Miracle-dz/UniFAR-FTUs huggingface dataset:
CCL5‐enhanced human immature dendritic cell migration through the basement membrane in vitro depends on matrix metalloproteinase‐9

The proinflammatory chemokine CC chemokine ligand 5 (CCL5) is a potent chemoattractant of immature dendritic cells (iDCs). It remains to be elucidated whether CCL5 may also enhance iDC migration through the basement membrane by affecting matrix metalloproteinase (MMP)‐9 secretion. In this study, iDCs were differentiated in vitro from human monocytes of healthy donors. Zymographic analysis of cellular membranes of nontreated iDCs revealed a basal secretion of the pro‐ and active MMP‐9, whereas only pro‐MMP‐9 was detected in conditioned media. Increasing concentrations of CCL5 significantly enhanced MMP‐9 secretion by iDCs, peaking at 100 ng/ml, which optimally increased iDC migration through a reconstituted basement membrane (Matrigel™) in vitro. The CCL5‐enhanced secretion of MMP‐9 occurred early (2 h) and was maintained at least for 10 h. A significant increase in MMP‐9 mRNA synthesis was detected by reverse transcriptase‐polymerase chain reaction, only at 6 h of CCL5 treatment, which suggests that the early effect of CCL5 (0–4 h) on MMP‐9 secretion was independent of mRNA synthesis, whereas the more delayed effect (6–10 h) could be mediated through an increase in MMP‐9 gene expression. In a Matrigel migration assay, the CCL5‐enhanced iDC migration was reduced significantly by specific inhibitors of MMP‐9, such as tissue inhibitor of metalloproteinase‐1 or an anti‐MMP‐9 antibody, which indicates that iDC migration through the basement membrane depends on MMP‐9. These results suggest that under inflammatory conditions, the chemokine CCL5 may enhance iDC migration through the basement membrane by rapidly increasing their MMP‐9 secretion.
VARS2 and TARS2 Mutations in Patients with Mitochondrial Encephalomyopathies

By way of whole‐exome sequencing, we identified a homozygous missense mutation in VARS2 in one subject with microcephaly and epilepsy associated with isolated deficiency of the mitochondrial respiratory chain (MRC) complex I and compound heterozygous mutations in TARS2 in two siblings presenting with axial hypotonia and severe psychomotor delay associated with multiple MRC defects. The nucleotide variants segregated within the families, were absent in Single Nucleotide Polymorphism (SNP) databases and are predicted to be deleterious. The amount of VARS2 and TARS2 proteins and valyl‐tRNA and threonyl‐tRNA levels were decreased in samples of afflicted patients according to the genetic defect. Expression of the corresponding wild‐type transcripts in immortalized mutant fibroblasts rescued the biochemical impairment of mitochondrial respiration and yeast modeling of the VARS2 mutation confirmed its pathogenic role. Taken together, these data demonstrate the role of the identified mutations for these mitochondriopathies. Our study reports the first mutations in the VARS2 and TARS2 genes, which encode two mitochondrial aminoacyl‐tRNA synthetases, as causes of clinically distinct, early‐onset mitochondrial encephalopathies.
Decision Support for SME Owners-Managers: A Performance Evaluation Benchmarking Tool

We present the PDG system, a decision support tool meant to evaluate SMEs from an external perspective in order to produce a diagnosis of their performance and potential, complemented with relevant recommendations on which owners-managers can base their decisions such as hiring new personnel or reinvesting in the company, for instance. We relate the PDG system to decision support systems and expert systems, and provide evidence showing how and why the PDG system exploits benchmarking in an original and valuable way for SMEs. Our research results show that benchmarking allows SMEs to improve their operational performance thus confirming the usefulness of benchmarking as a decision support tool, especially since traditional performance models for large enterprises do not apply well to SMEs. These results also confirm the value of the recommendations included in the PDG report concerning short-term actions to be undertaken to modify management practices.
Mechanisms of contour perception in monkey visual cortex. II. Contours bridging gaps

We have studied the mechanism of contour perception by recording from neurons in the visual cortex of alert rhesus monkeys. We used stimuli in which human observers perceive anomalous contours: A moving pair of notches in 2 bright rectangles mimicked an overlaying dark bar. For control, the notches were closed by thin lines so that the anomalous contours disappeared or half of the figure was blanked, with a similar effect. Orientation-selective neurons were studied. With the receptive fields centered in the gap, 23 of 72 (32%) neurons tested in area V2 responded to the moving “bar” even though the stimulus spared their response fields, and when the notches were closed, their responses were reduced or abolished. Likewise, when half of the figure was removed, the neurons usually failed to respond. Neurons with receptive fields within 4 degrees of the fovea signaled anomalous contours bridging gaps of 1 degree-3.5 degrees. The anomalous-contour responses were compared quantitatively with response field profiles and length-summation curves and found to exceed the predictions by linear-summation and summation- to-threshold models. Summation models also fail to explain the effect of closing lines which add only negligible amounts of light. In V1, only one of 26 neurons tested showed comparable responses, and only with a narrow gap. The others responded only when the stimulus invaded the response field and did not show the effect of closing lines, or failed to respond at all. The contour responses in V2, the nonadditivity, and the effect of closure can be explained by the previously proposed model (Peterhans et al., 1986), assuming that the corners excite end-stopped fields orthogonal to the contour whose signals are pooled in the contour neurons.
The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan

Purpose: The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma. Experimental Design: The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated. Results: MY5 and JJN3 cell lines exhibited the most sensitivity to ABT-737 with an EC50 of 0.2 and 0.5 μmol/L, respectively, with increased cell apoptosis and elevated activated caspase-3. We identified two distinct groups of myeloma patient samples that were either sensitive or resistant to the drug. Four of 15 patient bone marrow samples (27%) were highly sensitive to ABT-737 at doses of 0.25 and 0.5 μmol/L, which eliminated 80% to 90% of myeloma cells as a result of cellular apoptosis 3 days after drug treatment. ABT-737 showed a synergistic effect when combined with dexamethasone or melphalan in inducing myeloma cell death. Furthermore, the dexamethasone-resistant MM1(Dex)R myeloma cell line was highly sensitive to 0.2 μmol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 μmol/L ABT-737. ABT-737 dose dependently suppressed tumor growth in a xenograft MY5 mouse model. Conclusions: These studies show substantial antimyeloma activity of ABT-737 as a single agent or in combination with dexamethasone or melphalan and suggest a rationale for future clinical trials.
Unification in the low radio luminosity regime: evidence from optical line emission

We address the question of whether or not the properties of all low-luminosity flat spectrum radio sources, not just the obvious BL Lac objects, are consistent with them being the relativistically beamed counterparts of the low radio luminosity radio galaxies (the Fanaroff-Riley type 1, FR I). We have accumulated data on a well-defined sample of low redshift, core-dominated, radio sources all of which have one-sided core-jet structures seen with very long baseline interferometry, just like most BL Lac objects. We first compare the emission-line luminosities of the sample of core-dominated radio sources with a matched sample of FR I radio galaxies. The emission lines in the core-dominated objects are on average significantly more luminous than those in the comparison sample, inconsistent with the simplest unified models in which there is no orientation dependence of the line emission. We then compare the properties of our core-dominated sample with those of a sample of radio-emitting UGC galaxies selected without bias to core strength. The core-dominated objects fit well on the UGC correlation between line emission and radio core strength found by Verdoes Kleijn et al. The results are not consistent with all the objects participating in a simple unified model in which the observed line emission is orientation independent, though they could fit a single, unified model provided that some FR I radio galaxies have emission line regions that become more visible when viewed along the jet axis. However, they are equally consistent with a scenario in which, for the majority of objects, beaming has minimal effect on the observed core luminosities of a large fraction of the FR I population and that intrinsically stronger cores simply give rise to stronger emission lines. We conclude that FR I unification is much more complex than usually portrayed, and models combining beaming with an intrinsic relationship between core and emission line strengths need to be explored.
Botox combined with myofascial release physical therapy as a treatment for myofascial pelvic pain

Purpose To report the effects of combined onabotulinumtoxinA (Botox) injections and myofascial release physical therapy on myofascial pelvic pain (MFPP) by comparing pre- and posttreatment average pelvic pain scores, trigger points, and patient self-reported pelvic pain. Secondary outcomes were to examine posttreatment complications and determine demographic differences between patients with/without an improvement in pain. Materials and Methods This was an Institutional Review Board approved retrospective case series on women over 18 years with MFPP who received Botox and physical therapy between July 2006 and November 2014. Presence of trigger points and pelvic pain scores were determined by digital palpation of the iliococcygeus, puborectalis, obturator internus, and rectus muscles. Average pelvic pain scores (0–10) reflected an average of the scores obtained from palpation of each muscle. Self-reported improvement in pain was recorded as yes/no. Results Fifty women met the inclusion/exclusion criteria. Posttreatment, patients had lower average pelvic pain scores (3.7±4.0 vs. 6.4±1.8, p=0.005), and fewer trigger points (44% vs. 100%, p<0.001). Fifty-eight percent of patients (95% confidence interval, 44–72) noted an improvement in self-reported pain. Patients most likely to report no improvement in pain had chronic bowel disorders, while those most likely to report an improvement in pain had a history of past incontinence sling (p=0.03). Posttreatment complications included: constipation (8%), worsening urinary retention (2%), and urinary tract infection (4%). Conclusions Botox combined with soft tissue myofascial release physical therapy under anesthesia can be effective in treating women with chronic pelvic pain secondary to MFPP.
Optimal Buffer Allocation in Production Lines Using an Automata Search Tolga

In this paper, we use a learning automata search technique (LAST), which is based on game theory, to solve the optimal buffer allocation problem in production lines. We have incorporated the search algorithm within a simulator in order to optimize the performance of a production line. We have conducted experiments with this algorithm on some problems for which optimal solutions are available in the literature. We find encouraging preliminary results; the algorithm finds near optimal solutions in a relatively small number of iterations.
Estimating Individual Discount Rates in Denmark: A Field Experiment

We estimate individual discount rates with respect to time streams of money using controlled laboratory experiments. These discount rates are elicited by means of field experiments involving real monetary rewards. The experiments were carried out across Denmark using a representative sample of 268 people between 19 and 75 years of age. Individual discount rates are estimated for various households differentiated by socio-demographic characteristics such as income and age. Our conclusions are that discount rates are constant over the 12-month to 3-year horizons used in these experiments, and that discount rates vary substantially with respect to several socio-demographic variables. Hence we conclude that it would be reasonable to assume constant discount rates for specific household types, but not the same rates across all households.
Systematic Quantification of Negative Feedback Mechanisms in the Extracellular Signal-regulated Kinase (ERK) Signaling Network*

Cell responses are actuated by tightly controlled signal transduction pathways. Although the concept of an integrated signaling network replete with interpathway cross-talk and feedback regulation is broadly appreciated, kinetic data of the type needed to characterize such interactions in conjunction with mathematical models are lacking. In mammalian cells, the Ras/ERK pathway controls cell proliferation and other responses stimulated by growth factors, and several cross-talk and feedback mechanisms affecting its activation have been identified. In this work, we take a systematic approach to parse the magnitudes of multiple regulatory mechanisms that attenuate ERK activation through canonical (Ras-dependent) and non-canonical (PI3K-dependent) pathways. In addition to regulation of receptor and ligand levels, we consider three layers of ERK-dependent feedback: desensitization of Ras activation, negative regulation of MEK kinase (e.g. Raf) activities, and up-regulation of dual-specificity ERK phosphatases. Our results establish the second of these as the dominant mode of ERK self-regulation in mouse fibroblasts. We further demonstrate that kinetic models of signaling networks, trained on a sufficient diversity of quantitative data, can be reasonably comprehensive, accurate, and predictive in the dynamical sense.
Direction of arrival estimation using sparse ruler array design

In this paper, a new direction of arrival (DOA) estimation approach is addressed for the case of more sources than physical receiving antennas by considering a novel nonuniform array design. The new design utilizes the concept of minimum sparse rulers which are rulers having incomplete marks. The differences between marks in a sparse ruler cover all lags of the autocorrelation. In array processing, this set of differences can be used as a basis to construct a virtual uniform linear array having a higher number of antennas than the actual linear array. In order to attain the required rank condition of the observation matrix, the most recent spatial smoothing method is used. The MUSIC algorithm can then be applied leading to the desired high resolution result. It is also possible to compromise the resolution for a lower complexity level by exploiting the least-squares approach to generate the angular spectrum.
Increasing roughness of the human breast cancer cell membrane through incorporation of gold nanoparticles

Gold nanoparticles (AuNPs) have been proposed for use in the treatment of different types of cancer, including breast cancer. At present, neither the mechanisms of AuNP interaction with the plasma membrane surface and their delivery and intracellular distribution in cancer cells nor their effect on the plasma membrane so as to allow cell incorporation of larger amounts of AuNPs is known. The objective of this work was to study the interaction of bare 20 nm diameter AuNPs with the plasma membrane of human MCF-7 breast cancer cells, as well as their uptake, intracellular distribution, and induction of changes on the cell surface roughness. The dynamics of intracellular incorporation and the distribution of AuNPs were observed by confocal laser scanning microscopy. Changes in roughness were monitored in synchronized MCF-7 cells by atomic force microscopy high-resolution imaging at 6 hour intervals for 24 hours during a single cell cycle. The results show that bare AuNPs are capable of emitting fluorescence at 626 nm, without the need for a fluorescent biomarker, which allows monitoring their uptake and intracellular distribution until they reach the nucleus. These results are correlated with changes in cell roughness, which significantly increases at 12 hours of incubation with AuNPs, when compared with control cells. The obtained data provide bases to understand molecular processes of the use of AuNPs in the treatment of different diseases, mainly breast cancer.
Extracorporeal Free Flap Perfusion in Case of Prolonged Ischemia Time

Summary: In free flap surgery, a clinically established concept still has to be found for the reduction of ischemia-related cell damage in the case of prolonged ischemia. Although promising results using extracorporeal free flap perfusion in the laboratory have been published in the past, until now this concept has not yet paved its way into clinical routine. This might be due to the complexity of perfusion systems and a lack of standardized tools. Here, we want to present the results of the first extracorporeal free flap perfusion in a clinical setting using a simple approach without the application of a complex perfusion machinery.
Breaking down the cost of issuance : An analysis of the microstructure of emerging sovereign bond markets

1 I am especially grateful to Marc Flandreau for illuminating and useful comments on previous versions of this paper. I thank Thomas Dickinson for excellent research assistance provided during interviews in New York in 2006-2007 with market participants in the primary sovereign bond market (institutional investors and investment banks). Errors, shortcomings and views remain mine. Abstract This paper studies two key costs in the issuance of debt on the emerging sovereign bond market (1993-2007): primary market bond spreads and the fees paid to underwriters. I find bond spreads are influenced by a combination of an issuer's characteristics, external factors and the main characteristics of the issue. Underwriting fees, on the other hand, are mainly driven by issue characteristics. Furthermore, by analysing the determinants of underwriter-issuer matching, I find that issuer quality is not a key driver of matching. Other factors associated to issues characteristics and to external market conditions may affect matching. Finally, results suggest that prices (fees and spreads) differences between issues underwritten by the most reputable bank and other banks are explained by specialisation in the market following underwriters' comparative advantage for different segments of the market.
OECD GUIDELINE FOR THE TESTING OF CHEMICALS DRAFT PROPOSAL FOR A NEW GUIDELINE In Vitro Skin Irritation : Reconstructed Human Epidermis ( RhE ) Test Method

1. Skin irritation refers to the production of reversible damage to the skin following the application of a test chemical for up to 4 hours [as defined by the United Nations (UN) Globally Harmonized System of Classification and Labelling of Chemicals (GHS)](1). This Test Guideline provides an in vitro procedure that may be used for the hazard identification of irritant chemicals (substances and mixtures) in accordance with UN GHS and EU CLP Category 2 (1)(2)(3), as well as non-classified chemicals, i.e. UN GHS No-Category, for member countries or regions that do not adopt the optional UN GHS Category 3 (mild irritants). Depending on the regulatory framework and the classification system in use, this test method may be used to determine the skin irritancy of chemicals as a stand-alone replacement test for in vivo skin irritation testing, or as a partial replacement test, within a tiered testing strategy (4).
Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The “HIV Treatment as Prevention” Experience in a Canadian Setting

Background There has been renewed call for the global expansion of highly active antiretroviral therapy (HAART) under the framework of HIV treatment as prevention (TasP). However, population-level sustainability of this strategy has not been characterized. Methods We used population-level longitudinal data from province-wide registries including plasma viral load, CD4 count, drug resistance, HAART use, HIV diagnoses, AIDS incidence, and HIV-related mortality. We fitted two Poisson regression models over the study period, to relate estimated HIV incidence and the number of individuals on HAART and the percentage of virologically suppressed individuals. Results HAART coverage, median pre-HAART CD4 count, and HAART adherence increased over time and were associated with increasing virological suppression and decreasing drug resistance. AIDS incidence decreased from 6.9 to 1.4 per 100,000 population (80% decrease, p = 0.0330) and HIV-related mortality decreased from 6.5 to 1.3 per 100,000 population (80% decrease, p = 0.0115). New HIV diagnoses declined from 702 to 238 cases (66% decrease; p = 0.0004) with a consequent estimated decline in HIV incident cases from 632 to 368 cases per year (42% decrease; p = 0.0003). Finally, our models suggested that for each increase of 100 individuals on HAART, the estimated HIV incidence decreased 1.2% and for every 1% increase in the number of individuals suppressed on HAART, the estimated HIV incidence also decreased by 1%. Conclusions Our results show that HAART expansion between 1996 and 2012 in BC was associated with a sustained and profound population-level decrease in morbidity, mortality and HIV transmission. Our findings support the long-term effectiveness and sustainability of HIV treatment as prevention within an adequately resourced environment with no financial barriers to diagnosis, medical care or antiretroviral drugs. The 2013 Consolidated World Health Organization Antiretroviral Therapy Guidelines offer a unique opportunity to further evaluate TasP in other settings, particularly within generalized epidemics, and resource-limited setting, as advocated by UNAIDS.
Neurological Complications in Aortic Valve Surgery and Rehabilitation Treatment Used

Around the second decade of the twentieth century there was speculation about the possibility of cardiac surgery and its possible consequences in the central nervous system. To reduce these potential consequences as much as possible, research was carried out into three different approaches: systemic hypothermia, by placing the patient in a bath of icecold water, cross circulation between two people, and cardiopulmonary bypass (CPB) with a roller pump and an artificial oxygenator (Clau Terre, 2009). Shortly after using these procedures, it became clear there was an advantage provided by the CPB technique with an independent oxygenator and normal systemic flows that neither cross-circulation nor surface hypothermia could provide. It thus became possible to address increasingly complex congenital heart disease and ventricular septal defects, tetralogy of Fallot and other more complex examples. With the introduction of CPB, early neurological complications such as coma, cognitive impairment, strokes, etc. began to appear.