Miracle-dz/UniFAR-FTUs huggingface dataset:
Work in progress: A generic model for interactivity-intense intelligent tutor authoring tools

Intelligent Tutoring Systems (ITS) provide many features that improve learning and teaching experiences. ITS are usually interactivity-intense and content-specific. Interactivity-intense assignments are recommended for scaffolding learning, while content-specific systems can offer low flexibility regarding its possible pedagogical approaches and its uses by teachers. In order to overcome this limited flexibility, there are systems which let content-specific interactivity aside to provide authoring tools, with which teachers can author intelligent tutored assignments without programming. The generic model proposed herein intends to address this problem providing flexible authoring tools for interactivity-intense assignments with tutoring features, letting teachers benefit from the flexibility of content authoring tools as well as the interactivity usually restricted to content-specific ITS. We introduce an application framework which implements this model, which is available as free software.
Long‐term Depression of Glutamate Currents in Cultured Cerebellar Purkinje Neurons Does Not Require Nitric Oxide Signalling

Cerebellar long‐term depression (LTD) is produced when conjunctive stimulation of parallel fibre (PF) and climbing fibre (CF) inputs to a Purkinje neuron (PN) results in a prolonged decrease in the strength of the PF‐PN synapse. In cultured PNs, LTD may be induced by substituting depolarization of the PN and iontophoretic glutamate pulses for CF and PF stimulation, respectively, allowing an unambiguous analysis of post‐synaptic processes (Linden et al., Neuron, 7, 81–89, 1991). Recent studies have suggested that release of the newly described second messenger, nitric oxide, in the cerebellar molecular layer, is necessary for LTD produced in the slice preparation by PF/CF conjunctive stimulation (Shibuki and Okada, Nature, 349, 326–328, 1991) or PF/depolarization conjunctive stimulation (Crepel and Jaillard, NeuroReport, 1, 133–136, 1990). We report that LTD of glutamate currents produced without synaptic stimulation in cultured PNs is unaffected by reagents that stimulate (sodium nitroprusside) or inhibit (haemoglobin, NG‐nitro‐l‐arginine) nitric oxide signalling.
BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.

UNLABELLED Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma. SIGNIFICANCE This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.
Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery.

The diffusion of monocarboxylates such as lactate and pyruvate across the plasma membrane of mammalian cells is facilitated by a family of integral membrane transport proteins, the monocarboxylate transporters (MCTs). Currently, at least eight unique members of the MCT family have been discovered and orthologs to each have been identified in a variety of species. Four MCTs (MCT1-MCT4) have been functionally characterized. Each isoform possesses unique biochemical properties such as kinetic constants and sensitivity to known MCT inhibitors. Several fold changes in the expression of MCTs may be evoked by altered physiological conditions, yet the molecular mechanisms underlying the regulation of MCTs are poorly understood. Post-translational regulation of MCT1 and MCT4 occurs, in part, by interaction with CD147, an accessory protein that is necessary for trafficking, localization, and functional expression of these transporters. Because of the physiological importance of monocarboxylates to the overall maintenance of metabolic homeostasis, the function of MCTs is significant to several pathologies that occur with disease, such as ischemic stroke and cancer. Finally, the expression of MCT1 in the epithelium of the small intestine and colon and in the blood-brain barrier may provide routes for the intestinal and blood to brain transfer of carboxylated pharmaceutical agents and other exogenous monocarboxylates.
Version management for tightly integrated software engineering environments

The paper introduces a version management model which exploits knowledge about the contents of documents. This is in contrast to most existing models which basically consider versioned objects as flat (attributed) files. The benefits of the approach are illustrated by describing some sample operations which are not possible with a conventional model. The paper then discusses a feasible implementation of the model on top of an existing object-oriented database management system. Finally, it discusses related work and indicates how a sophisticated configuration management system is being built on top of the version management system. <<ETX>>
On application of non-negative matrix factorization for ad hoc microphone array calibration from incomplete noisy distances

We propose to use non-negative matrix factorization (NMF) to estimate the unknown pairwise distances and reconstruct a distance matrix for microphone array position calibration. We develop new multiplicative update rules for NMF with incomplete input matrix that take into account the symmetry of the distance matrix. Additionally, we develop a convex matrix completion method which is related to an l2-regularized symmetric NMF. Thorough experiments demonstrate that the proposed methods lead to substantial improvement over the state-of-the-art techniques in a wide range of signal-to-noise and unknown-distance ratios. The convex symmetric matrix completion method was found to be the most robust method with less computational cost.
Dynamic software updates: a VM-centric approach

Software evolves to fix bugs and add features. Stopping and restarting programs to apply changes is inconvenient and often costly. Dynamic software updating (DSU) addresses this problem by updating programs while they execute, but existing DSU systems for managed languages do not support many updates that occur in practice and are inefficient. This paper presents the design and implementation of Jvolve, a DSU-enhanced Java VM. Updated programs may add, delete, and replace fields and methods anywhere within the class hierarchy. Jvolve implements these updates by adding to and coordinating VM classloading, just-in-time compilation, scheduling, return barriers, on-stack replacement, and garbage collection. Jvolve, is safe: its use of bytecode verification and VM thread synchronization ensures that an update will always produce type-correct executions. Jvolve is flexible: it can support 20 of 22 updates to three open-source programs--Jetty web server, JavaEmailServer, and CrossFTP server--based on actual releases occurring over 1 to 2 years. Jvolve is efficient: performance experiments show that incurs no overhead during steady-state execution. These results demonstrate that this work is a significant step towards practical support for dynamic updates in virtual machines for managed languages.
Absorption and Distribution of Deuterium-Labeled trans-and cis-11-Octadecenoic Acid in Human Plasma and Lipoprotein Lipids

Triglycerides of deuterium-labeled trans-11-, trans11-cis-11and cis-9-octadecenoic acid (l1t-18:1-2H, 11c-18:1-2H) were simultaneously fed to two young adult male subjects. Plasma lipids from blood samples collected periodically for 48 hr were analyzed by gas chromatography-mass spectroscopy. The results indicate (i) the 1.H1-18:1-2H acids and 9c-18:12H were equally well absorbed; (ii) relative turnover rates were higher for the ~11-18-1-2H acids in plasma triglycerides; (iii) incorporation of the Ml18:1-2H acids into plasma phosphatidylcholine was similar to 9c-18:1-2H, but distribution at the 1and 2-acyl positions was substantially different; (iv) esterification of cholesterol with 11t-18:1 was extremely low; (v) chain shortening of the MI-18:1-2H acids was 2-3 times greater than for 9c-18:1-2H; (vi) no evidence for desaturation or elongation of the 18:1·2H acids was detected; and (vii) a 40% isotopic dilution of the 18:1-2H acids in the chylomicron triglyceride fraction indicated the presence of a substantial intestinal triglyceride pool. Based on our present knowledge, these metabolic results for ~11­ 18:1 acids present in hydrogenated oils and animal fats indicate that the ~11 isomers are no more likely than 9c-18:1 to contribute to dietary fat-related health problems. Lipids 21, 589-595 (1986).
Benthic Primary Production Budget of a Caribbean Reef Lagoon (Puerto Morelos, Mexico)

High photosynthetic benthic primary production (P) represents a key ecosystem service provided by tropical coral reef systems. However, benthic P budgets of specific ecosystem compartments such as macrophyte-dominated reef lagoons are still scarce. To address this, we quantified individual and lagoon-wide net (Pn) and gross (Pg) primary production by all dominant functional groups of benthic primary producers in a typical macrophyte-dominated Caribbean reef lagoon near Puerto Morelos (Mexico) via measurement of O2 fluxes in incubation experiments. The photosynthetically active 3D lagoon surface area was quantified using conversion factors to allow extrapolation to lagoon-wide P budgets. Findings revealed that lagoon 2D benthic cover was primarily composed of sand-associated microphytobenthos (40%), seagrasses (29%) and macroalgae (27%), while seagrasses dominated the lagoon 3D surface area (84%). Individual Pg was highest for macroalgae and scleractinian corals (87 and 86 mmol O2 m−2 specimen area d−1, respectively), however seagrasses contributed highest (59%) to the lagoon-wide Pg. Macroalgae exhibited highest individual Pn rates, but seagrasses generated the largest fraction (51%) of lagoon-wide Pn. Individual R was highest for scleractinian corals and macroalgae, whereas seagrasses again provided the major lagoon-wide share (68%). These findings characterise the investigated lagoon as a net autotrophic coral reef ecosystem compartment revealing similar P compared to other macrophyte-dominated coastal environments such as seagrass meadows and macroalgae beds. Further, high lagoon-wide P (Pg: 488 and Pn: 181 mmol O2 m−2 lagoon area d−1) and overall Pg:R (1.6) indicate substantial benthic excess production within the Puerto Morelos reef lagoon and suggest the export of newly synthesised organic matter to surrounding ecosystems.
Improvement of fluvastatin bioavailability by loading on nanostructured lipid carriers

The aim of this study is to prepare fluvastatin nanostructured lipid carriers (FLV-NLCs) in order to find an innovative way to alleviate FLV-associated disadvantages. The limitations include poor solubility and extensive first-pass metabolism, resulting in low (30%) bioavailability and short elimination half-life (1–3 hours). FLV-NLCs were prepared by hot emulsification–ultrasonication method. Ten runs were created by three-level factorial design (32) to optimize FLV-NLCs formulation process. In this study, two factors, four responses, and three-level factorial design were endorsed. The studied variables were lipid:oil ratio (X1) and sonication time (X2). However, the responses parameter determined the particle size (Y1, nm), entrapment efficiency percent (EE%, Y2), particles zeta potential (Y3), and 80% of the drug release after 24 hours (X4). Furthermore, stability and in vivo pharmacokinetics were studied in rats. The optimized consisted formula had an average particle size of 165 nm with 75.32% entrapment efficiency and 85.32% of drug released after 24 hours, demonstrating a sustaining drug release over 24 hours. An in vivo pharmacokinetic study revealed enhanced bioavailability by >2.64-fold, and the mean residence time was longer than that of FLV. We concluded that NLCs could be promising carriers for sustained/prolonged FLV release with enhanced oral bioavailability.
Role of the Glycine Betaine and Carnitine Transporters in Adaptation of Listeria monocytogenes to Chill Stress in Defined Medium

ABSTRACT The food-borne pathogen Listeria monocytogenes proliferates at refrigeration temperatures, rendering refrigeration ineffective in the preservation of Listeria-contaminated foods. The uptake and intracellular accumulation of the potent compatible solutes glycine betaine and carnitine has been shown to be a key mediator of the pathogen's cold-tolerant phenotype. To date, three compatible solute systems are known to operate in L. monocytogenes: glycine betaine porter I (BetL), glycine betaine porter II (Gbu), and the carnitine transporter OpuC. We investigated the specificity of each transporter towards each compatible solute at 4°C by examining mutant derivatives of L. monocytogenes 10403S that possess each of the transporters in isolation. Kinetic and steady-state compatible solute accumulation data together with growth rate experiments demonstrated that under cold stress glycine betaine transport is primarily mediated by Gbu and that Gbu-mediated betaine uptake results in significant growth stimulation of chill-stressed cells. BetL and OpuC can serve as minor porters for the uptake of betaine, and their action is capable of providing a small degree of cryotolerance. Under cold stress, carnitine transport occurs primarily through OpuC and results in a high level of cryoprotection. Weak carnitine transport occurs via Gbu and BetL, conferring correspondingly weak cryoprotection. No other transporter in L. monocytogenes 10403S appears to be involved in transport of either compatible solute at 4°C, since a triple mutant strain yielded neither transport nor accumulation of glycine betaine or carnitine and could not be rescued by either osmolyte when grown at that temperature.
Molecular Endoscopic Ultrasound for Diagnosis of Pancreatic Cancer

Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer.
Dissection of the odontoblast differentiation process in vitro by a combination of FGF1, FGF2, and TGFβ1

Dental papillae (DP) isolated from first lower molars of 17‐day‐old mouse embryos were cultured in the presence of combinations of the following growth factors: FGF1, FGF2, and TGFβ1. After 6 days in culture, only the DP treated with FGF1+TGFβ1 contained differentiated odontoblast‐like cells at the periphery of the explants, and these cells secreted extracellular matrix similar to predentin. Surprisingly, treatments with FGF2+TGFβ1 induced cell polarization at the surface of the explants but no matrix secretion was observed. Electron microscopy and histochemical analysis of odontoblast markers showed that differentiated cells induced by FGF1+TGFβ1 exhibited cytological features of functional odontoblasts with matrix vesicle secretion and mineral formation, positive alkaline‐phosphatase activity, and type‐I collagen production. DP cultured in the presence of FGF2+TGFβ1 showed cell polarization and long and thin cell processes containing matrix vesicles; however, type‐I collagen secretion was not detected and alkaline‐phosphatase activity was completely inhibited. Our results indicate that, in our culture system, exogenous combinations of FGF1, FGF2, and TGFβ1 interact with preodontoblasts and induce cell polarization or differentiation, which can be studied separately in vitro. Thus, FGF1 and TGFβ1 do have a synergic effect to promote morphological and functional features of differentiated odontoblasts whereas FGF2 seems to modulate TGFβ1 action, causing morphological polarization of preodontoblasts but limiting the functional activity of these cells in terms of type‐I collagen secretion and alkaline‐phosphatase activity. Dev Dyn 2000;218:480–489. © 2000 Wiley‐Liss, Inc.
Marijuana and T Iymphocyte rosettes

The effect of marijuana smoking on sheep cell rosetting properties of both early (active) and total T lymphocytes was studied in vitro. Significantly fewer active rosettes were formed by T cells from a population of 35 who appeared to be chronic marijuana smokers than the 34 controls. The late, or cold‐enhanced rosettes formed by smokers and nonsmokers were similar, suggesting that similar numbers of rosette‐forming T cells were present in the peripheral blood of smokers. These data suggest that marijuana smoking may affect the function of a subpopulation of T lymphocytes, identified by their capacity to form early rosettes, possibly by affecting these cell membranes.
Proline Residues within Spacer Peptide p1 Are Important for Human Immunodeficiency Virus Type 1 Infectivity, Protein Processing, and Genomic RNA Dimer Stability

ABSTRACT The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.
The anisotropic elastoplastic behaviour of perforated sheet metal

In this report the anisotropic elastoplastic behaviour of perforated sheet metal is investigated. Due to the perforation, which consists of a large number of small rectangular holes positioned in a regular pattern, the mechanical behaviour of the sheet is strongly anisotropic. All considerations are confined to geometricallinarity (small displacements, rotations and strains). A practical application of the above indicated problem, is the drawing process of shadow masks used in colour television tubes. The shape of a flat mask after drawing approximately follows the glass screen panel. From electron optical requirements both the shape and the position of a hole with respect to the screen panel are important. Therefore the drawing process has to be reproducible within relatively small tolerances. The prediction of the stress and strain distribution over the sheet during the stretching part of the drawing process is the main goal to be achieved in this report. An outline of this report is given below. In chapter 1 an overview of the general elastoplastic continuum theory is treated. This theory is mainly based on [2]. The rank four continuum elastoplastic tensor is derived. Although this (non-consistent) tensor is not very suitable in iterative solution procedures as used in finite element codes, it is often implemented in commercial FEM packages. As a special case of the theory presented in chapter 1, chapter 2 deals with the one dimensional theory. This theory is well suited to illustrate the basic ideas and methods in computational elastoplastics. Further the theory forms the basis of the return mapping algorithm which is developed for the problem under consideration. The numerical implementation in FEM is discussed. The theory in chapter 2 is mainly based on the work of Simo (e.g. [10] and [11]). In chapter 3 the elastoplastic behaviour of the shadow mask is investigated via numerical computations on a representive part of the sheet. The suitability of the anisotropic Hill criterion, standard available in some commercial FEM packages, is examined. In chapter 4 a new elastoplastic algorithm is presented. This algorithm is implemented in the FEM package MARC. In chapter 5 some numerical benchmarks with the new algorithm are carried out. The sheet drawing on a double sided curved punch is hereby included. The main purpose of these examples is to see whether numerical convergence can be obtained, rather then an extensive interpretation and verification of the computed results.