Miracle-dz/UniFAR-FTUs huggingface dataset:
Quinacrine promotes autophagic cell death and chemosensitivity in ovarian cancer and attenuates tumor growth

A promising new strategy for cancer therapy is to target the autophagic pathway. In the current study, we demonstrate that the antimalarial drug Quinacrine (QC) reduces cell viability and promotes chemotherapy-induced cell death in an autophagy-dependent manner more extensively in chemoresistant cells compared to their isogenic chemosensitive control cells as quantified by the Chou-Talalay methodology. Our preliminary data, in vitro and in vivo, indicate that QC induces autophagy by downregulating p62/SQSTM1 to sensitize chemoresistant cells to autophagic- and caspase-mediated cell death in a p53-independent manner. QC promotes autophagosome accumulation and enhances autophagic flux by clearance of p62 in chemoresistant ovarain cancer (OvCa) cell lines to a greater extent compared to their chemosensitive controls. Notably, p62 levels were elevated in chemoresistant OvCa cell lines and knockdown of p62 in these cells resulted in a greater response to QC treatment. Bafilomycin A, an autophagy inhibitor, restored p62 levels and reversed QC-mediated cell death and thus chemosensitization. Importantly, our in vivo data shows that QC alone and in combination with carboplatin suppresses tumor growth and ascites in the highly chemoresistant HeyA8MDR OvCa model compared to carboplatin treatment alone. Collectively, our preclinical data suggest that QC in combination with carboplatin can be an effective treatment for patients with chemoresistant OvCa.
The Idiosyncratic Nature of Sibling Adrs Issued by Mexican Firms: A Clinical Study

We examine the relative prices of "sibling" American Depositary Receipts (ADRs). These ADRs are issued by the same foreign firms against shares with different voting rights. Though superior and inferior voting siblings begin their US trading experience at nearly equal values, relative prices of Mexican and non-Mexican sibling ADRs quickly move in opposite directions. Superior voting ADRs command a median premium for non-Mexican firms, but a median discount for Mexican issuers. The Mexican evidence represents an extreme exception to the inverse relation between the voting premium documented in other countries and the degree of legal protection enjoyed by outside shareholders. This apparent anomaly cannot be explained by differences in cash flow rights, total or systematic risk, liquidity, voting control of major blockholders, or ownership restrictions. Despite voting premiums and discounts, neither sibling in most pairs appears to have been an attractive investment for US investors.
Translation in Bacillus subtilis: roles and trends of initiation and termination, insights from a genome analysis.

We analysed the Bacillus subtilis protein coding sequences termini, and compared it to other genomes. The analysis focused on signals, com-positional biases of nucleotides, oligonucleotides, codons and amino acids and mRNA secondary structure. AUG is the preferred start codon in all genomes, independent of their G+C content, and seems to induce less stable mRNA structures. However, it is not conserved between homologous genes neither is it preferred in highly expressed genes. In B.subtilis the ribosome binding site is very strong. We found that downstream boxes do not seem to exist either in Escherichia coli or in B.subtilis. UAA stop codon usage is correlated with the G+C content and is strongly selected in highly expressed genes. We found less stable mRNA structures at both termini, which we related to mRNA-ribosome and mRNA-release-factor interactions. This pattern seems to impose a peculiar A-rich nucleotide and codon usage bias in these regions. Finally the analysis of all proteins from B.subtilis revealed a similar amino acid bias near both termini of proteins consisting of over-representation of hydrophilic residues. This bias near the stop codon is partially release-factor specific.
Melanoma-Reactive Class I-Restricted Cytotoxic T Cell Clones Are Stimulated by Dendritic Cells Loaded with Synthetic Peptides, but Fail to Respond to Dendritic Cells Pulsed with Melanoma-Derived Heat Shock Proteins In Vitro1

Immunization with heat shock proteins (hsp) isolated from cancer cells has been shown to induce a protective antitumor response. The mechanism of hsp-dependent cellular immunity has been attributed to a variety of immunological activities mediated by hsp. Hsp have been shown to bind antigenic peptides, trim the bound peptides by intrinsic enzymatic activity, improve endocytosis of the chaperoned peptides by APCs, and enhance the ability of APCs to stimulate peptide-specific T cells. We have investigated the potential capacity of hsp70 and gp96 to function as a mediator for Ag-specific CTL stimulation in an in vitro model for human melanoma. Repetitive stimulation of PBLs by autologous DCs loaded with melanoma-derived hsp did not increase the frequency of T cells directed against immunodominant peptides of melanoma-associated Ags Melan-A and tyrosinase. In contrast, repeated T cell stimulation with peptide-pulsed DCs enhanced the number of peptide-specific T cells, allowing HLA/peptide multimer-guided T cell cloning. We succeeded in demonstrating that the established HLA-A2-restricted CTL clones recognized HLA-A2+ APCs exogenously loaded with the respective melanoma peptide as well as melanoma cells processing and presenting these peptides in the context of HLA-A2. We were not able to show that these melanoma-reactive CTL clones were stimulated by autologous dendritic cells pulsed with melanoma-derived hsp. These results are discussed with respect to various models for proving the role of hsp in T cell stimulation and to recent findings that part of the immunological antitumor activities reported for hsp are independent of the chaperoned peptides.
Tidal capture of stars by intermediate‐mass black holes

Recent X-ray observations and theoretical modelling have made it plausible that some ultraluminous X-ray sources (ULX) are powered by intermediate-mass black holes (IMBHs). N-body simulations have also shown that for certain initial conditions runaway merging of stars happens in dense star clusters, which could lead to the formation of IMBHs. In the present paper we have performed N-body simulations of young clusters such as MGG-11 of M82 in which IMBHs form through runaway merging. We took into account the effect of tidal energy dissipation of stars passing close to the IMBH to study the tidal capture and disruption of stars by IMBHs. In our simulations, IMBHs have a high chance of capturing stars through tidal energy dissipation within a few core relaxation times. For similar to 30 per cent of our runs a ULX is formed through tidal capture within 7-12 Myr, consistent with the age limits of MGG-11. Our results strengthen the case for some ULX being powered by IMBHs.
Turismo y crecimiento económico: el caso de Uruguay

Argentine is the principal source of tourism in the Uruguayan case. Its effects in the economic growth is analyzed in the present paper by using quarterly data from 1987.I to 2006.IV. Co-integration analysis shows the existence of one cointegrated vector among real per capita GDP, Argentinean tourism expenditure, and real exchange rate between Uruguay and Argentine. Granger-causality test suggests that causality positively goes in one way from expenditure to real per capita GDP.
Perception of Sung Speech in Bimodal Cochlear Implant Users

Combined use of a hearing aid (HA) and cochlear implant (CI) has been shown to improve CI users’ speech and music performance. However, different hearing devices, test stimuli, and listening tasks may interact and obscure bimodal benefits. In this study, speech and music perception were measured in bimodal listeners for CI-only, HA-only, and CI + HA conditions, using the Sung Speech Corpus, a database of monosyllabic words produced at different fundamental frequencies. Sentence recognition was measured using sung speech in which pitch was held constant or varied across words, as well as for spoken speech. Melodic contour identification (MCI) was measured using sung speech in which the words were held constant or varied across notes. Results showed that sentence recognition was poorer with sung speech relative to spoken, with little difference between sung speech with a constant or variable pitch; mean performance was better with CI-only relative to HA-only, and best with CI + HA. MCI performance was better with constant words versus variable words; mean performance was better with HA-only than with CI-only and was best with CI + HA. Relative to CI-only, a strong bimodal benefit was observed for speech and music perception. Relative to the better ear, bimodal benefits remained strong for sentence recognition but were marginal for MCI. While variations in pitch and timbre may negatively affect CI users’ speech and music perception, bimodal listening may partially compensate for these deficits.
Maintenance of GLUT4 expression in smooth muscle prevents hypertension-induced changes in vascular reactivity

Previous studies have shown that expression of GLUT4 is decreased in arterial smooth muscle of hypertensive rats and mice and that total body overexpression of GLUT4 in mice prevents enhanced arterial reactivity in hypertension. To demonstrate that the effect of GLUT4 overexpression on vascular responses is dependent on vascular smooth muscle GLUT4 rather than on some systemic effect we developed and tested smooth‐muscle‐specific GLUT4 transgenic mice (SMG4). When made hypertensive with angiotensin II, both wild‐type and SMG4 mice exhibited similarly increased systolic blood pressure. Responsiveness to phenylephrine, serotonin, and prostaglandin F2α was significantly increased in endothelium‐intact aortic rings from hypertensive wild‐type mice but not in aortae of SMG4 mice. Inhibition of Rho‐kinase equally reduced serotonin‐stimulated contractility in aortae of hypertensive wild‐type and SMG4‐mice. In addition, acetylcholine‐stimulated relaxation was significantly decreased in aortic rings of hypertensive wild‐type mice, but not in rings of SMG4 mice. Inhibition of either prostacylin receptors or cyclooxygenase‐2 reduced relaxation in rings of hypertensive SMG4 mice. Inhibition of cyclooxygenase‐2 had no effect on relaxation in rings of hypertensive wild‐type mice. Cyclooxygenase‐2 protein expression was decreased in hypertensive wild‐type aortae but not in hypertensive SMG4 aortae compared to nonhypertensive controls. Our results demonstrate that smooth muscle expression of GLUT4 exerts a major effect on smooth muscle contractile responses and endothelium‐dependent vasorelaxation and that normal expression of GLUT4 in vascular smooth muscle is required for appropriate smooth muscle and endothelial responses.
RUNNING HEAD : INDIVIDUAL DIFFERENCES Individual Differences that Influence Reading Comprehension

Theories about reading have moved away from viewing the reader as a passive recipient of textual input, as a tabula rasa upon which the author sketches his or her message. Under this view, reading comprehension is easily explained by the success of the textual input entering and staying intact within the mind of the reader. Adopting this view, some character educators can assert that reading moral stories to children will build moral literacy and moral character, due to the nature of the stories themselves. That is, as long as the children ‘hear’ the stories, they will absorb the story messages. This is the view promulgated by former secretary of education, William Bennett, in his wildly popular book, The Book of virtues. Bennett (1993) contends that hearing moral stories will develop moral literacy, which then leads to moral character. There is no evidence for his claims. William Kilpatrick (1992) agrees with Bennett, saying that “good books do their own work in their own way” and “it is not necessary or wise for adults to explain the ‘moral’ in each story” (p. 268). In fact, there is evidence against the claims made by Bennett, Kilpatrick and others, evidence that will be reviewed in this chapter. Recent research has disconfirmed such a ‘passive reader’ theory. Instead, we find that the reader is an active comprehender who uses his or her knowledge and strategies to construct meaning from a text (Pressley & Afflerbach, 1995). The reading process resembles more the interaction of a breeze on a landscape. The breeze has an influence on the features, moving dirt and debris about and shaping erosion, but only so far as the structures of the landscape allow. Constructivist reading theory takes into account the nature of the reader (the landscape) in response to the textual input. Constructivist reading research tells us that at least five things about the reader matter in reading comprehension: reader skills, reader knowledge, reader cognitive development, reader culture, reader purpose. Leaving the discussion of general reading comprehension skills to others, this chapter address the influence of: (1) Reader expertise in the knowledge domain of the text; (2) The socio-moral cognitive development of the reader; (3) The degree to which the cultural assumptions of the text match those of the reader; (4) The reader’s purpose for reading (e.g., for fun or to study). All four factors concern elements that the reader brings to the reading situation and that affect the reader’s processing of the text.
Minimax Robust Decentralized Detection in Parallel Sensor Networks

Minimax robust decentralized detection is studied for parallel sensor networks. Random variables corresponding to sensor observations are assumed to follow a distribution function, which belongs to an uncertainty class. It has been proven that, for some uncertainty classes, if all probability distributions are absolutely continuous with respect to a common measure, the joint stochastic boundedness property, which is the fundamental rule for the derivations in Veerevalli’s work, does not hold. This raises a natural question whether minimax robust decentralized detection is possible if the uncertainty classes do not own this property. The answer to this question has been shown to be positive, which leads to a generalization of the work of Veerevalli. Moreover, due to a direct consequence of Tsitsiklis’s work, quantization functions at the sensors are not required to be monotone. For the proposed model, some specific examples have been provided and possible generalizations have been discussed.
Old Cryptococcus neoformans Cells Contribute to Virulence in Chronic Cryptococcosis

ABSTRACT Does cell age matter in virulence? The emergence of persister cells during chronic infections is critical for persistence of infection, but little is known how this occurs. Here, we demonstrate for the first time that the replicative age of the fungal pathogen Cryptococcus neoformans contributes to persistence during chronic meningoencephalitis. Generationally older C. neoformans cells are more resistant to hydrogen peroxide stress, macrophage intracellular killing, and antifungal agents. Older cells accumulate in both experimental rat infection and in human cryptococcosis. Mathematical modeling supports the concept that the presence of older C. neoformans cells emerges from in vivo selection pressures. We propose that advanced replicative aging is a new unanticipated virulence trait that emerges during chronic fungal infection and facilitates persistence. Therapeutic interventions that target old cells could help in the clearance of chronic infections. IMPORTANCE Our findings that the generational age of Cryptococcus neoformans cells matters in pathogenesis introduces a novel concept to eukaryotic pathogenesis research. We propose that emerging properties of aging C. neoformans cells and possibly also other fungal pathogens contribute to persistence and virulence. Whereas the replicative life span of strains may not matter for virulence per se, age-related resilience and thus the generational age of individual C. neoformans cells within a pathogen population could greatly affect persistence of the pathogen population and therefore impact outcome. Our findings that the generational age of Cryptococcus neoformans cells matters in pathogenesis introduces a novel concept to eukaryotic pathogenesis research. We propose that emerging properties of aging C. neoformans cells and possibly also other fungal pathogens contribute to persistence and virulence. Whereas the replicative life span of strains may not matter for virulence per se, age-related resilience and thus the generational age of individual C. neoformans cells within a pathogen population could greatly affect persistence of the pathogen population and therefore impact outcome.
Escape the waterfall: Agile for aerospace

Agile is an umbrella software methodology that incorporates many of the best practices of the last couple of decades. In this paper, we will examine some of those key techniques for possible application in the aerospace domain, starting with a brief literature review to identify the key Agile publications and the germane DO-178B work. Virtually all Agile practices can be mapped to a DO-178B software development process. We provide a detailed analysis of the key practices, with a preliminary assessment of the ease of implementation for each. An analysis of a number of the difficulties involving transitioning from a traditional waterfall software development process to Agile practices will show that, though difficult, a transition is possible. The transition to Agile development does not require sudden, sweeping change, but instead can be accomplished through incorporating Agile methods into an existing process. We will document successful integration of test-driven development, pair programming, refactoring, an iterative approach, and other Agile methods into a traditional DO-178B software development process. We conclude with a call for a collaborative effort to further explore Agile as an answer to the urgent need for new approaches to complex systems that have become increasingly difficult to verify and validate.
Susceptibility in vitro of canine methicillin-resistant and -susceptible staphylococcal isolates to fusidic acid, chlorhexidine and miconazole: opportunities for topical therapy of canine superficial pyoderma

Objectives Increasing multidrug resistance amongst canine pathogenic staphylococci has renewed interest in topical antibacterial therapy for skin infections in the context of responsible veterinary prescribing. We therefore determined the activity in vitro of three clinically relevant topical agents and synergism between two of them against Staphylococcus pseudintermedius and Staphylococcus aureus. Methods The MICs of fusidic acid (n = 199), chlorhexidine (n = 198), miconazole (n = 198) and a 1:1 combination of miconazole/chlorhexidine (n = 198) were determined for canine isolates [50 MRSA and 49 methicillin-resistant S. pseudintermedius (MRSP), 50 MSSA and 50 methicillin-susceptible S. pseudintermedius (MSSP)] collected from the UK and Germany using an agar dilution method (CLSI VET01-A4). Fractional inhibitory concentration (FIC) indices were calculated to assess the interaction of miconazole with chlorhexidine. Results MICs of each drug/combination were significantly (P < 0.0005) higher for S. aureus when compared with S. pseudintermedius. Most strains (n = 172) had an MIC of fusidic acid of ≤0.03 mg/L (MIC ≥64 mg/L, n = 5 MRSA). All strains had MICs of chlorhexidine of 0.5–4 mg/L, except for one MRSA (MIC = 8 mg/L). All but four strains had MICs of miconazole of 1–4 mg/L (MIC = 16 mg/L, n = 3; MIC = 256 mg/L, n = 1). Miconazole/chlorhexidine (1:1 ratio) had a synergistic effect against 49/50 MRSA, 31/50 MSSA, 12/49 MRSP and 23/49 MSSP. Conclusions Since the majority of these staphylococci, including methicillin-resistant isolates, had MICs that should be readily exceeded by topical skin application of these agents, their therapeutic efficacy for canine superficial pyoderma should be assessed. The synergistic interaction shown in vitro supports further clinical evaluation of miconazole/chlorhexidine combination therapy for staphylococcal infection.
Phenotypic convergence along a gradient of predation risk

A long-standing question in ecology is whether phenotypic plasticity, rather than selection per se, is responsible for phenotypic variation among populations. Plasticity can increase or decrease variation, but most previous studies have been limited to single populations, single traits and a small number of environments assessed using univariate reaction norms. Here, examining two genetically distinct populations of Daphnia pulex with different predation histories, we quantified predator-induced plasticity among 11 traits along a fine-scale gradient of predation risk by a predator (Chaoborus) common to both populations. We test the hypothesis that plasticity can be responsible for convergence in phenotypes among different populations by experimentally characterizing multivariate reaction norms with phenotypic trajectory analysis (PTA). Univariate analyses showed that all genotypes increased age and size at maturity, and invested in defensive spikes (neckteeth), but failed to quantitatively describe whole-organism response. In contrast, PTA quantified and qualified the phenotypic strategy the organism mobilized against the selection pressure. We demonstrate, at the whole-organism level, that the two populations occupy different areas of phenotypic space in the absence of predation but converge in phenotypic space as predation threat increases.
Using ontological and document similarity to estimate museum exhibit relatedness

Exhibits within cultural heritage collections such as museums and art galleries are arranged by experts with intimate knowledge of the domain, but there may exist connections between individual exhibits that are not evident in this representation. For example, the visitors to such a space may have their own opinions on how exhibits relate to one another. In this article, we explore the possibility of estimating the perceived relatedness of exhibits by museum visitors through a variety of ontological and document similarity-based methods. Specifically, we combine the Wikipedia category hierarchy with lexical similarity measures, and evaluate the correlation with the relatedness judgements of visitors. We compare our measure with simple document similarity calculations, based on either Wikipedia documents or Web pages taken from the Web site for the museum of interest. We also investigate the hypothesis that physical distance in the museum space is a direct representation of the conceptual distance between exhibits. We demonstrate that ontological similarity measures are highly effective at capturing perceived relatedness and that the proposed RACO (Related Article Conceptual Overlap) method is able to achieve results closest to relatedness judgements provided by human annotators compared to existing state-of-the art measures of semantic relatedness.