Miracle-dz/UniFAR-FTUs huggingface dataset:
Head and Neck Squamous-Cell Cancer and its Association with Polymorphic Enzymes of Xenobiotic Metabolism and Repair

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene–environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (–70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (–70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64–71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18–63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.
Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

BACKGROUND The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.
Personalizing Pedestrian Accessible way-finding with mPASS

This work presents users evaluation of mPASS (mobile Pervasive Accessibility Social Sensing), a system to provide citizens with personalized accessible way finding. mPASS collects data both from crowdsourcing and from crowdsensing, in order to obtain a detailed georeferenced description of the urban environment accessibility. It combines these data with a user profile, with the aim of tailoring paths and maps to users' preferences and needs. To drive the design of our application, we assessed our first proposal through a preliminary questionnaire, showing mPASS mockups to 60 uses with disability and elderly users. On the basis of the results of such questionnaire, we developed a prototype and we tested it with a small group of pilot users. This paper presents results of both the assessments.
ETS-1 Transcription Factor Binds Cooperatively to the Palindromic Head to Head ETS-binding Sites of the Stromelysin-1 Promoter by Counteracting Autoinhibition*

Stromelysin-1 (matrix metalloproteinase-3) is a member of the matrix metalloproteinase family. Regulation of its gene expression is critical for tissue homeostasis. Patterns of increased co-expression of stromelysin-1 and ETS-1 genes have been observed in pathological processes. Stromelysin-1 promoter is transactivated by ETS proteins through two palindromic head to head ETS-binding sites, an unusual configuration among metalloproteinase promoters. By using surface plasmon resonance, electrophoretic mobility shift assay, and photo-cross-linking, we showed that full-length human ETS-1 (p51) binds cooperatively to the ETS-binding site palindrome of the human stromelysin-1 promoter, with facilitated binding of the second ETS-1 molecule to form an ETS-1·DNA·ETS-1 ternary complex. The study of N-terminal deletion mutants allowed us to conclude that cooperative binding implied autoinhibition counteraction, requiring the 245–330-residue region of the protein that is encoded by exon VII of the gene. This region was deleted in the natural p42 isoform of ETS-1, which was unable to bind cooperatively to the palindrome. Transient transfection experiments showed a good correlation between DNA binding and promoter transactivation for p51. In contrast, p42 showed a poorer transactivation, reinforcing the significance of cooperative binding for full transactivation. It is the first time that ETS-1 was shown to be able to counteract its own autoinhibition.
Single-Cell Characterization of Retrograde Signaling by Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is a key regulator of hippocampal synaptic plasticity in the developing and adult nervous system. It can be released from pyramidal neuron dendrites in an activity-dependent manner and has therefore been suggested to serve as a signal that provides the retrograde intercellular communication necessary for Hebbian plasticity and hippocampal-dependent learning. Although much has been learned about BDNF function by field stimulation of hippocampal neurons, it is not known whether moderate action potential-independent depolarization of single cells is capable of releasing sufficient BDNF to influence transmission at individual synapses. In this study, we show directly at the single-cell level that such modulation can occur. By using K-252a, anti-BDNF antibody, and interruption of regulated release, we confirm a model in which postsynaptic depolarization elicits calcium-dependent release of BDNF that diffuses retrogradely and enhances presynaptic transmitter release.
CCR2 Deficiency Decreases Intimal Hyperplasia After Arterial Injury

Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2−/− mice showed a 61.4% reduction (P <0.01) in intimal area and a 62% reduction (P <0.05) in intima/media ratio when compared with CCR2+/+ littermates. The response of CCR2+/− mice was not significantly different from that of CCR2+/+ mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2−/− mice when compared with CCR2+/+ littermates (P <0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2−/− or CCR2+/+ mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury.
Chorioretinal anastomosis after radial optic neurotomy for central retinal vein occlusion.

OBJECTIVES To evaluate the incidence of chorioretinal anastomosis after radial optic neurotomy and to determine its effect on visual acuity and foveal thickness in patients with central retinal vein occlusion. METHODS We conducted a prospective, uncontrolled, interventional study of 14 patients with preoperative visual acuities below 20/125. Pars plana vitrectomy and radial optic neurotomy were performed. Fluorescein angiography and optical coherence tomography were used to monitor the evolution of macular edema. RESULTS All patients underwent radial optic neurotomy with no major complications. Eight patients (57.1%) gained 1 or more lines of visual acuity while the visual acuity of 6 patients (42.9%) improved by 2 or more lines (mean visual acuity, 20/80; P<.001) (mean visual acuity gain, 3 lines). The decrease in macular thickness was shown to be statistically significant (P<.001) (median, 282 microm). Retinochoroidal shunts developed in 6 eyes (42.9%) at the site of the radial optic neurotomy. MAIN OUTCOME MEASURES Improvement in visual acuity and a decrease in foveal thickness seen on optical coherence tomography. CONCLUSIONS Surgical decompression of central retinal vein occlusion via radial optic neurotomy seems to be a promising technique that improves or at least stabilizes the course of severe central retinal vein occlusion. Improvement may occur because of optic nerve decompression, vitrectomy, and by inducing new chorioretinal shunts that drain retinal circulation to the choroid and accelerate resolution of retinal edema.
Significantly increased antibody response to heterogeneous nuclear ribonucleoproteins in cerebrospinal fluid of multiple sclerosis patients but not in patients with human T-lymphotropic virus type I—associated myelopathy/tropical spastic paraparesis

It has been reported that antibodies (Abs) against heterogeneous nuclear ribonucleoproteins (hnRNPs) are associated with human T-lymphotropic virus type I (HTLV-I)—associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). However, these studies were done under nonmasked conditions. In order to determine whether Abs against hnRNPs associate with HAM/TSP and MS, the authors assayed Abs against two major hnRNPs, hnRNP A1 and A2/B1, in 105 cerebrospinal fluid (CSF) samples under fully masked conditions. Samples included 40 cases of HAM/TSP, 28 of MS, and 37 of other neurological diseases. Anti-hnRNP A1 Abs, and especially anti-hnRNP A2/B1 Abs, were found significantly more often in the CSF of MS patients than in other groups. However, there was no difference in the incidence of anti-hnRNP A1 Abs between HAM/TSP and other disease groups.
A dynamic model of the windlass mechanism of the foot: evidence for early stance phase preloading of the plantar aponeurosis

SUMMARY In the present study we have estimated the temporal elongation of the plantar aponeurosis (PA) during normal walking using a subject-specific multi-segment rigid-body model of the foot. As previous studies have suggested that muscular forces at the ankle can pre-load the PA prior to heel-strike, the main purpose of the current study was to test, through modelling, whether there is any tension present in the PA during early stance phase. Reflective markers were attached to bony landmarks to track the kinematics of the calcaneus, metatarsus and toes during barefoot walking. Ultrasonography measurements were performed on three subjects to determine both the location of the origin of the PA on the plantar aspect of the calcaneus, and the radii of the metatarsal heads. Starting with the foot in a neutral, unloaded position, inverse kinematics allowed calculation of the tension in the five slips of the PA during the whole duration of the stance phase. The results show that the PA experienced tension significantly above rest during early stance phase in all subjects (P<0.01), thus providing support for the PA-preloading hypothesis. The amount of preloading and the maximum elongation of the slips of the PA decreased from medial to lateral. The mean maximum tension exerted by the PA was 1.5 BW (body weight) over the three subjects.
Bridging the gap between theory and implementation in cognitive networks: developing reasoning in today's networks

Communication networks are becoming increasingly complex and dynamic. The networking paradigm commonly employed, on the other hand, has not changed over the years, and, as a result, performs poorly in today's environments. Only very recently, a new paradigm named cognitive networking has been devised with the objective to make networks more intelligent, thereby overcoming traditional limitations and potentially achieving better performance. According to such vision, networks should be able to monitor themselves, reason upon the environment, act towards the achievement of specific goals and learn from experience. Thus far, several cognitive network architectures have been conceived and proposed in the literature, but, despite researchers seem to agree on the need for a holistic approach, their architectures pursue such a global vision only in part, as they do not consider networks nor network nodes in their entirety. In the present work, we analyze the aspects to be tackled in order to enable this holistic view and propose to base reasoning on both intra- and inter-node interactions, with the ultimate aim to devise a complete cognitive network architecture. After a thorough analysis of advantages and drawbacks of generic reasoning framework, we select the most apt to form the basis on which to build the cognitive network we envision. We first formalize its application in network environments, by determining the steps to follow in the process to equip traditional network with cognitive capabilities. Then, we shift the focus from the design side to the implementation side, by identifying the problems that could be faced when realizing such a network, and by proposing a set of optional refinements that could be taken into account to further improve the performance in some specific situations. Finally, we tackle the problem of reducing the time needed for the cognitive process to reason. Validation through simulations shows that explicitly considering cross-layer intra- and inter-node interactions when reasoning has a twofold effect. First, it leads to better performance levels than those that can be achieved by today's non-intelligent networks, and second, it helps to better understand existent causal relationships between variables in a network.
Development and Stem Cells Research Article

INTRODUCTION The midbrain dopaminergic (mDA) neuron has been a prime target in stem cell research and developmental neurobiology owing to its association with Parkinson's disease. Recent years have witnessed a rapid advancement in understanding the regulatory cascade that governs ventral midbrain neuroepithelial cell fate specification and the differentiation and maintenance of mDA neurons (Andersson Overexpression of mDA transcription factors offers a valid strategy for generating DA neurons from embryonic stem cells (ESCs) that, during development, the transcription factors employed act only on regionally specified mDA-competent ventral midbrain progenitors, but the extent to which such progenitor populations can be generated from pluripotent stem cells using currently available paradigms remains unclear. Several studies indicate that ESCs give rise to forebrain-like identity under defined conditions or to heterogeneous progenitor phenotypes, which exhibit a broad
Length‐related changes in activation threshold and wave form of motor units in human masseter muscle.

Action potentials of single motor units in the human masseter muscle were recorded during isometric contractions at different muscle lengths over most of the working range of the temporomandibular articulation. The shape of the unit potential wave form changed progressively as the muscle length changed. This was considered to be due principally to a change in the geometric relationship of the electrode to the muscle fibres at various muscle lengths. The recruitment thresholds for all units increased sharply when the jaw opening approached the maximal gape. The pattern of change of unit thresholds with muscle length closely paralleled the curve of length versus passive tension for the combined jaw‐closing muscles, temporomandibular articulation and associated soft tissues. It was concluded that the change in unit recruitment thresholds with length is likely to be a consequence of the length‐passive tension relationship of the muscles, joint and soft tissues. The results of this study indicate that attempts to assign masseter motor units to one or other of the accepted functional categories on the basis of recruitment force or wave form only are unlikely to give reliable results.
Salt-Inducible Kinase 2 Regulates Mitotic Progression and Transcription in Prostate Cancer

Salt-inducible kinase 2 (SIK2) is a multifunctional kinase of the AMPK family that plays a role in CREB1-mediated gene transcription and was recently reported to have therapeutic potential in ovarian cancer. The expression of this kinase was investigated in prostate cancer clinical specimens. Interestingly, auto-antibodies against SIK2 were increased in the plasma of patients with aggressive disease. Examination of SIK2 in prostate cancer cells found that it functions both as a positive regulator of cell-cycle progression and a negative regulator of CREB1 activity. Knockdown of SIK2 inhibited cell growth, delayed cell-cycle progression, induced cell death, and enhanced CREB1 activity. Expression of a kinase-dead mutant of SIK2 also inhibited cell growth, induced cell death, and enhanced CREB1 activity. Treatment with a small-molecule SIK2 inhibitor (ARN-3236), currently in preclinical development, also led to enhanced CREB1 activity in a dose- and time-dependent manner. Because CREB1 is a transcription factor and proto-oncogene, it was posited that the effects of SIK2 on cell proliferation and viability might be mediated by changes in gene expression. To test this, gene expression array profiling was performed and while SIK2 knockdown or overexpression of the kinase-dead mutant affected established CREB1 target genes; the overlap with transcripts regulated by forskolin (FSK), the adenylate cyclase/CREB1 pathway activator, was incomplete. Implications: This study demonstrates that targeting SIK2 genetically or therapeutically will have pleiotropic effects on cell-cycle progression and transcription factor activation, which should be accounted for when characterizing SIK2 inhibitors. Mol Cancer Res; 13(4); 620–35. ©2014 AACR.
A combined loglinear/MDS model for mapping journals by citation analysis

Loglinear analysis of interjournal citations permits objective evaluation of the network of journals in and around a discipline. Citation frequency is modeled as a probabilistic Poisson process, with its expectation being the product of the “influence” of the cited journal on the citing journal, and of the citing journal’s “receptivity. ” The “influence” is itself modeled as the product of the cited journal’s “importance,” and of the “similarity” between the two journals. Loglinear analysis is used to extract maximum likelihood estimates of journals’ importances and receptivitles and a matrix of similarities from their citation matrix. Multidimensional scaling of the derived similarities matrix provides an interpretable map of the journais’ relative configuration. As an application of the method, the major marketing journals are mapped relative to journals of related disciplines, showing the influence that the psychology and management disciplines have had upon the marketing literature.
Pressure effects on the composition and thermal behavior of lipids from the deep-sea thermophile Methanococcus jannaschii

The deep-sea archaeon Methanococcus jannaschii was grown at 86 degrees C and under 8, 250, and 500 atm (1 atm = 101.29 kPa) of hyperbaric pressure in a high-pressure, high-temperature bioreactor. The core lipid composition of cultures grown at 250 or 500 atm, as analyzed by supercritical fluid chromatography, exhibited an increased proportion of macrocyclic archaeol and corresponding reductions in aracheol and caldarchaeol compared with the 8-atm cultures. Thermal analysis of a model core-lipid system (23% archaeol, 37% macrocyclic archaeol, and 40% caldarchaeol) using differential scanning calorimetry revealed no well-defined phase transition in the temperature range of 20 to 120 degrees C. Complementary studies of spin-labeled samples under 10 and 500 atm in a special high-pressure, high-temperature electron paramagnetic resonance spectroscopy cell supported the differential scanning calorimetry phase transition data and established that pressure has a lipid-ordering effect over the full range of M. jannaschii's growth temperatures. Specifically, pressure shifted the temperature dependence of lipid fluidity by ca. 10 degrees C/500 atm.
Assessing and Interpreting Object-Oriented Software Complexity with Structured and Independent Metrics

Object-oriented software complexity is difficult to assess due to its manifold influences from cognition science or algorithmic complexity theory. A practical process for a structured complexity assessment is presented in this paper. It starts with considerations for measurement and data preparation. Using mathematical transformation techniques, independent complexity metrics are gained. With these results, complexity aspects of a software system can be defined. This makes a complexity comparison through system classes possible, which helps getting an overview on large systems. These process steps are then illustrated with an industrial example.