Miracle-dz/UniFAR-FTUs huggingface dataset:
Raf and PI3K are the Molecular Targets for the Anti‐metastatic Effect of Luteolin

Metastases are the primary cause of human cancer deaths. Luteolin, a naturally occurring phytochemical, has chemopreventive and/or anticancer properties in several cancer cell lines. However, anti‐metastatic effects of luteolin in vivo and the underlying molecular mechanisms and target(s) remain unknown. Luteolin suppresses matrix metalloproteinase (MMP)‐2 and ‐9 activities and invasion in murine colorectal cancer CT‐26 cells. Western blot and kinase assay data revealed that luteolin inhibited Raf and phosphatidylinositol 3‐kinase (PI3K) activities and subsequently attenuated phosphorylation of MEK and Akt. A pull‐down assay indicated that luteolin non‐competitively bound with ATP to suppress Raf activity and competitively bound with ATP to inhibit PI3K activity. GW5074, a Raf inhibitor, and LY294002, a PI3K inhibitor, inhibited MMP‐2 and ‐9 activities and invasion in CT‐26 cells. An in vivo mouse study showed that oral administration (10 or 50 mg/kg) of luteolin significantly inhibited tumor nodules and tumor volume of lung metastasis induced by intravenous injection of CT‐26 cells. Luteolin also inhibited MMP‐9 expression and activity in CT‐26‐induced mouse lung tissue. These results suggest that luteolin may have considerable potential for development as an anti‐metastatic agent. Copyright © 2012 John Wiley & Sons, Ltd.
Shear‐Controlled Single‐Step Mouse Embryonic Stem Cell Expansion and Embryoid Body–Based Differentiation

To facilitate the exploitation of embryonic stem cells (ESCs) and ESC‐derived cells, scale‐up of cell production and optimization of culture conditions are necessary. Conventional ESC culture methods are impractical for large‐scale cell production and lack robust microenvironmental control. We developed two stirred‐suspension culture systems for the propagation of undifferentiated ESCs—microcarrier and aggregate cultures—and compared them with tissue‐culture flask and Petri dish controls. ESCs cultured on glass microcarriers had population doubling times (∼14–17 hours) comparable to tissue‐culture flask controls. ESC growth could be elicited in shear‐controlled stirred‐suspension culture, with population doubling times ranging between 24 and 39 hours at 100 rpm impeller speed. Upon removal of leukemia inhibitory factor, the size‐controlled ESC aggregates developed into embryoid bodies (EBs) capable of multilineage differentiation. A comprehensive analysis of ESC developmental potential, including flow cytometry for Oct‐4, SSEA‐1, and E‐cadherinprotein expression, reverse transcription–polymerase chain reaction for Flk‐1, HNF3‐β, MHC, and Sox‐1 gene expression, and EB differentiation analysis, demonstrated that the suspension‐cultured ESCs retained the developmental potential of the starting cell population. Analysis of E‐cadherin−/− and E‐cadherin+/− cells using both systems provided insight into the mechanisms behind the role of cell aggregation control, which is fundamental to these observations. These cell‐culture tools should prove useful for both the production of ESCs and ESC‐derived cells and for investigations into adhesion, survival, and differentiation phenomena during ESC propagation and differentiation.
Age-Related Urinary Excretion of BK Polyomavirus by Nonimmunocompromised Individuals

ABSTRACT Two polyomaviruses, BK virus (BKV) and JC virus (JCV), are ubiquitous in the human population, generally infecting children asymptomatically and then persisting in renal tissue. It is generally thought that reactivation leads to productive infection for both viruses, with progeny shed in the urine. Several studies have shown that the rate of JC viruria increases with the age of the host, but a systematic approach to examine the shedding of BKV has not been developed. To elucidate the relationship between BK viruria and host age, we obtained urine from donors (healthy volunteers or nonimmunocompromised patients) who were divided into nine age groups, each containing 50 members. A high-sensitivity PCR was used to detect BKV and JCV DNA from urinary samples, and the specificity of amplification was confirmed by sequencing or restriction analysis of the amplified fragments. The rate of BK viruria was relatively low in subjects aged <30 years but gradually increased with age in subjects aged ≥30 years. However, BK viruria was less frequent than JC viruria in adults. The detected BKV isolates were classified into subtypes, and detection rates for individual subtypes were compared among age groups; this analysis showed that viruria of subtypes I (the most prevalent subtype) and IV (the second most prevalent subtype) occurred more frequently in older subjects. Therefore, our results reveal new aspects of BK viruria in nonimmunocompromised individuals.
Associations between women's subjective perceptions of daily occupations and life satisfaction, and the role of perceived control.

BACKGROUND/AIM More knowledge is needed about the role of perceived control in the associations between different perceptions of daily occupations and positive health outcomes. The aim was to explore the associations between different subjective perceptions of daily occupations, in terms of occupational balance, occupational meaning, occupational value and satisfaction with occupations, and life satisfaction, and the role of perceived control in those associations. METHODS A questionnaire including questions about perceptions of daily occupations, perceived control and life satisfaction were answered by a random sample of 488 middle-aged Swedish women. Multiple logistic regression analysis was used to test the associations between perceptions of daily occupations and life satisfaction, and the role of perceived control. RESULTS After adjustments for perceived control women who perceived a high level of satisfaction with work and leisure, occupational balance, occupational meaning and occupational value perceived greater life satisfaction than the other women. Perceived control was not significant in the model. CONCLUSIONS It seems that occupational balance and occupational meaning were pivotal for the women's life satisfaction, but satisfaction with work and leisure, as well as perceived occupational value, was also of importance. The assumption that perceived control would have a role in the association between perceptions of occupations and life satisfaction was not confirmed. SIGNIFICANCE OF THE STUDY The results indicate that occupational therapists need to focus on occupational balance, occupational meaning, occupational value and satisfaction with work and leisure to promote positive health outcomes, in terms of life satisfaction, when working with middle-aged female clients.
Risk-assessment tools in the prevention of pressure ulcers.

Some screening tools exist for assessing increased risk of the development of pressure ulcers, but none of these tools has undergone actual testing for validity and predictive value. This is important in clinical practice because the combination of high sensitivity and rather low specificity implies that the number of patients at increased risk is overestimated and thus overtreated (i.e., unnecessary preventive measures are taken). Risk scores are usually composed of items considered to influence the development of pressure ulcers. Although for some scoring systems attempts have been made to enhance specificity by changing the cutoff points or the relative value of individual items, good results have not been achieved. The influence that individual items have on the development of pressure ulcers and the impact of this influence on score outcomes has not yet been established. In this study, 65 patients with and 58 patients without pressure ulcers were compared using all of the known risk factors analyzed by multivariate logistic regression. We found that only the Norton, Douglas, and Dutch Consensus Meeting scoring systems appeared to predict the development of pressure ulcers. Also, it appeared that incontinence for urine and the presence of both neurologic disorders and friction forces to the skin effectively predict the development of pressure ulcers. Considering the important implications of this study, a larger study--consisting of several thousand patients--should be performed to assess in more detail the variables currently perceived as risk factors and construct and evaluate a scoring system based on these results.
Change in the Th1/Th2 Phenotype of Memory T‐Cell Clones from Rheumatoid Arthritis Synovium

The stability of established memory T helper (Th)1/Th2 cells in chronic inflammatory diseases is not clear, and a shift of the cytokine balance could control chronic inflammation. In order to study the regulation of the Th phenotype of memory T cells, polyclonal T‐cell lines and clones with a Th1, Th0 or Th2 phenotype were developed from rheumatoid synovial tissue. Th1 [interleukin (IL)‐12 + anti‐IL‐4] and Th2 (IL‐4 + anti‐IL‐12) promoting environments and IL‐2 were used to manipulate the cytokine profile. Polyclonal T‐cell lines of predominantly Th1 type could be shifted to produce Th2 cytokines, and polyclonal Th2/Th0 lines could be shifted to produce Th1 cytokines. However, this shift was due to an amplification of CD8+ T cells with a memory phenotype and a loss of the CD4+ T cells, giving Tc2 or Tc1 profiles, respectively. Th2 clones cultured repeatedly with IL‐2 switched to either a Th0 or a Th1 phenotype, while both Th1 and Th0 memory clones kept a stable phenotype. Addition of Th2‐promoting conditions strongly reduced the production of both interferon‐gamma and IL‐17, while Th1‐promoting conditions increased the production of these cytokines. These results demonstrate that RA Th2 clones readily switch, while Th1 and Th0 clones are stable. However, induction of Th2 cytokines can be obtained in polyclonal polarized memory T cells due to amplification of Tc2 cells.
The Cytochrome c Maturation Locus of Legionella pneumophila Promotes Iron Assimilation and Intracellular Infection and Contains a Strain-Specific Insertion Sequence Element

ABSTRACT Previously, we obtained a Legionella pneumophila mutant, NU208, that is hypersensitive to iron chelators when grown on standard Legionella media. Here, we demonstrate that NU208 is also impaired for growth in media that simply lack their iron supplement. The mutant was not, however, impaired for the production of legiobactin, the only known L. pneumophila siderophore. Importantly, NU208 was also highly defective for intracellular growth in human U937 cell macrophages and Hartmannella and Acanthamoeba amoebae. The growth defect within macrophages was exacerbated by treatment of the host cells with an iron chelator. Sequence analysis demonstrated that the transposon disruption in NU208 lies within an open reading frame that is highly similar to the cytochrome c maturation gene, ccmC. CcmC is generally recognized for its role in the heme export step of cytochrome biogenesis. Indeed, NU208 lacked cytochrome c. Phenotypic analysis of two additional, independently derived ccmC mutants confirmed that the growth defect in low-iron medium and impaired infectivity were associated with the transposon insertion and not an entirely spontaneous second-site mutation. trans-complementation analysis of NU208 confirmed that L. pneumophila ccmC is required for cytochrome c production, growth under low-iron growth conditions, and at least some forms of intracellular infection. Although ccm genes have recently been implicated in iron assimilation, our data indicate, for the first time, that a ccm gene can be required for bacterial growth in an intracellular niche. Complete sequence analysis of the ccm locus from strain 130b identified the genes ccmA-H. Interestingly, however, we also observed that a 1.8-kb insertion sequence element was positioned between ccmB and ccmC. Southern hybridizations indicated that the open reading frame within this element (ISLp 1) was present in multiple copies in some strains of L. pneumophila but was absent from others. These findings represent the first evidence for a transposable element in Legionella and the first identification of an L. pneumophila strain-specific gene.
The effects of varying tympanic-membrane material properties on human middle-ear sound transmission in a three-dimensional finite-element model.

An anatomically based three-dimensional finite-element human middle-ear (ME) model is used to test the sensitivity of ME sound transmission to tympanic-membrane (TM) material properties. The baseline properties produce responses comparable to published measurements of ear-canal input impedance and power reflectance, stapes velocity normalized by ear-canal pressure (PEC), and middle-ear pressure gain (MEG), i.e., cochlear-vestibule pressure (PV) normalized by PEC. The mass, Young's modulus (ETM), and shear modulus (GTM) of the TM are varied, independently and in combination, over a wide range of values, with soft and bony TM-annulus boundary conditions. MEG is recomputed and plotted for each case, along with summaries of the magnitude and group-delay deviations from the baseline over low (below 0.75 kHz), mid (0.75-5 kHz), and high (above 5 kHz) frequencies. The MEG magnitude varies inversely with increasing TM mass at high frequencies. Increasing ETM boosts high frequencies and attenuates low and mid frequencies, especially with a bony TM annulus and when GTM varies in proportion to ETM, as for an isotropic material. Increasing GTM on its own attenuates low and mid frequencies and boosts high frequencies. The sensitivity of MEG to TM material properties has implications for model development and the interpretation of experimental observations.
On the Statistical Properties of Multiscale Permutation Entropy: Characterization of the Estimator’s Variance

Permutation Entropy (PE) and Multiscale Permutation Entropy (MPE) have been extensively used in the analysis of time series searching for regularities. Although PE has been explored and characterized, there is still a lack of theoretical background regarding MPE. Therefore, we expand the available MPE theory by developing an explicit expression for the estimator’s variance as a function of time scale and ordinal pattern distribution. We derived the MPE Cramér–Rao Lower Bound (CRLB) to test the efficiency of our theoretical result. We also tested our formulation against MPE variance measurements from simulated surrogate signals. We found the MPE variance symmetric around the point of equally probable patterns, showing clear maxima and minima. This implies that the MPE variance is directly linked to the MPE measurement itself, and there is a region where the variance is maximum. This effect arises directly from the pattern distribution, and it is unrelated to the time scale or the signal length. The MPE variance also increases linearly with time scale, except when the MPE measurement is close to its maximum, where the variance presents quadratic growth. The expression approaches the CRLB asymptotically, with fast convergence. The theoretical variance is close to the results from simulations, and appears consistently below the actual measurements. By knowing the MPE variance, it is possible to have a clear precision criterion for statistical comparison in real-life applications.
Characterization of Biofilm Formation and the Role of BCR1 in Clinical Isolates of Candida parapsilosis

ABSTRACT In Candida parapsilosis, biofilm formation is considered to be a major virulence factor. Previously, we determined the ability of 33 clinical isolates causing bloodstream infection to form biofilms and identified three distinct groups of biofilm-forming strains (negative, low, and high). Here, we establish two different biofilm structures among strains forming large amounts of biofilm in which strains with complex spider-like structures formed robust biofilms on different surface materials with increased resistance to fluconazole. Surprisingly, the transcription factor Bcr1, required for biofilm formation in Candida albicans and C. parapsilosis, has an essential role only in strains with low capacity for biofilm formation. Although BCR1 leads to the formation of more and longer pseudohyphae, it was not required for initial adhesion and formation of mature biofilms in strains with a high level of biofilm formation. Furthermore, an additional phenotype affected by BCR1 was the switch in colony morphology from rough to crepe, but only in strains forming high levels of biofilm. All bcr1Δ/Δ mutants showed increased proteolytic activity and increased susceptibility to the antimicrobial peptides protamine and RP-1 compared to corresponding wild-type and complemented strains. Taken together, our results demonstrate that biofilm formation in clinical isolates of C. parapsilosis is both dependent and independent of BCR1, but even in strains which showed a BCR1-independent biofilm phenotype, BCR1 has alternative physiological functions.
THE ECONOMIC-DETERMINANTS OF AUDITOR COMPENSATION IN THE INITIAL PUBLIC OFFERINGS MARKET

This paper examines the determinants of auditor compensation in the initial public offering (IPO) market. ' This setting offers the opportunity to investigate simultaneously two audit-pricing issues. First, investigating the determinants of IPO auditor compensation helps us assess the generalizability of previous audit fee research. Numerous studies (e.g., Simunic [1980], Francis and Simon [1987], and Ettredge and Greenberg [1990]) have used survey data to investigate the deter-
Circulating hematopoietic stem cells in patients with neovascular age-related macular degeneration.

PURPOSE Circulating hematopoietic stem cells (HSCs) appear to have roles in the formation of choroidal neovascularization (CNV) in age-related macular degeneration (AMD). This study was conducted to investigate whether the number or function of HSCs plays a role in neovascular AMD. METHODS Eighty-one patients with neovascular AMD who underwent comprehensive fundus examinations every 3 months were included. The number of CD34(+) HSCs isolated from peripheral blood was counted by flow cytometry. Serum cytokine levels were assessed by enzyme-linked immunosorbent assay. To examine the function of circulating HSCs, mononuclear cells were cultured and then colony forming unit (CFU-EC) and migration were measured. RESULTS The number of circulating CD34(+) HSCs was significantly increased in the patients with active CNV without major systemic diseases (stable: 3.8 +/- 0.3 cells/microL, active: 5.5 +/- 0.7 cells/microL, stable versus active: P < 0.05). The number of HSCs correlated positively with the erythropoietin serum level (r = 0.47, P = 0.002). Although there was no significant difference in the CFU-EC between the patients with CNV and the control subjects, a significant decrease of CFU-EC was observed in the patients with bilateral or larger CNV. CONCLUSIONS The findings suggest that CD34(+) HSCs may be recruited from bone marrow through a signal from active CNV. Furthermore, HSCs may play a role in the severity of CNV.
The familial aggregation of depressive symptoms, antisocial behavior, and alcohol abuse.

This study describes results from an ongoing family study of adolescent boys and their families designed to investigate potential risk factors for substance abuse. The adolescent treatment probands have severe drug and alcohol related problems and were recruited through a residential rehabilitation program. To date, the sample includes 251 individuals: 39 male probands and their families and 34 control families matched for age and geographic location (zip code). Probands and participating family members are given a structured interview which assesses alcohol and drug problems, and various psychiatric symptoms. The purpose of the present study was to examine the coaggregation of depressive symptoms, antisocial behavior, and alcohol misuse. Multivariate pedigree analyses were performed using a model that allowed for the estimation of vertical familial transmission, residual sibling resemblance, and assortative mating. Spouse correlations were estimated at . 57, . 21, and . 31 for antisocial behavior, depressive symptoms, and alcohol abuse, respectively. Residual sibling environment (i.e., sibling resemblance unaccounted for by parent-offspring transmission) was not found for alcohol problem symptoms, but did contribute to resemblance for antisocial behavior and depressive symptoms. The proportion of variance accounted for by vertical familial transmission was estimated at approximately 30 to 40%. More important, correlations among the transmissible family factors for these psychiatric syndromes ranged from . 58 to . 73, suggesting substantial overlap among the underlying familial antecedents for these disorders.
Effect of renal transplantation in childhood on longitudinal growth and adult height.

BACKGROUND Severe growth failure is frequently observed in children suffering from end-stage renal disease (ESRD). METHODS We analyzed the effect of renal transplantation (RTx) on longitudinal growth and final height in 37 children (19 girls) with ESRD with a mean follow-up of 8.5 years. The mean age at RTx was 11.3 years. RESULTS In children transplanted before start of puberty, mean height velocity increased significantly from 4.9 to 8.0 cm/year (P < 0.01), resulting in an increase in standardized height of 0.6 SD within two years post RTx. Although peak height velocity during puberty was significantly increased compared with healthy children, total pubertal height gain was reduced by 20% because of its shortened duration. Mean standardized height significantly increased from the time of RTx until final height by 1.3 SD and 0.7 SD in children transplanted before and after start of puberty, respectively. Mean adult height (boys 170 cm; girls 151 cm) was normal (> -2 SD) in 68% of patients. Change in standardized height from RTx until adult height was associated with initial degree of stunting and glomerular filtration rate (GFR; cumulative r2 0.49). Total pubertal height gain was associated with the age at start of puberty, GFR, and age at RTx (cumulative r2 0.57). CONCLUSION RTx in children with ESRD induces moderate catch-up growth during the prepubertal growth period. However, final height is reduced in about one third of patients due to the reduced pubertal height gain and preexisting height deficit at the time of RTx.
Drug metabolite profiling and elucidation of drug-induced hepatotoxicity

Drug metabolism studies, together with pathologic and histologic evaluation, provide critical data sets to help understand mechanisms underlying drug-related hepatotoxicity. A common practice is to trace morphologic changes resulting from liver injury back to perturbation of biochemical processes and to identify drug metabolites that affect those processes as possible culprits. This strategy can be illustrated in efforts of elucidating the cause of acetaminophen-, troglitazone- and valproic acid-induced hepatic necrosis, microvesicular steatosis and cholestasis with the aid of information from qualitative and quantitative analysis of metabolites. From a pharmaceutical research perspective, metabolite profiling represents an important function because a structure–activity relationship is essential to rational drug design. In addition, drugs are known to induce idiosyncratic hepatotoxicity, which usually escapes the detection by preclinical safety assessment and clinical trials. This issue is addressed, at present, by eliminating those molecules that are prone to metabolic bioactivation, based on the concept that formation of electrophilic metabolites triggers covalent protein modification and subsequent organ toxicity. Although pragmatic, such an approach has its limitations as a linear correlation does not exist between toxicity and the extent of bioactivation. It may be possible in the future that the advance of proteomics, metabonomics and genomics would pave the way leading to personalized medication in which beneficial effect of a drug is maximized, whereas toxicity risk is minimized.