Miracle-dz/UniFAR-FTUs huggingface dataset:
Focal Adhesion Kinase and Protein Kinase B Cooperate to Suppress Doxorubicin-Induced Apoptosis of Breast Tumor Cells

Focal adhesion kinase (FAK) is up-regulated in a variety of cancers, including breast cancer, in association with poor disease prognosis. In the present study, we examined the role of FAK in the control of anticancer drug-induced apoptosis of mammary adenocarcinoma MTLn3 cells. Doxorubicin caused the formation of well defined focal adhesions and stress fibers early after treatment, which was later followed by their loss in association with the onset of apoptosis. Phosphorylation of FAK on tyrosine 397 decreased only during the onset of doxorubicin-induced apoptosis in a Bcl-2 and caspase-independent manner. Doxorubicin also caused an early activation of protein kinase B (PKB). Expression of the dominant-negative acting focal adhesion kinase-related nonkinase (FRNK) sensitized MTLn3 cells to apoptosis caused by doxorubicin. FRNK inhibited the doxorubicin-induced activation of PKB. In addition, inhibition of phosphatidylinositide-3 (PI-3) kinase with wortmannin inhibited the activation of PKB by doxorubicin. Both wortmannin and transient overexpression of the dual lipid/protein phosphatase and tensin homolog deleted on chromosome 10 enhanced doxorubicin-induced cell death. Altogether, these data fit with a model wherein FAK is involved in the doxorubicin-induced activation of the PI-3 kinase/PKB signaling route, thereby suppressing the onset of apoptosis caused by doxorubicin.
Flu virus susceptibility of ago 1 / 3 double null mice Enhanced Susceptibility to Influenza A Virus of Ago 1 / 3 1 Double Null Mice 2

22 RNAi is a critical component of many cellular anti-viral responses in plants, 23 invertebrates, and mammals. However, its in vivo role in host protection from the 24 negative sense RNA virus Influenza Type A is unclear. Here we have examined the role 25 of RNAi in host defense to flu by analyzing Argonaute 1 and 3 double knock out mice, 26 deficient in components of the RNA induced silencing complex. Compared to littermate 27 controls, flu-infected double knock out mice exhibited increased mortality, consistent with 28 more severe alveolitis and pneumonitis. These data indicate that optimal resistance to 29 flu requires Argonaute 1 and/or 3. Enhanced mortality of double knock out mice was 30 associated neither with increased viral replication nor with differential pulmonary 31 recruitment or function of innate and adaptive immune cells. Given the absence of 32 detectable immune defects, our results support the notion that the enhanced flu 33 susceptibility of DKO mice arises from an intrinsic impairment in the ability of lung cells 34 to tolerate flu-elicited inflammation. 35 36 on S etem er 3, 2017 by gest http/jvi.asm . rg/ D ow nladed fom Flu virus susceptibility of ago1/3 double null mice
Multiple Longevity Phenotypes and the Transition from Health to Senescence

Three different longevity phenotypes exist in Drosophila and other model systems, but only two are known in humans. The “missin” phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The lability of the onset of senescence indicates that the mechanisms involved are plastic and can be altered. Only interventions that involve the upregulation of stress resistance genes, probably via the JNK pathway and/or dFOXO3a transcription factor, seem capable of generating a delayed onset of senescence phenotype. The data suggest that the cellular mechanisms responsible for maintaining the cell in a healthy state are under constant attack by ROS and/or abnormal protein accumulation. A stochastic growth factor/signal transduction failure may be the proximal event responsible for the decreased efficiency of the cell's defenses, resulting in the onset of senescence, degradation of the gene interaction network, and continuing loss of function.
Interplay between steroid receptors and neoplastic progression in sarcoma tumors

Steroid hormones are expressed at low levels in mesenchymal cells and are highly expressed in soft tissue sarcoma. In human soft tissue fibrosarcoma cell line (HT‐1080), the epidermal growth factor (EGF) stimulates the express of matrix metal (MMPs) expression through a Src‐dependent mechanism. In human fibrosarcomas, increased expression of MMPs correlates with the metastatic progression. Our recent data in human breast cancer cell line MCF‐7, demonstrates that EGF stimulates estradiol receptor (ER) phosphorylation on tyrosine at position 537 thereby promoting the association of a complex among EGF receptor (EGFR), androgen receptor (AR), ER, and Src that activates EGF‐dependent signaling pathway. In the present study, we demonstrate that, in HT‐1080 cells, the Src kinase activity is involved in EGFR phosphorylation and this activity is regulated by an interplay between Src, steroid receptors, and EGFR. In these cells, estradiol (E2)/ER and synthetic androgen (R1881)/AR trans‐activate EGFR leading to the downstream signaling and to ERK activation. Indeed, the association between ER/AR and EGFR enhances metastatic progression of fibrosarcoma tumors. A population pilot study performed on 16 patients with soft tissue neoplasias highlights that MMPs expression correlates with progression of anaplastic sarcoma as well as overexpression of EGFR. These findings suggest that there is a crosstalk among AR, ER, and EGFR that lead to src activation also in fibrosarcoma cells. J. Cell. Physiol. 226: 2997–3003, 2011. © 2011 Wiley‐Liss, Inc.
Fixed cervical count and the origin of the mammalian diaphragm

Why is mammalian cervical count fixed across the historically long and ecologically broad mammalian radiation? Multiple lines of evidence, considered together, suggest a link between fixed cervical count and the muscularization of the diaphragm, a key innovation in mammalian history. We test this hypothesis by documenting the anteroposterior (AP) movement of the diaphragm, a lateral plate derivative, relative to that of the somitic thoracolumbar transition in unusually patterned mammals, by comparing the temporal occurrence of an osteological proxy for the diaphragm and fixed cervical counts in the fossil record, and by quantifying morphological differentiation within the mammalian cervical series. We then integrate these anatomical observations with details of diaphragm function and development to propose a sequence of innovations in mammalian evolution that could have led to fixed cervical count. We argue that the novel commitment of migratory muscle precursor cells (MMPs) of mid‐cervical somites to a fate in the abaxial diaphragm defined these somites as a new and uniquely mammalian modular subunit. We further argue that the coordination of primaxial abaxial patterning constrained subsequent AP migration of the forelimb, thereby secondarily fixing cervical count.
Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease.

This study was designed to determine whether the plasma level of apolipoprotein A-I is a better discriminator of angiographically documented coronary-artery disease than the level of high-density-lipoprotein (HDL) cholesterol in male subjects. The level of plasma apolipoprotein A-I in 83 patients with coronary-artery disease was 96.7 +/- 4.2 mg per deciliter (mean +/- S.E.M.), which was significantly lower (P less than 0.0001) than the level in 25 patients without coronary-artery disease (146.9 +/- 2.1 mg per deciliter). The levels of HDL cholesterol were also lower (P less than 0.0001) in patients with coronary-artery disease (31.9 +/- 1.5 mg per deciliter) than in those without it (45.9 +/- 2.3 mg per deciliter). A stepwise discriminant analysis, however, indicated the superiority of apolipoprotein A-I over HDL cholesterol in detecting coronary-artery disease. Furthermore, a linear discriminant analysis suggested that although HDL cholesterol by itself was a discriminator of coronary-artery disease, it did not provide a substantial increase in discriminatory value over that provided by apolipoprotein A-I; in contrast, apolipoprotein A-I levels added discriminatory value to the information obtained by measuring HDL cholesterol alone. We conclude that apolipoprotein A-I by itself is more useful than HDL cholesterol for identifying patients with coronary-artery disease.
The evaluation of platelet indices and markers of inflammation, coagulation and disease progression in treatment‐naïve, asymptomatic HIV‐infected individuals

Cardiovascular disease and thrombotic events have emerged as major causes of mortality in people living with HIV. Activated platelets play a key role in both inflammation and thrombosis. Haematology analysers measure a variety of platelet indices, which could be surrogate markers of platelet activation. Flow cytometry offers the discrimination of platelet subpopulations and evaluation of the activation status of platelets. This study aimed to measure platelet indices in untreated HIV infection and to evaluate their relationship with markers of immune activation and disease progression.
Molecular architecture of the Saccharomyces cerevisiae activated spliceosome

The activated spliceosome (Bact) is in a catalytically inactive state and is remodeled into a catalytically active machine by the RNA helicase Prp2, but the mechanism is unclear. Here, we describe a 3D electron cryomicroscopy structure of the Saccharomyces cerevisiae Bact complex at 5.8-angstrom resolution. Our model reveals that in Bact, the catalytic U2/U6 RNA-Prp8 ribonucleoprotein core is already established, and the 5′ splice site (ss) is oriented for step 1 catalysis but occluded by protein. The first-step nucleophile—the branchsite adenosine—is sequestered within the Hsh155 HEAT domain and is held 50 angstroms away from the 5′ss. Our structure suggests that Prp2 adenosine triphosphatase–mediated remodeling leads to conformational changes in Hsh155’s HEAT domain that liberate the first-step reactants for catalysis.
Dynamic modeling of food‐chain accumulation of brominated flame retardants in fish from the Ebro River Basin, Spain

Since the 1980s, brominated flame retardants (BFRs) have been detected in air, sewage sludge, sediment, fish, shellfish, birds, and mammals, including humans. However, model studies regarding BFR food‐chain accumulation are scarce. In the present study, the accumulation of hexabromocyclododecane and brominated diphenyl ethers (BDEs) 47, 153, 154, and 183 in benthivorous barbel (Barbus graellsii) and pelagic bleak (Alburnus alburnus) from four locations in the Ebro river basin in Spain was modeled using a first‐order, one‐compartment model with sediment interaction. The model accounted for BFR uptake from water, ingested sediment, and food; release via water and feces; growth; and in situ binding of BFRs to black carbon. Rate constants were derived from allometric regressions. For most BFRs, dynamically modeled biota‐sediment accumulation factors (BSAFs) were close to measured values, whereas steady‐state model BSAFs were too high, especially for BDEs 153, 154, and 183. Differences between BSAFs for individual fish were explained by differences in age, growth, and feeding behavior. On average, modeled BSAFs for barbel were 50% higher than those for bleak because of extra BFR uptake through sediment ingestion and older age of barbel specimens.
Prognostic Consequences of the Location of Positive Surgical Margins in Organ-Confined Prostate Cancer

Introduction: The purpose of the present study was to evaluate and compare the risk of progression in organ-confined prostate cancers (stage pT2), according to the location of positive surgical margins. Materials and Methods: Between 1988 and 2001, 538 consecutive men underwent radical prostatectomy for localized prostate cancer. All patients had preoperative physical examinations, serum PSA assays (Hybritech assay, N.l. <4 ng/ml) and ultrasound-guided sextant biopsies to confirm diagnosis. Radical prostatectomy specimens were analyzed according to the Stanford protocol. Positive margins were classified as single or multiple and main locations (apex, bladder neck and posterolateral) were noted. Postoperative follow-up data were obtained through routine serum PSA assays. Biochemical recurrence was defined as a single postoperative PSA level >0.2 ng/ml. Biochemical progression was studied in patients with organ-confined tumors (stage pT2) according to the location of the single positive margin. Kaplan-Meier analysis was performed to determine the actuarial biochemical recurrence-free likelihood and the log-rank test was used for statistical analysis. Differences were considered significant when the p value was <0.05. Results: 371 patients had organ-confined tumors, and 60 patients (16.1%) had solitary positive margins (apex 26, bladder neck 14, posterolaterally 20). Eleven patients (18.3%) had biochemical progression. 5-year biochemical free progression was 54.5, 76.9 and 87.9% for apex, bladder and the posterolateral location, respectively (p < 0.05). Conclusions: In the present study, a positve surgical margin at the apex was associated with worse clinical prognosis compared to the bladder neck and posterolateral locations.
A single-chip, functional tester for VLSI circuits

A single-chip functional tester for VLSI circuits that integrates the vector memory, the error memory, a decompressor, and 16 sets of independently controlled pin electronics on a 9.0*9.4-mm chip is described. The device contains over 200 K transistors and is fabricated using a 1.6- mu m CMOS technology. The integrated pin electronics support a per-pin tester architecture, allowing the transitions for each pin to be independently adjusted to better than 1 ns. The chip dissipates less than 0.75 W running at 25 M vectors/s. By integrating all tester functions on a single chip, it is possible to build all extremely compact tester. A 256-pin tester requires only 16 chips. This size makes it possible to reduce the length of the transmission line between the device under test and the tester to under 10 cm, minimizing signal reflections and enabling the delivery of high-fidelity waveforms. <<ETX>>
The effect of repeated blood donations on the iron status of male Saudi blood donors.

BACKGROUND Regular blood donation can lead to iron deficiency. Screening donors' serum ferritin levels at the time of first donation and subsequently once every year is a very rational way to pick up iron deficiency in a voluntary blood donor population. The aim of this study was to determine the effect of blood donation and the prevalence of erythropoiesis with iron deficiency (sideropenia) in Saudi male blood donors. MATERIALS AND METHODS The study was prospectively conducted, between December 2008 and March 2009, on 182 male native Saudi blood donors at King Fahd Central Hospital in Jazan region, Saudi Arabia. Each donor gave 450 ± 50 mL of whole blood. Following the donation, samples were removed into 2.5 mL EDTA tubes for measurement of mean cell volume (MCV) and mean corpuscular haemoglobin (MCH) and into 7.5 mL plain tubes for estimation of iron and serum ferritin concentrations. The blood donors were divided into five groups, according to the number of donations they had given in the preceding 3 years. The blood donors in group I were first-time donors, with no previous history of blood donation. Group II donors had donated once in the last 3 years. Subjects in groups III, IV and V had donated more than once in the preceding 3 years and were considered regular donors. RESULTS The mean serum iron was significantly higher among subjects with no previous history of blood donation (group I) than among regular donors who had donated twice or more. The difference in serum ferritin concentration was statistically significant (p<0.05) when comparing regular donors in group III (72.4 μg/L), group IV (67.4 μg/L) and group V (26.2 μg/L) with first-time blood donors (131.4 μg/L). In contrast, the difference in the concentration of serum ferritin between subjects in group II (98.9 μg/L), who had donated once in the last 3 years, and in first-time blood donors (131.4 μg/L) was not statistically significant (p<0.131). None of the group I donors suffered from iron deficiency, whereas 2.8% of the donors who had donated between two to five times had iron deficiency. The prevalence of erythropoiesis with iron deficiency in regular blood donors was 4.3%. CONCLUSION The results of this study show that an increase in the number of donations results in an increase in the frequency of depleted iron stores and subsequently in erythropoiesis with iron deficiency, although the level of haemoglobin remained acceptable for blood donation. This result may indicate the need to review the guidelines on acceptance of donors.
The Influence of Perceived Belonging on Massively Multiplayer Online Role-Playing Games

While some service providers of Massively Multiplayer Online Role-Playing Games (MMORPGs) lose significant numbers of players over time, others maintain a strong growth trajectory. Drawing from the Uses and Gratifications Theory and the Need to Belong theory, we believe that an individual’s Perceived Belonging (i.e., the degree to which a person feels connected to and accepted by others) positively influences his/her Actual MMORPG Usage, i.e., how often he/she plays MMORPGs. After collecting 71 online questionnaires and applying a structural equation modeling approach, we found that Perceived Belonging’s positive influence on Actual MMORPG Usage is fully mediated by Perceived Enjoyment. Overall, our study suggests that MMORPG service providers should include belonging-oriented aspects into their games, such as the possibility of interacting and cooperating with other players, in order to increase individuals’ game usage through their Perceived Belonging.
Constraint satisfaction approach to product configuration with cost estimation

Due to the dynamism and heterogeneity of today’s markets, mass customization has been widely applied in the manufacturing industry with the objective of satisfying individual customer needs while maintaining near mass production efficiency. Product family design is an effective approach for mass customization where problem modeling and solution are two significant concerns. As a large amount of data with diverse variety need to be represented (including production data, customer requirements and design knowledge), powerful knowledge representation models are necessary to capture the large variety and complexity of data. Given a configuration problem description and representation, efficient reasoning methods are also required for configuration solution search and optimization. Cost is a critical composition and criterion for product family design; however, the integration of cost estimation and product family design has not been successfully addressed. In this thesis, an extended Dynamic Constraint Satisfaction Problem (DCSP) based product configuration and cost estimation system is proposed to to effectively represent the large amount of data with great variety and complexity in product family design as DCSP terms (i.e., variables, domains and constraints). In the extended DCSP-based system, structural constraints are proposed to capture the inherent hierarchy among modules and components. Activation constraints are composed to represent derivation relationships among variables in the extended DCSP-based system. As both structural and activation constraints can activate variables into the DCSP according to triggering conditions (i.e., hierarchical and derivation relationships among variables), they are utilized to dynamically extend the search space of
Singlet semiconductor to ferromagnetic metal transition in FeSi.

Adding the local Coulomb repulsion to the local density approximation, the so-called $\mathrm{LDA}+U$ scheme, leads us to predict a first order transition from a singlet semiconductor to ferromagnetic metal in FeSi with increasing magnetic field. Extensions to finite temperature lead to the interpretation that the anomalous behavior at room temperature and zero field arises from proximity to the critical point of this transition. This critical point at a finite field may be accessible in currently available magnetic fields.
Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein.

Previous studies in mice with disrupted mdr1a P-glycoprotein genes have shown that the oral bioavailability of paclitaxel is very low because of the presence of this drug-transporting protein in the intestinal wall. Additional studies with cyclosporin A have shown that this P-glycoprotein-inhibiting agent is able to increase the bioavailability of paclitaxel in mouse models and in patients. However, the potential immune-suppressive side effects of cyclosporin A renders this compound less suitable for chronic use in cancer patients. In this paper we present the results obtained with GF120918, an experimental P-glycoprotein inhibitor, on the oral bioavailability of paclitaxel in both wild-type and mdrlab knockout mice. GF120918 (25 mg/kg) was administered p.o. by gavage 15 min or 2 h before oral or i.v. dosing of paclitaxel, respectively. Paclitaxel plasma levels were quantified by high-performance liquid chromatography. GF120918 increased the plasma values for areas under the concentration-time curve of oral paclitaxel in wild-type mice by 6.6-fold from 408 to 2701 ng x ml(-1) h. Calculated relative to their respective values for area under the concentration-time curve after i.v. administration, GF120918 increased the oral bioavailability of paclitaxel in wild-type mice from 8.5 to 40.2%. The plasma pharmacokinetics of paclitaxel in mdr1ab knockout mice was not altered by GF120918, whereas the pharmacokinetics of paclitaxel in wild-type mice receiving GF120918 became comparable with mdr1ab knockout mice. This result indicates that GF120918 at this dose-level selectively and completely blocks P-glycoprotein in the intestines and does not notably interfere in the elimination of paclitaxel by metabolism or other transporters. On the basis of this result, GF120918 has been selected for additional study in humans.
Personalizing the Fitting of Hearing Aids by Learning Contextual Preferences From Internet of Things Data

The lack of individualized fitting of hearing aids results in many patients never getting the intended benefits, in turn causing the devices to be left unused in a drawer. However, living with an untreated hearing loss has been found to be one of the leading lifestyle related causes of dementia and cognitive decline. Taking a radically different approach to personalize the fitting process of hearing aids, by learning contextual preferences from user-generated data, we in this paper outline the results obtained through a 9-month pilot study. Empowering the user to select between several settings using Internet of things (IoT) connected hearing aids allows for modeling individual preferences and thereby identifying distinct coping strategies. These behavioral patterns indicate that users prefer to switch between highly contrasting aspects of omnidirectionality and noise reduction dependent on the context, rather than relying on the medium “one size fits all” program frequently provided by default in hearing health care. We argue that an IoT approach facilitated by the usage of smartphones may constitute a paradigm shift, enabling continuous personalization of settings dependent on the changing context. Furthermore, making the user an active part of the fitting solution based on self-tracking may increase engagement and awareness and thus improve the quality of life for hearing impaired users.