholarship on boundary permeability by exploring the mechanisms by which American evangelicals negotiate their boundaries as they adapt to their surroundings. Based on a qualitative content analysis of 109 articles from two evangelical missionary periodicals published over a period of over 20 years, I examine the use of both boundary-strengthening and boundary-weakening processes employed by evangelical missionaries and missiologists (or “boundary agents”). I find that almost every instance of boundary weakening is also accompanied by boundary strengthening, suggesting that symbolic boundaries are becoming selectively permeable through a process I identify as “symbolic filtering. ” In conclusion, the article briefly considers the implications of these findings for the broader discussion of symbolic boundaries and religious pluralism.
Detection of Mycobacterium avium subsp. paratuberculosis in Retail Cheeses from Greece and the Czech Republic

ABSTRACT We investigated the presence of Mycobacterium avium subsp. paratuberculosis in retail cheeses from Greece and the Czech Republic. We found that 31.7% and 3.6% of our samples reacted positive by PCR and culture, respectively. Consumption of these cheeses is likely to result in human exposure to M. avium subsp. paratuberculosis, albeit at a low level for viable cells.
Acute pulmonary embolism in patients with HIV disease.

OBJECTIVES: To determine the incidence, mode of presentation, and outcome of pulmonary embolism (PE) in patients with HIV infection. METHODS: Retrospective review of clinical case records, imaging department database, and necropsy reports of patients admitted to the specialist HIV/AIDS unit at UCL hospitals from April 1993 to August 1997 in order to identify those with a diagnosis of PE. RESULTS: During the study period there were 3792 admissions of whom 10 (0.26%) had PE. All patients with PE presented with fever, seven were dyspnoeic, and seven had cough: all were thought initially to have respiratory infection. Only five patients had pleural pain. All 10 patients had abnormal baseline chest radiographs. The diagnosis in six was made by computed tomograph (CT) pulmonary angiography, in two was made by ventilation perfusion (V/Q) scanning, in one by both techniques, and in one at necropsy. CT angiography in addition to identifying thrombus also showed concomitant lung parenchymal abnormalities in all but one patient. Nine patients with PE had one or more risk factors for venous thromboembolism as did 34/40 case matched controls (odds ratio = 1.67; 95% confidence interval = 0.18-15.5). All patients diagnosed in life were anticoagulated and five survived. CONCLUSIONS: PE was uncommon in this HIV infected population. The diagnosis should be considered in patients with respiratory infection which does not respond to antibiotics. Identifiable risk factors for venous thromboembolism appear to be unhelpful in increasing clinical index of suspicion for PE. As baseline chest radiographs are frequently abnormal, the diagnostic utility of V/Q scanning may be reduced and CT pulmonary angiography is the imaging modality of first choice.
The bachelor’s to Ph.D. STEM pipeline no longer leaks more women than men: a 30-year analysis

For decades, research and public discourse about gender and science have often assumed that women are more likely than men to “leak” from the science pipeline at multiple points after entering college. We used retrospective longitudinal methods to investigate how accurately this “leaky pipeline” metaphor has described the bachelor’s to Ph.D. transition in science, technology, engineering, and mathematics (STEM) fields in the U.S. since the 1970s. Among STEM bachelor’s degree earners in the 1970s and 1980s, women were less likely than men to later earn a STEM Ph.D. However, this gender difference closed in the 1990s. Qualitatively similar trends were found across STEM disciplines. The leaky pipeline metaphor therefore partially explains historical gender differences in the U.S., but no longer describes current gender differences in the bachelor’s to Ph.D. transition in STEM. The results help constrain theories about women’s underrepresentation in STEM. Overall, these results point to the need to understand gender differences at the bachelor’s level and below to understand women’s representation in STEM at the Ph.D. level and above. Consistent with trends at the bachelor’s level, women’s representation at the Ph.D. level has been recently declining for the first time in over 40 years.
The oxidation of fatty acids by mycelium of Penicillium roqueforti.

SUMMARY: Low concentrations of fatty acids with less than 14 carbon atoms were oxidized without a lag phase over a wide range of pH values by mycelium of Penicillium roqueforti. The effect of the fatty acids upon oxygen uptake by a given weight of mycelium, and the nature of the products of oxidation, were dependent upon the concentration and chain length of the fatty acid and the pH value of the system. The C9-C12 fatty acids which showed the greatest inhibitory effect were not oxidized to the corresponding methyl ketone with one less carbon atom in such high yields as the less toxic C6-C8 acids. The C6-C8 fatty acids markedly inhibited endogenous respiration at low pH values but this inhibition was reversed by increasing the pH value. The toxic effect associated with some fatty acids was less pronounced against mycelium which had been previously shaken over an extended period in phosphate buffer. It is suggested that the cellular regulation of fatty acid oxidation and methyl ketone formation involves deacylation of β-oxo acyl thiolester which provides an alternative means of recycling coenzyme A when oxidation of acetyl CoA is impaired.
Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety

Knock-in mice were generated that harbored a leucine-to-serine mutation in the α4 nicotinic receptor near the gate in the channel pore. Mice with intact expression of this hypersensitive receptor display dominant neonatal lethality. These mice have a severe deficit of dopaminergic neurons in the substantia nigra, possibly because the hypersensitive receptors are continuously activated by normal extracellular choline concentrations. A strain that retains the neo selection cassette in an intron has reduced expression of the hypersensitive receptor and is viable and fertile. The viable mice display increased anxiety, poor motor learning, excessive ambulation that is eliminated by very low levels of nicotine, and a reduction of nigrostriatal dopaminergic function upon aging. These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease.
Serum Total Cholesterol Concentrations and Awareness, Treatment, and Control of Hypercholesterolemia Among US Adults: Findings From the National Health and Nutrition Examination Survey, 1999 to 2000

Background—Serum cholesterol concentrations have decreased in the US population. Whether the decline continued during the 1990s is unknown. Methods and Results—We used data from 4148 men and women aged ≥20 years who had a total cholesterol determination or reported using cholesterol-lowering medications and who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000 (this is a cross-sectional health examination survey of the US population), and we compared the results with data from 15 719 participants in NHANES III (1988 to 1994). For all adults, the age-adjusted mean total cholesterol concentration decreased from 5.31 mmol/L (205 mg/dL) in NHANES III to 5.27 mmol/L (203 mg/dL) in NHANES 1999 to 2000 (P =0.159). The age-adjusted mean total cholesterol concentration decreased by 0.02 mmol/L (0.7 mg/dL) among men (P =0.605) and 0.06 mmol/L (2.3 mg/dL) among women (P =0.130). Significant decreases were observed among men aged ≥75 years, black men, and Mexican-American women. Among participants who had a total cholesterol concentration ≥5.2 mmol/L (200 mg/dL) or who reported using cholesterol-lowering medications, 69.5% reported having had their cholesterol checked, 35.0% were aware that they had hypercholesterolemia, 12.0% were on treatment, and 5.4% had a total cholesterol concentration <5.2 mmol/L (200 mg/dL) after age adjustment. Conclusions—The mean serum total cholesterol concentration of the adult US population in 1999 to 2000 has changed little since 1988 to 1994. The low percentage of adults with controlled blood cholesterol concentration suggests the need for a renewed commitment to the prevention, treatment, and control of hypercholesterolemia.
Topological design of communication networks using multiobjective genetic optimization

Designing communication networks is a complex, multi-constraint and multi-criterion optimization problem. We present a multi-objective genetic optimization approach to setting up a network while simultaneously minimizing network delays and installation costs subject to reliability and flow constraints. In this paper, we use a Pareto-converging genetic algorithm, present results for two test networks and compare results with another heuristic method.