Miracle-dz/UniFAR-FTUs huggingface dataset:
Pubertal exposure to ethinylestradiol promotes different effects on the morphology of the prostate of the male and female gerbil during aging

In rodents, the final growth and maturation of the prostate occur at puberty, a crucial period for prostate development. The present study is a serological, morphological, morphometric, and immunohistochemical analysis of the effects of exposure to ethinylestradiol (EE) (15 µg/kg/day) during puberty (EE/PUB group) on the male ventral and female prostate in senile gerbils. In the study, male and female gerbils (Meriones unguiculatus) (42 days) received by gavage 15 μg/kg/day of EE (a component of the contraceptive pill), diluted in 100 µL of Nujol® for 1 week (EE/PUB group). In the control group, males and females were not treated. Animals were killed (n = 5) after 12 months in the experimental groups. In the senile male in the EE/PUB group, we observed a reduction in testosterone levels and a decrease in the prostatic epithelial thickness, as well as in the thickness of the muscle layer. In addition, an increase in PIN multiplicity and prostatic inflammation was observed. In the senile female in the EE/PUB group, we observed increased testosterone and estradiol levels, an enhanced prostatic epithelial thickness and an increase in the thickness of the muscle layer. Immunohistochemical analysis revealed an increase in positive cells (%) for AR and PCNA in the male prostate and an increase in positive basal cells for p63 in the female prostate of the EE/PUB group. Exposure to EE during puberty resulted in an inhibitory action on the male ventral prostate and an anabolic effect on the female prostate in senile gerbils. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 477–489, 2017.
Proteomic Evaluation and Validation of Cathepsin D Regulated Proteins in Macrophages Exposed to Streptococcus pneumoniae*

Macrophages are central effectors of innate immune responses to bacteria. We have investigated how activation of the abundant macrophage lysosomal protease, cathepsin D, regulates the macrophage proteome during killing of Streptococcus pneumoniae. Using the cathepsin D inhibitor pepstatin A, we demonstrate that cathepsin D differentially regulates multiple targets out of 679 proteins identified and quantified by eight-plex isobaric tag for relative and absolute quantitation. Our statistical analysis identified 18 differentially expressed proteins that passed all paired t-tests (α = 0.05). This dataset was enriched for proteins regulating the mitochondrial pathway of apoptosis or inhibiting competing death programs. Five proteins were selected for further analysis. Western blotting, followed by pharmacological inhibition or genetic manipulation of cathepsin D, verified cathepsin D-dependent regulation of these proteins, after exposure to S. pneumoniae. Superoxide dismutase-2 up-regulation was temporally related to increased reactive oxygen species generation. Gelsolin, a known regulator of mitochondrial outer membrane permeabilization, was down-regulated in association with cytochrome c release from mitochondria. Eukaryotic elongation factor (eEF2), a regulator of protein translation, was also down-regulated by cathepsin D. Using absence of the negative regulator of eEF2, eEF2 kinase, we confirm that eEF2 function is required to maintain expression of the anti-apoptotic protein Mcl-1, delaying macrophage apoptosis and confirm using a murine model that maintaining eEF2 function is associated with impaired macrophage apoptosis-associated killing of Streptococcus pneumoniae. These findings demonstrate that cathepsin D regulates multiple proteins controlling the mitochondrial pathway of macrophage apoptosis or competing death processes, facilitating intracellular bacterial killing.
A Trojan Horse Detection Technology Based on Behavior Analysis

This paper presents the model of the Trojan-detection system which is based on behavior analysis. Through the abstract description of the Trojan's behavior, according to certain rules to establish a behavior feature database, and combining the heuristic analyzer to further analysis and then to judge whether the program is the Trojans, at last the system does the appropriate processing. The experiments show this method is effective and efficient in real time and light load, and can be used to in practice to monitor the computer system in real time.
Effective Entropy: Security-Centric Metric for Memory Randomization Techniques

User space memory randomization techniques are an emerging field of cyber defensive technology which attempts to protect computing systems by randomizing the layout of memory. Quantitative metrics are needed to evaluate their effectiveness at securing systems against modern adversaries and to compare between randomization technologies. We introduce Effective Entropy, a measure of entropy in user space memory which quantitatively considers an adversary's ability to leverage low entropy regions of memory via absolute and dynamic intersection connections. Effective Entropy is indicative of adversary workload and enables comparison between different randomization techniques. Using Effective Entropy, we present a comparison of static Address Space Layout Randomization (ASLR), Position Independent Executable (PIE) ASLR, and a theoretical fine grain randomization technique.
Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites

Dopamine D2 receptors are highly expressed in the dorsal striatum where they participate in the regulation of (i) tyrosine hydroxylase (TH), in nigrostriatal nerve terminals, and (ii) the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), in medium spiny neurons. Two isoforms of the D2 receptor are generated by differential splicing of the same gene and are referred to as short (D2S) and long (D2L) dopamine receptors. Here we have used wild-type mice, dopamine D2 receptor knockout mice (D2 KO mice; lacking both D2S and D2L receptors) and D2L receptor-selective knockout mice (D2L KO mice) to evaluate the involvement of each isoform in the regulation of the phosphorylation of TH and DARPP-32. Incubation of striatal slices from wild-type mice with quinpirole, a dopamine D2 receptor agonist, decreased the state of phosphorylation of TH at Ser-40 and its enzymatic activity. Both effects were abolished in D2 KO mice but were still present in D2L KO mice. In wild-type mice, quinpirole inhibits the increase in DARPP-32 phosphorylation at Thr-34 induced by SKF81297, a dopamine D1 receptor agonist. This effect is absent in D2 KO as well as D2L KO mice. The inability of quinpirole to regulate DARPP-32 phosphorylation in D2L KO mice cannot be attributed to decreased coupling of D2S receptors to G proteins, because quinpirole produces a similar stimulation of [35S]GTPγS binding in wild-type and D2L KO mice. These results demonstrate that D2S and D2L receptors participate in presynaptic and postsynaptic dopaminergic transmission, respectively.
APPLIED MULTIRESPONSE METAMODELING FOR QUEUING NETWORK SIMULATION EXPERIMENTS: PROBLEMS AND PERSPECTIVES

A complete performance evaluation study of a simulated system should consider possible alternatives and response predictions to potential parameter changes. Simulation sensitivity analysis and metamodeling constitute an efficient approach for this kind of problems. However, this approach is usually despised, mainly because, a sophisticated methodological treatment is required. Such a methodology should take into account, peculiarities, inherent to queuing network models, as for example, multiple responses, large number of model parameters, many qualitative parameters etc. This work aims to illustrate the combined use of the proper statistical techniques to cope with this sort of problems and to show the need for a sound methodological framework that will bring this approach closer to the queuing network simulation practice.
A structural view of ligand-dependent activation in thermoTRP channels

Transient Receptor Potential (TRP) proteins are a large family of ion channels, grouped into seven sub-families. Although great advances have been made regarding the activation and modulation of TRP channel activity, detailed molecular mechanisms governing TRP channel gating are still needed. Sensitive to electric, chemical, mechanical, and thermal cues, TRP channels are tightly associated with the detection and integration of sensory input, emerging as a model to study the polymodal activation of ion channel proteins. Among TRP channels, the temperature-activated kind constitute a subgroup by itself, formed by Vanilloid receptors 1–4, Melastatin receptors 2, 4, 5, and 8, TRPC5, and TRPA1. Some of the so-called “thermoTRP” channels participate in the detection of noxious stimuli making them an interesting pharmacological target for the treatment of pain. However, the poor specificity of the compounds available in the market represents an important obstacle to overcome. Understanding the molecular mechanics underlying ligand-dependent modulation of TRP channels may help with the rational design of novel synthetic analgesics. The present review focuses on the structural basis of ligand-dependent activation of TRPV1 and TRPM8 channels. Special attention is drawn to the dissection of ligand-binding sites within TRPV1, PIP2-dependent modulation of TRP channels, and the structure of natural and synthetic ligands.
Retinal vessel tree as biometric pattern

In current society, reliable authentication and authorization of individuals are becoming more and more necessary tasks for everyday activities or applications. Just for instance, common situations such as accessing to a building restricted to authorized people (members, workers,.), taking a flight or performing a money transfer require the verification of the identity of the individual trying to perform these tasks. When considering automation of the identity verification, the most challenging aspect is the need of high accuracy, in terms of avoiding incorrect authorizations or rejections. While the user should not be denied to perform a task if authorized, he/she should be also ideally inconvenienced to a minimum which further complicates the whole verification process Siguenza Pizarro & Tapiador Mateos (2005). With this scope in mind, the term biometrics refers to identifying an individual based on his/her distinguished intrinsic characteristics. Particularly, this characteristics usually consist of physiological or behavioral features. Physiological features, such as fingerprints, are physical characteristics usually measured at a particular point of time. Behavioral characteristics, such as speech or handwriting, make reference to the way some action is performed by every individual. As they characterize a particular activity, behavioral biometrics are usually measured over time and are more dependant on the individual’s state of mind or deliberated alteration. To reinforce the active versus passive idea of both paradigms, physiological biometrics are also usually referred to as static biometrics while behavioral ones are referred to as dynamic biometrics. The traditional authentication systems based on possessions or knowledge are widely spread in the society but they have many drawbacks that biometrics try to overcome. For instance, in the scope of the knowledge-based authentication, it is well known that password systems are vulnerable mainly due to the wrong use of users and administrators. It is not rare to find some administrators sharing the same password, or users giving away their own to other people. One of the most common problems is the use of easily discovered passwords (child names, birth dates, car plate,.). On the other hand, the use of sophisticated passwords consisting of numbers, upper and lower case letters and even punctuation marks makes it harder to remember them for an user. Nevertheless, the password systems are easily broken by the use of brute forcewhere powerful computers generate all the possible combinations and test it against the authentication system. In the scope of the possession-based authentication, it is obvious that the main concerns are 6
Software risk management: principles and practices

The emerging discipline of software risk management is described. It is defined as an attempt to formalize the risk-oriented correlates of success into a readily applicable set of principles and practices. Its objectives are to identify, address, and eliminate risk items before they become either threats to successful software operation or major sources of software rework. The basic concepts are set forth, and the major steps and techniques involved in software risk management are explained. Suggestions for implementing risk management are provided. <<ETX>>
A conserved protein interaction network involving the yeast MAP kinases Fus3 and Kss1

The Saccharomyces cerevisiae mitogen-activated protein kinases (MAPKs) Fus3 and Kss1 bind to multiple regulators and substrates. We show that mutations in a conserved docking site in these MAPKs (the CD/7m region) disrupt binding to an important subset of their binding partners, including the Ste7 MAPK kinase, the Ste5 adaptor/scaffold protein, and the Dig1 and Dig2 transcriptional repressors. Supporting the possibility that Ste5 and Ste7 bind to the same region of the MAPKs, they partially competed for Fus3 binding. In vivo, some of the MAPK mutants displayed reduced Ste7-dependent phosphorylation, and all of them exhibited multiple defects in mating and pheromone response. The Kss1 mutants were also defective in Kss1-imposed repression of Ste12. We conclude that MAPKs contain a structurally and functionally conserved docking site that mediates an overall positively acting network of interactions with cognate docking sites on their regulators and substrates. Key features of this interaction network appear to have been conserved from yeast to humans.
Intestinal prokinesia by two esters of 4-amino-5-chloro-2- methoxybenzoic acid: involvement of 5-hydroxytryptamine-4 receptors and dissociation from cardiac effects in vivo.

In five fasting, conscious dogs, we compared the prokinetic action of two selective 5-hydroxytryptamine-4 (5-HT4) receptor agonists with low affinity for 5-HT3 receptors ML10302 (2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate) and SR59768 (2-[(3S)-3-hydroxypiperidino]ethyl 4-amino-5-chloro-2-methoxybenzoate) in the duodenum and jejunum, using cisapride as a reference compound. Heart rate and rate-corrected QT (QTc) also were monitored to assess whether or not the cardiac effects of cisapride are shared by other 5-HT4 receptor agonists. Both ML10302 and SR59768 dose-dependently stimulated spike activity in the duodenum with similar potencies (dose range, 3-300 nmol/kg i.v.; ED50 values: 24 and 23 nmol/kg i.v., respectively), mimicking the effect of cisapride (30-3000 nmol/kg i.v.). The maximal effect was achieved with the dose of 100 nmol/kg i.v. for both compounds. Similar findings were obtained in the jejunum. Atropine and GR125487 (1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl-methyl 5-fluoro-2-methoxy-1H-indole-3-carboxylate, selective 5-HT4 receptor antagonist), at doses having no effect per se, antagonized intestinal prokinesia by maximal doses of ML10302 and SR59768. Neither ML10302 nor SR59768 had any effect on heart rate or QTc at any of the doses tested, whereas cisapride, at the highest dose (3000 nmol/kg), induced tachycardia and lengthened the QTC (p <.01). In conclusion, ML10302 and SR59768 share with cisapride a similar prokinetic action in the canine duodenum and jejunum in vivo. This effect is mediated by pathways involving activation of 5-HT4 and muscarinic receptors. Unlike cisapride, which induces tachycardia and prolongs the QTc by a mechanism probably unrelated to 5-HT4 receptor activation, ML10302 and SR59768 are devoid of cardiac effects in this model.
Customer Adoption of Internet Banking: An Empirical Investigation in Taiwanese Banking Context

In these days, banks work hard to attract consumers and keep their market share by providing them with more innovative services through Internet banking. Banking services are now just at the distance of one click from the mouse. The purpose of this paper is to explore how and why specific factors affect adoption of Internet banking in Taiwan context. The findings suggest six identified factors are significant in respect of customers’ adoption of Internet banking services. Convenience, accessibility and feature availability are the main motivators for consumers to use Internet banking service. Results also reveal that security and privacy play important roles in discouraging the customers to use Internet banking services. Conclusions and managerial suggestions are proposed to provide a practical contribution for bank managers to better understand customers’ perception of e-banking service quality and enhance customers’ adoption rates.
Statistical nonparametric speech synthesis using sparse Gaussian processes

This paper proposes a statistical nonparametric speech synthesis technique based on a sparse Gaussian process regression (GPR). In our previous study, we proposed GPR-based speech synthesis where each frame of synthesis units is modeled by a regression of Gaussian processes. Preliminary experiments of synthesizing several phones including both vowels and conso-nants showed a potential of the technique. In this paper, the previous work is extended to full-sentence speech synthesis using sparse GPs and context modiﬁcation. Speciﬁcally, cluster-based sparse Gaussian processes such as local GPs and partially independent conditional (PIC) approximation are examined as a computationally feasible approach. Moreover, frame-level context is extended to include not only a position context from a current phone but also adjacent phones to generate smoothly changing speech parameters. Objective and subjective evaluation results show that the proposed technique outperforms the HMM-based speech synthesis with minimum generation error training.
When core competence is not enough: functional interplay of the DEAD-box helicase core with ancillary domains and auxiliary factors in RNA binding and unwinding

Abstract DEAD-box helicases catalyze RNA duplex unwinding in an ATP-dependent reaction. Members of the DEAD-box helicase family consist of a common helicase core formed by two RecA-like domains. According to the current mechanistic model for DEAD-box mediated RNA unwinding, binding of RNA and ATP triggers a conformational change of the helicase core, and leads to formation of a compact, closed state. In the closed conformation, the two parts of the active site for ATP hydrolysis and of the RNA binding site, residing on the two RecA domains, become aligned. Closing of the helicase core is coupled to a deformation of the RNA backbone and destabilization of the RNA duplex, allowing for dissociation of one of the strands. The second strand remains bound to the helicase core until ATP hydrolysis and product release lead to re-opening of the core. The concomitant disruption of the RNA binding site causes dissociation of the second strand. The activity of the helicase core can be modulated by interaction partners, and by flanking N- and C-terminal domains. A number of C-terminal flanking regions have been implicated in RNA binding: RNA recognition motifs (RRM) typically mediate sequence-specific RNA binding, whereas positively charged, unstructured regions provide binding sites for structured RNA, without sequence-specificity. Interaction partners modulate RNA binding to the core, or bind to RNA regions emanating from the core. The functional interplay of the helicase core and ancillary domains or interaction partners in RNA binding and unwinding is not entirely understood. This review summarizes our current knowledge on RNA binding to the DEAD-box helicase core and the roles of ancillary domains and interaction partners in RNA binding and unwinding by DEAD-box proteins.
Factors associated with concordant estrogen receptor expression at diagnosis and centralized re-assay in a Danish population-based breast cancer study

Background. Estrogen receptor (ER) expression predicts tamoxifen response, which halves the risk of breast cancer recurrence. We examined clinical factors associated with concordance between ER expression at diagnosis and centralized re-assay, and the association of concordance with breast cancer recurrence. Material and methods. We used immunohistochemistry to assess ER expression on archived fixed, paraffin-embedded breast carcinoma tissue excised from women aged 35–69 years, diagnosed 1985–2001 in Jutland, Denmark. We calculated the percentage agreement, positive predictive value (PPV) and negative predictive value (NPV) of ER status at diagnosis and re-assay. We used logistic regression to investigate factors associated with concordance, and its association with recurrence (odds ratios (OR) and associated 95% confidence intervals (95%CI)). Results. ER was re-assayed in 91% of patients (n = 1530). Concordance was better in ER + than ER– tumors (PPV = 94% vs. NPV = 75%). Factors associated with concordance included menopausal status, tumor size, surgical procedure, diagnostic period, lymph node status and time to recurrence. ER + women at diagnosis who re-assayed ER + were less likely to have recurrent disease (OR = 0.49, 95% CI = 0.28, 0.86) than those who re-assayed ER–. In originally ER– women, concordance was not associated with recurrence (OR = 0.97, 95% CI = 0.66, 1.42). Conclusions. Several clinical factors were associated with ER assay concordance. Some women were ineffectively treated with tamoxifen, or required but did not receive tamoxifen. We observed almost exactly the protective effect of endocrine therapy among tamoxifen-treated ER + women whose tumors expressed the ER on re-assay, compared with those ER– on re-assay. Diagnostic pathology results for ER + tumors appear a valid and useful resource for research studies. However, those for ER– tumors have lower validity. Study-specific considerations regarding the aims, diagnostic period, and consequences of including ER– patients with truly ER + disease ought to be examined when using diagnostic pathology results for ER– tumors in research studies.
Imaging of lung function using hyperpolarized helium‐3 magnetic resonance imaging: Review of current and emerging translational methods and applications

During the past several years there has been extensive development and application of hyperpolarized helium‐3 (HP 3He) magnetic resonance imaging (MRI) in clinical respiratory indications such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, radiation‐induced lung injury, and transplantation. This review focuses on the state‐of‐the‐art of HP 3He MRI and its application to clinical pulmonary research. This is not an overview of the physics of the method, as this topic has been covered previously. We focus here on the potential of this imaging method and its challenges in demonstrating new types of information that has the potential to influence clinical research and decision making in pulmonary medicine. Particular attention is given to functional imaging approaches related to ventilation and diffusion‐weighted imaging with applications in chronic obstructive pulmonary disease, cystic fibrosis, asthma, and radiation‐induced lung injury. The strengths and challenges of the application of 3He MRI in these indications are discussed along with a comparison to established and emerging imaging techniques. J. Magn. Reson. Imaging 2010;32:1398–1408. © 2010 Wiley‐Liss, Inc.