Miracle-dz/UniFAR-FTUs huggingface dataset:
The Na+/H+ Exchanger NHE6 Modulates Endosomal pH to Control Processing of Amyloid Precursor Protein in a Cell Culture Model of Alzheimer Disease*

Background: NHE6 transports protons out of the endosomal lumen in exchange for cations. Results: Localization and processing of amyloid precursor protein are altered by NHE6 expression. Conclusion: NHE6 controls Aβ production and is down-regulated in Alzheimer disease brains. Significance: NHE6 and related orthologs may be risk factors for Alzheimer disease. Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na+/H+ exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps. Like APP, NHE6 expression was induced upon differentiation of SH-SY5Y neuroblastoma cells and localized to an endosomal compartment. Therefore, we investigated whether NHE6 expression altered APP localization and processing in a stably transfected cell culture model of human APP expression. We show that co-expression with NHE6 or treatment with the Na+/H+ ionophore monensin shifted APP away from the trans-Golgi network into early and recycling endosomes in HEK293 cells. NHE6 alkalinized the endosomal lumen, similar to monensin, and significantly attenuated APP processing and Aβ secretion. In contrast, Aβ production was elevated upon NHE6 knockdown. We show that NHE6 transcript and protein levels are lowered in Alzheimer brains relative to control. These findings, taken together with emerging genetic evidence linking endosomal Na+/H+ exchangers with Alzheimer disease, suggest that proton leak pathways may regulate Aβ generation and contribute to disease etiology.
Random coding techniques for nonrandom codes

This work provides techniques to apply the channel coding theorem and the resulting error exponent, which was originally derived for totally random block-code ensembles, to ensembles of codes with less restrictive randomness demands. As an example, the random coding technique can even be applied for an ensemble that contains a single code. For a specific linear code, we get an upper bound for the error probability, which equals Gallager's (1968) random coding bound, up to a factor determined by the maximum ratio between the weight distribution of the code, and the expected random weight distribution.
Targeting Mammalian Target of Rapamycin Synergistically Enhances Chemotherapy-Induced Cytotoxicity in Breast Cancer Cells

Purpose: The serine-threonine kinase mammalian target of rapamycin has emerged as a potential target for cancer therapy. Rapamycin and rapamycin analogs are undergoing clinical trials and have induced clinical responses in a subgroup of patients. Rapamycin has also been reported to enhance the efficacy of several cytotoxic agents. The aim of this study was to determine the nature of the interactions between rapamycin and chemotherapeutic agents used as first- and second-line agents against breast cancer. Experimental Design: We performed a multiple drug effect/combination index isobologram analysis in cells sensitive and resistant to rapamycin alone in vitro, and we evaluated the in vivo efficacy of combination therapy in a rapamycin-sensitive model. Results: In vitro, synergistic interactions were observed in combinations with paclitaxel, carboplatin, and vinorelbine. Additive effects were observed in combinations with doxorubicin and gemcitabine. Rapamycin dramatically enhanced paclitaxel- and carboplatin-induced apoptosis. This effect was sequence dependent and mediated at least partly through caspase activation. Furthermore, rapamycin enhanced chemosensitivity to paclitaxel and carboplatin in HER2/neu-overexpressing cells, suggesting a potential approach to these poorly behaving tumors. Cell lines that are resistant to the growth-inhibitory effect of rapamycin were also resistant to rapamycin-mediated chemosensitization. In vivo, rapamycin combined with paclitaxel resulted in a significant reduction in tumor volume compared with either agent alone in rapamycin-sensitive tumors. Conclusions: Rapamycin potentiates the cytotoxicity of selected chemotherapeutic agents in cell lines sensitive to the effects of rapamycin due to aberrations in the phosphatidylinositol 3′-kinase/Akt pathway, suggesting that combination therapy may be effective in patients selected for aberrations in this pathway.
Reducing dominance in multiple-mouse learning activities

In resource-constrained classrooms in the developing world, it is common for several students to share each computer. Unfortunately, dominance behavior often naturally emerges in these situations, when one child monopolizes the mouse and keyboard. One way to mitigate this phenomenon is by providing each child with a mouse and a corresponding on-screen cursor so that everyone can interact. Though such multiple-mouse configurations reduce the possibility of total domination by one individual, they do not automatically eliminate dominance behavior completely. We propose the use of a design for small-group learning on shared computers based on enforced turn-taking in a split-screen, multiple-mouse environment. In an evaluation with 104 rural schoolchildren in India, we found that dominance behavior was indeed reduced through these design choices.
Overexpression of p 27 Klpl Inhibits the Growth of Both Normal and Transformed Human Mammary Epithelial Cells 1

We previously reported increased expression of p27Klpl in a series of human breast cancer cell lines, as compared to cell lines established from normal mammary epithelial cells. These data were surprising because this protein exerts a growth-inhibitory function in normal cells, and p27Klpl has been proposed as a candidate tumor suppressor gene. A possible explanation for the paradoxical increase in p27Klpl in the breast cancer cell lines is that they had become refractory to the inhibitory effects of this protein. To address this question, here, we transfected the MCF7 breast cancer cell line and the MCF10F nontumorigenic mammary epithelial cell line with a vector containing the p27Klpl cDNA to obtain derivatives that express increased levels of p27Klpl. The increased expression of p27Kipl in both of these cell lines was associated with lengthening of the Gt phase, an increase in the doubling time, a decreased saturation density, and a decreased plating efficiency. In the MCF7 cells, anchorage-independent growth and in vivo tumorigenicity were also suppressed. These effects were associated with decreased cyclin E-associated in vitro kinase activity in both cell lines. The increased expression of p27Klpl was associated with a decreased level of expression of cyclin Dl in the MCF10F cells but an increased level of the cyclin Dl protein in the MCF7 cell line. Both derivatives expressed slightly increased levels of the cyclin E protein. Thus, breast cancer cells are still responsive to p27Klpl-mediated inhibi tion of cell growth despite the high basal level of this protein. These results suggest that therapeutic strategies that further increase the level of ex pression of p27K>plor mimic its activity might be useful in cancer therapy.
Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction.

BACKGROUND Apart from its established effects on vessel patency after percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor blockade by abciximab may improve myocardial perfusion by inhibition of the interaction of platelets and platelet aggregates with the microvasculature. We investigated the effect of abciximab with stent placement in acute myocardial infarction. METHODS AND RESULTS In a prospective randomized trial, patients undergoing stenting in acute myocardial infarction within 48 hours after onset of symptoms were randomly assigned to receive either standard-dose heparin or abciximab plus low-dose heparin. Immediately after the procedure and at 14-day angiographic follow-up, we assessed flow velocity in the recanalized vessel with the Doppler wire and regional wall motion by the centerline method. End points were changes in papaverine-induced peak flow velocities and in wall motion indices. We assigned 98 patients to standard heparin and 102 to abciximab. We obtained 152 paired flow measurements and 151 paired left ventricular function studies. Residual stenoses of the treated lesions did not differ between the 2 groups. Improvement of peak flow velocity (mean [95% CI]: 18.1 cm/s [13.6 to 22.6 cm/s], n=80, versus 10.4 cm/s [5.4 to 15.4 cm/s], n=72, P=0.024) and wall motion index (0.44 SD/chord [0.29 to 0.59 SD/chord], n=79 versus 0. 15 SD/chord [0.00 to 0.30 SD/chord], n=72, P=0.007) was significantly greater in patients assigned to abciximab than in those on heparin alone. At follow-up, the abciximab group had a higher global left ventricular ejection fraction than the heparin group (62% [59% to 65%] versus 56% [53% to 59%], P=0.003). CONCLUSIONS Abciximab had important effects beyond the maintenance of large-vessel patency. It improved the recovery of microvascular perfusion and concomitantly enhanced the recovery of contractile function in the area at risk.
Multiple urban and asthma-related risks and their association with asthma morbidity in children.

OBJECTIVE To determine whether a multi-dimensional cumulative risk index (CRI) is a stronger predictor of asthma morbidity in urban, school-aged children with asthma, than poverty or severity alone. METHODS A total of 163 children with asthma, ages 7-15 years (42% female; 69% ethnic minority) and their primary caregivers completed interview-based questionnaires, focusing on potential cultural, contextual, and asthma-specific risks that can impact asthma morbidity. RESULTS Higher levels of cumulative risks were associated with more asthma morbidity, after controlling for poverty level or asthma severity. Analyses by ethnic group and subgroup also supported the relationship between the CRI and specific indices of asthma morbidity. CONCLUSIONS This study demonstrates the utility of multiple-dimensional risk models for predicting variations in asthma morbidity in urban children. Research efforts with urban families who have children with asthma need to consider the context of urban poverty as it relates to children's cultural backgrounds and specific asthma outcomes.
Design, synthesis and processing of PVDF‐based dielectric polymers

Due to the appealing piezoelectric, pyroelectric, and ferroelectric (FE) properties, poly(vinylidene fluoride) (PVDF)-based dielectric polymers have been attracting great attention from both the academic and industrial communities. Depending on the molecular structure and the processing method, PVDF-based dielectric polymers can exhibit rich dielectric polarisation behaviours covering normal FE, relaxor FE, anti-FE-like and linear dielectric responses, which enables a wide spectrum of application fields such as non-volatile memories, piezoelectric and pyroelectric sensors, actuators, electrocaloric refrigeration, and film capacitors. In this study, the authors first briefly introduce the current practical/promising applications of PVDF-based dielectric polymers, and the corresponding optimum dielectric polarisation behaviour and crystal structure are proposed accordingly. The chemical synthesis and modification strategies for obtaining various fluoropolymers beyond PVDF homopolymer are then summarised with an emphasis on the relationship between the molecular structure and the dielectric polarisation behaviour. In addition, the effect of processing methods on the crystal structure and dielectric properties of the PVDF-based polymers is discussed. Finally, some newly developed processing techniques applicable to PVDF-based polymers are described.
Preparation of Polymer Membranes by In Situ Interfacial Polymerization

Membranes currently have a wide application in sewage treatment and water purification processes, in seawater desalination, and in various technological processes where high product purity is required. Deposition of an ultrathin skin layer of TFC (thin-film composite) and TFN (thin-film nanocomposite) onto the surface of membranes is discussed in this article. Their presence improves membrane properties such as retention of impurities and permeability. The aim of this paper is to present the current state of knowledge about the methods of preparing composite and nanocomposite membranes. The properties of the prepared TFC membranes can be modified by changing the type and concentration of the reacting monomers, and the physical conditions in which the membrane preparation process itself is carried out are also significant. Additionally, the properties of TFN membranes can be further modified with nanocomposites. The membranes are characterized by different properties not only because they have nanoparticles in their structure but also because their concentration and the way they are blended into the membrane structure were changed. This paper provides information on modifications of TFN membranes with nanoparticles, as well as modification by changes in polymerization reaction conditions and monomer concentration. Examples of the use of TFN and TFC membranes are also presented.
The 2BeOn system - A multimedia workbench for telework and interactive television research

This paper refers to the implementation of the 2BeOn system, a multimedia workbench designed to test and evaluate the integration of communication and management services supporting work, leisure and information activities. The association of synchronous and asynchronous communication services is planned to provide a more complete answer to user needs in what concerns their interpersonal communication. The system results from a transdisciplinary effort and is being applied to support research in Telework and Interactive Television areas. Regarding Telework, the focus relies in building an integrated environment of communication, collaborative and management services to support remote work. From the perspective of Interactive Television the system aims to understand how the users may exploit online communication services, when engaged in leisure or information TV programs.
Synthesis, characterization, and cytocompatibility of elastomeric, biodegradable poly(ester-urethane)ureas based on poly(caprolactone) and putrescine.

The engineering of tissue for mechanically demanding applications in the cardiovascular system is likely to require mechanical conditioning of cell-scaffold constructs prior to their implantation. Scaffold properties amenable to such an application include high elasticity and strength coupled with controllable biodegradative and cell-adhesive properties. To fulfill such design criteria, we have synthesized a family of poly(ester-urethane)ureas (PEUUs) from polycaprolactone and 1,4-diisocyanatobutane. Lysine ethyl ester (Lys) or putrescine was used as chain extenders. To encourage cell adhesion, PEUUs were surface modified with radio-frequency glow discharge followed by coupling of Arg-Gly-Asp-Ser (RGDS). The synthesized PEUUs were highly flexible, with breaking strains of 660-895% and tensile strengths from 9.2-29 MPa. Incubation in aqueous buffer for 8 weeks resulted in mass loss, from >50% (Lys chain extender) to 10% (putrescine chain extender). Human endothelial cells cultured for 4 days with medium containing the degradation products from PEUUs with either the Lys or putrescine chain extender showed no toxic effects. Cell adhesion was 85% of that measured on tissue-culture polystyrene for unmodified PEUU surfaces (p < 0.01) and >160% (p < 0.001) of polystyrene on RGDS-modified PEUUs. These biodegradable PEUUs demonstrate potential for future application as cell scaffolds in cardiovascular tissue-engineering or other soft-tissue applications.
Degeneration of Neuromuscular Junction in Age and Dystrophy

Functional denervation is a hallmark of aging sarcopenia as well as of muscular dystrophy. It is thought to be a major factor reducing skeletal muscle mass, particularly in the case of sarcopenia. Neuromuscular junctions (NMJs) serve as the interface between the nervous and skeletal muscular systems, and thus they may receive pathophysiological input of both pre- and post-synaptic origin. Consequently, NMJs are good indicators of motor health on a systemic level. Indeed, upon sarcopenia and dystrophy, NMJs morphologically deteriorate and exhibit altered characteristics of primary signaling molecules, such as nicotinic acetylcholine receptor and agrin. Since a remarkable reversibility of these changes can be observed by exercise, there is significant interest in understanding the molecular mechanisms underlying synaptic deterioration upon aging and dystrophy and how synapses are reset by the aforementioned treatments. Here, we review the literature that describes the phenomena observed at the NMJ in sarcopenic and dystrophic muscle as well as to how these alterations can be reversed and to what extent. In a second part, the current information about molecular machineries underlying these processes is reported.
Interactive retrieval of multimedia objects based on self-organising maps

In this article we present an approach for the interactive retrieval of objects from databases that is based on the similarity of the objects. The considered objects are grouped based on their similarity to realise interactive associative search and visual exploration of the database. This enables a user to navigate through similar objects. If a textual description is available, the navigation, especially the search for the first appropriate object, is supported by conventional key-word search methods. The method can be applied to databases consisting of arbitrary objects if at least a description based on a numerical feature vector can be given.
Crowdsourced conceptualization of complex scientific knowledge and discovery of discoveries

The major morphological features of a galaxy are thought to be determined by the assembly history and net spin of its surrounding dark halo. In the simplest scenario, disk galaxies form predominantly in halos with high angular momentum and quiet recent assembly history, whereas spheroids are the slowly-rotating remnants of repeated merging events. We explore these assumptions using one hundred systems with halo masses similar to that of the Milky Way, identified in a series of cosmological gasdynamical simulations: the Galaxies Intergalactic Medium Calculation (GIMIC). At z = 0, the simulated galaxies exhibit a wide variety of morphologies, from dispersion-dominated spheroids to pure disk galaxies. Surprisingly, these morphological features are very poorly correlated with their halo properties: disks form in halos with high and low net spin, and mergers play a negligible role in the formation of spheroid stars, most of which form in-situ. With hindsight, this weak correlation between halo and galaxy properties is unsurprising given the small fraction of the available baryons ( 40%) that end up in galaxies. More important to morphology is the coherent alignment of the angular momentum of baryons that accrete over time to form a galaxy. Spheroids tend to form when the spin of newly-accreted gas is misaligned with that of the extant galaxy, leading to the episodic formation of stars with different kinematics that cancel out the net rotation of the system. Disks, on the other hand, form out of gas that flows in with similar angular momentum to that of earlier-accreted material. Gas accretion from a hot corona thus favours disk formation, whereas gas that flows “cold”, often along separate, misaligned filaments, favours the formation of spheroids. In this scenario, most spheroids consist of superpositions of stellar components with distinct kinematics, age, and metallicity, an arrangement that might survive to the present day given the paucity of major mergers. Since angular momentum is acquired largely at turnaround, morphology is imprinted early by the interplay of the tidal field and the shape of the material destined to form the galaxy.
Boundary potential of lipid bilayers: methods, interpretations and biological applications

The electric field distribution at boundaries of cell membranes consists of diffuse part of the electrical double layer and the potential drop over the polar area generally attributed to dipole effects. This report focuses on the molecular nature of dipole components of boundary potential and its relation to bilayer structure as it follows from different experimental approaches and molecular dynamic (MD) simulations. Alterations of the total boundary potential (BP) of planar bilayer lipid membranes (BLM) can be detected by the method of Intramembraneous Field Compensation, developed in our laboratory. When combined with traditional electrokinetic measurements in liposome suspension and Volta potential control at lipid monolayers it reveals alterations of the dipole potential induced by multivalent cations (Be2+, Gd3+) about 100-150 mV. It is related to the lipid phase transition detected by isotherm titration calorimetry (ITC) measurements. IFC method combined with perfusion of the cell show reversible electrostatic effects due to lysine adsorption and irreversible binding of polylysines accompanied by fast positive changes of BP as electrokinetic measurements, and slow negative ones attributed to BP dipole component. According to model proposed it related with changes of lipid hydration state varied by incorporation of ions or organic molecules into the lipid monolayer. Molecular dynamic simulations support this idea and relate dipole effects with H-bonded water molecules and lipid lateral coordination. Both effects are assumed as the principal reason of Gd3+ blocking effect on E.coli mechanosensitive channels.