Miracle-dz/UniFAR-FTUs huggingface dataset:
ISO-66, a novel inhibitor of macrophage migration inhibitory factor, shows efficacy in melanoma and colon cancer models

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses.
T E C H N I C a L a D V a N C E Open Access

A new web-based method for automated analysis of muscle histology Abstract Background: Duchenne Muscular Dystrophy is an inherited degenerative neuromuscular disease characterised by rapidly progressive muscle weakness. Currently, curative treatment is not available. Approaches for new treatments that improve muscle strength and quality of life depend on preclinical testing in animal models. The mdx mouse model is the most frequently used animal model for preclinical studies in muscular dystrophy research. Standardised pathology-relevant parameters of dystrophic muscle in mdx mice for histological analysis have been developed in international, collaborative efforts, but automation has not been accessible to most research groups. A standardised and mainly automated quantitative assessment of histopathological parameters in the mdx mouse model is desirable to allow an objective comparison between laboratories.
p 38 Mitogen-Activated Protein Kinase Regulates Human T Cell IL-5 Synthesis 1

Involvement of p38 mitogen-activated protein (MAP) kinase in human T cell cytokine synthesis was investigated. p38 MAP kinase was clearly induced in human Th cells activated through the TCR. SB203580, a highly selective inhibitor of p38 MAP kinase, inhibited the induction of p38 MAP kinase in human Th cells. Major T cell cytokines, IL-2, IL-4, IL-5, and IFNg, were produced by Der f 2-specific Th clones upon stimulation through the TCR. IL-5 synthesis alone was significantly inhibited by SB203580 in a dose-dependent manner, whereas the production of IL-2, IL-4, and IFNg was not affected. The proliferation of activated T cells was not affected. IL-5 synthesis of human Th clones induced upon stimulation with rIL-2, phorbol ester plus anti-CD28 mAb, and immobilized anti-CD3 mAb plus soluble anti-CD28 mAb was also suppressed by SB203580 in the same concentration response relationship. The results clearly indicated that IL-5 synthesis by human Th cells is dependent on p38 MAP kinase activity, and is regulated distinctly from IL-2, IL-4, and IFNg synthesis. Selective control of IL-5 synthesis will provide a novel treatment devoid of generalized immune suppression for bronchial asthma and atopic dermatitis that are characterized by eosinophilic inflammation. The Journal of Immunology,1999, 163: 4763–4771.
Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy.

AIMS The SENIORS trial recently demonstrated that nebivolol reduces the composite risk of all-cause mortality and cardiovascular hospital admission in elderly patients with chronic heart failure and, importantly, that ejection fraction does not influence the clinical effects of nebivolol. An echocardiographic substudy was designed to evaluate the effects of nebivolol on systolic and diastolic left ventricular (LV) function in patients stratified according to the presence or absence of systolic LV dysfunction. METHODS AND RESULTS The substudy randomized 112 patients in 29 European centres, of whom 104 were evaluable for the study; 43 had an ejection fraction (EF) <or=35% and 61 had an EF>35%. LV end-systolic volume (ESV), EF, mitral valve E/A ratio, and E-wave deceleration time were assessed at baseline and after 12 months. Echocardiograms were submitted to a core laboratory to perform quantitative analysis in blinded condition. In the group with EF</=35%, nebivolol reduced ESV (adjusted difference between treatments 25.8 mL, 95%CI: -46.6; -5.0, P=0.016) and improved EF (adjusted difference between treatments 4.6%, 95%CI: 1.3;7.9, P=0.008); no changes were observed in the E/A ratio or E-wave deceleration time. In EF>35% group, no significant changes in either systolic or diastolic parameters were observed. CONCLUSION In patients with heart failure and advanced systolic LV dysfunction, nebivolol reduces ventricular size and improves EF. The absence of detectable changes with standard echocardiography in patients with predominant diastolic heart failure questions the mechanism of benefit on morbidity/mortality in such patients.
Joint modelling of the probability distribution function and power spectrum of the Lyα forest: comparison with observations at z= 3

We present results of joint modelling of the probability distribution function (PDF) and the one-dimensional power spectrum (PS) of the Lya forest flux decrement. The sensitivity of these statistical measures to the shape and amplitude of the linear matter power spectrum is investigated using N-body simulations of two variants of the ACDM cosmology. In the first model, the linear power spectrum has a scale-invariant spectral index n s = 1, whereas in the second, it has a negative running spectral index (RSI), dn/d lnk < 0. We generate mock catalogues of quasi-stellar object (QSO) spectra, and compare their statistical properties to those of the observations at z = 3. We perform a joint fit of the PS and the PDF. A scale-invariant model with σ 8 = 0.9 matches the data well if the mean temperature of the intergalactic medium is T ≤ 1.5 x 10 4 K. For higher temperature, it tends to overestimate the flux PS over scales k ≤ 0.01 s km -1 . The discrepancy is less severe when the PS alone is fitted. However, models matching the PS alone do not yield a good fit to the PDF. A joint analysis of the flux PS and PDF tightens the constraints on the model parameters and reduces systematic biases. The RSI model is consistent with the observed PDF and PS only if the temperature is T ≥ 2 x 10 4 K. The best-fitting models reproduce the slope and normalization of the column density distribution, irrespective of the shape and amplitude of the linear power spectrum. They are also consistent with the observed linewidth distribution, given the large uncertainties. Our joint analysis suggests that σ 8 is likely to be in the range 0.7-0.9 for a temperature 1 x 10 4 ≤ T ≤ 2 x 10 4 K and a reasonable reionization history.
The birth of Prolog

The programming language, Prolog, was born of a project aimed not at producing a programming language but at processing natural languages; in this case, French. The project gave rise to a preliminary version of Prolog at the end of 1971 and a more definitive version at the end of 1972. This article gives the history of this project and describes in detail the preliminary and then the final versions of Prolog. The authors also felt it appropriate to describe the Q-systems since it was a language which played a prominent part in Prolog's genesis.
The Indoleamine-2,3-Dioxygenase (IDO) Inhibitor 1-Methyl-D-tryptophan Upregulates IDO1 in Human Cancer Cells

1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.
Watching the rich and famous: the cultivation effect of reality television shows and the mediating role of parasocial experiences

ABSTRACT This study used cultivation theory to explore the relationship between exposure to reality television shows and college students’ beliefs about wealth and materialism. In addition, this study suggested parasocial experiences with reality show casts via social media as a mediating variable explaining the cultivation effects of reality shows. The survey results from 178 college students indicated a significant relationship between reality show exposure and beliefs about wealth and materialism. Also, the parasocial relationship developed with reality show casts had significant mediating impact. Findings contribute to the application of cultivation theory in explaining the effects of reality television show viewing in the new media environment.
Correlations between Central Massive Objects and Their Host Galaxies: From Bulgeless Spirals to Ellipticals

Recent observations reveal that a majority of galaxies contain a central massive object (CMO), either a supermassive black hole (SMBH) or a compact stellar nucleus, regardless of the galaxy mass or morphological type. The masses of these CMOs correlate tightly with those of the host galaxies, MCMO ≈ 0.002Mgal. Several recent studies argue that feedback from black holes can successfully explain the MBH-σ correlation in massive elliptical galaxies that contain SMBHs. However, puzzles remain in spirals or dwarf spheroids that do not appear to have black holes but instead harbor a compact central stellar cluster. Here we use three-dimensional, smoothed particle hydrodynamics simulations of both isolated and merging galaxies to study the formation and evolution of CMOs in bulgeless disk galaxies, and the transition of the CMO-host relations from late-type bulgeless spirals to early-type ellipticals. Our simulations show that the mass of the CMO correlates with that of the host galaxy in both isolated bulgeless spirals and in ellipticals formed through mergers, and that MCMO correlates with the global star formation efficiency in the galaxy. We find that the final mass of the CMO is dominated by the accreted mass, rather than the initial fragment mass, and that both the final accreted CMO mass and the recently formed stellar mass increase monotonically with the total mass of the galaxy. Our results suggest that the observed correlations may be established primarily by the depletion of gas in the central region by accretion and star formation, and may hold for all galaxy types. A systematic search for CMOs in the nuclei of bulgeless disk galaxies would offer a test of this conclusion.
Financial risk tolerance: An analysis of unexplored factors

Using data from a survey alliance between Kiplinger's Personal Finance Magazine, PBS's Nightly Business Report, and FinaMetrica, this study explores various demographical and attitudinal factors related to financial risk tolerance. Investigating risk tolerance scores of more than 2,000 individuals immediately after the 2008 Global Financial Crisis, we find a positive relationship between risk tolerance and income, investment knowledge and positive stock market expectations. Risk tolerance is found to be lower for females, older individuals, those that currently use a financial advisor and individuals that perceive the stock market to be riskier than two years before.
Investigating former pupils’ experiences and perceptions of CLIL in Finland: a retrospective analysis

ABSTRACT The educational approach known as Content and Language Integrated Learning (CLIL), in which content is taught partly through a foreign language, has gained great popularity in Europe in the past few decades. In Finland, CLIL has been in use since 1991 and, despite some fluctuations in its popularity, has gained a relatively stable place in the Finnish education system. CLIL has been extensively studied, but previous CLIL research has mostly focused on pupils currently enrolled in CLIL. This study takes a novel perspective by investigating CLIL retrospectively, through the eyes of former pupils. The data used are in-depth interviews with 24 former pupils who attended a CLIL class in Finland in the 1990s. The interviews were analyzed using qualitative content analysis. The findings reveal that the participants had overwhelmingly positive memories of their CLIL programme. They felt strongly that CLIL had positively affected their English language proficiency, particularly their vocabulary and speaking skills. Most believed that CLIL had not adversely affected their content learning. Despite the overall satisfaction, a few participants suggested ways to develop CLIL, which are also discussed. The results of this case study broaden our understanding of CLIL and have implications for language education policy.
An Evaluation of Dvorak Technique-Based Tropical Cyclone Intensity Estimates

Abstract The satellite-based Dvorak technique (DVKT) is the most widely available and readily used tool for operationally estimating the maximum wind speeds associated with tropical cyclones. The DVKT itself produces internally consistent results, is reproducible, and has shown practical accuracy given the high cost of in situ or airborne observations. For these reasons, the DVKT has been used in a reasonably uniform manner globally for approximately 20 years. Despite the nearly universal use of this technique, relatively few systematic verifications of the DVKT have been conducted. This study, which makes use of 20 yr of subjectively determined DVKT-based intensity estimates and best-track intensity estimates influenced by aircraft observations (i.e., ±2 h) in the Atlantic basin, seeks to 1) identify the factors (intensity, intensity trends, radius of outer closed isobar, storm speed, and latitude) that bias the DVKT-based intensity estimates, 2) quantify those biases as well as the general error charact.
Abnormal Liver Stiffness Assessed Using Transient Elastography (Fibroscan®) in HIV-Infected Patients without HBV/HCV Coinfection Receiving Combined Antiretroviral Treatment

Background and Aims Liver stiffness measurement (LSM) using transient elastography (Fibroscan®) can identify individuals with potential underlying liver disease. We evaluated the prevalence of abnormal LSM values as assessed using LSM and its predictors in HIV-infected asymptomatic patients receiving combined antiretroviral treatment (cART) without HBV/HCV coinfection. Methods We prospectively recruited 93 patients who had consistently been undergoing cART for more than 12 months at Severance Hospital in Seoul, Republic of Korea, from June to December 2010. LSM values >5.3 kPa were defined as abnormal. Results Thirty-nine (41.9%) had abnormal LSM values. On multivariate correlation analysis, the cumulative duration of boosted and unboosted protease inhibitors (PIs) were the independent factors which showed a negative and positive correlation to LSM values, respectively (β = –0.234, P = 0.023 and β = 0.430, P<0.001). In multivariate logistic regression analysis, the cumulative exposure duration of boosted-PIs and γ-glutamyltranspeptidase levels were selected as the independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively (odds ratio [OR], 0.941; 95% confidence interval [CI], 0.889–0.997; P = 0.039 and OR, 1.032; 95% CI, 1.004–1.060; P = 0.023). Conclusion The high percentage of HIV-infected asymptomatic patients receiving cART without HBV/HCV coinfection had abnormal LSM values. The cumulative exposure duration of boosted-PIs and γ-GT level were independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively.
Use of a Fluorescent Imaging Plate Reader-Based Calcium Assay to Assess Pharmacological Differences between the Human and Rat Vanilloid Receptor

The cloned vanilloid receptor 1 (VR1) is a ligand-gated calcium channel that is believed to be the capsaicin-activated vanilloid receptor found in native tissues, based on similarities regarding molecular mass, tissue distribution, and electrophysiological properties. Using a Fluorescent Imaging Plate Reader (FLIPR), along with Fluo-3 to signal intracellular calcium levels ([Ca++]i), rat VR1 (rVR1) and a human orthologue (hVR1) were pharmacologically characterized with various VR1 ligands. HEK-293 cells, stably expressing rVR1 or hVR1, exhibited dose-dependent increases in [Ca++]i when challenged with capsaicin (EC50s ≅ 10 nM). Responses to capsaicin were blocked by the VR1 antagonist capsazepine and were dependent on VR1 expression. Potencies for 10 structurally diverse VR1 agonists revealed rVR1 potencies highly correlated to that of hVR1 ( R 2 = 0.973). However, a subset of agonists (tinyatoxin, gingerol, and zingerone) was approximately 10-fold more potent for rVR1 compared to hVR1. Schild analysis for blockade of capsaicin-induced responses by capsazepine was consistent with competitive antagonism, whereas ruthenium red displayed noncompetitive antagonism. Compared to rVR1, hVR1 was more sensitive to blockade by both antagonists. For both rVR1 and hVR1, time-response waveforms elicited by resiniferatoxin increased more gradually compared to other agonists. Tinyatoxin also displayed slow responses with hVR1 but showed rapid responses with rVR1. Thus, FLIPR technology can be used to readily reveal differences between rVR1 and hVR1 pharmacology with respect to potencies, efficacies, and kinetics for several VR1 ligands.
Heavy light meson decay constant from QCD sum rules in three loop approximation

In this paper we compute the decay constant of the pseudo-scalar heavy-light mesons in the heavy quark effective theory framework of QCD sum rules. In our analysis we include the recently evaluated three-loop result of order $\alpha_s^2$ for the heavy-light current correlator. The value of the bottom quark mass, which essentially limits the accuracy of the sum rules for $B$ meson, is extracted from the nonrelativistic sum rules for $\Upsilon$ resonances in the next-to-next-to-leading approximation. We find stability of our result with respect to all types of corrections and the specific form of the sum rule which reduces the uncertainty. Our results $f_B=206\pm 20$ MeV and $f_D=195\pm 20$ MeV for the $B$ and $D$ meson decay constants are in impressive agreement with recent lattice calculations.
Angiogenic Properties of Human Dental Pulp Stem Cells

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is a key process in tissue engineering. If blood supply cannot be established rapidly, there is insufficient oxygen and nutrient transport and necrosis of the implanted tissue will occur. Recent studies indicate that the human dental pulp contains precursor cells, named dental pulp stem cells (hDPSC) that show self-renewal and multilineage differentiation capacity. Since these cells can be easily isolated, cultured and cryopreserved, they represent an attractive stem cell source for tissue engineering. Until now, only little is known about the angiogenic abilities and mechanisms of the hDPSC. In this study, the angiogenic profile of both cell lysates and conditioned medium of hDPSC was determined by means of an antibody array. Numerous pro-and anti-angiogenic factors such as vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and endostatin were found both at the mRNA and protein level. hDPSC had no influence on the proliferation of the human microvascular endothelial cells (HMEC-1), but were able to significantly induce HMEC-1 migration in vitro. Addition of the PI3K-inhibitor LY294002 and the MEK-inhibitor U0126 to the HMEC-1 inhibited this effect, suggesting that both Akt and ERK pathways are involved in hDPSC-mediated HMEC-1 migration. Antibodies against VEGF also abolished the chemotactic actions of hDPSC. Furthermore, in the chicken chorioallantoic membrane (CAM) assay, hDPSC were able to significantly induce blood vessel formation. In conclusion, hDPSC have the ability to induce angiogenesis, meaning that this stem cell population has a great clinical potential, not only for tissue engineering but also for the treatment of chronic wounds, stroke and myocardial infarctions.
Empirical Bernstein Bounds and Sample-Variance Penalization

We give improved constants for data dependent and variance sensitive confidence bounds, called empirical Bernstein bounds, and extend these inequalities to hold uniformly over classes of functions whose growth function is polynomial in the sample size n. The bounds lead us to consider sample variance penalization, a novel learning method which takes into account the empirical variance of the loss function. We give conditions under which sample variance penalization is effective. In particular, we present a bound on the excess risk incurred by the method. Using this, we argue that there are situations in which the excess risk of our method is of order 1/n, while the excess risk of empirical risk minimization is of order 1/√n. We show some experimental results, which confirm the theory. Finally, we discuss the potential application of our results to sample compression schemes.