Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibiting ACAT1/SOAT1 in Microglia Stimulates Autophagy-Mediated Lysosomal Proteolysis and Increases Aβ1–42 Clearance

Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a resident endoplasmic reticulum enzyme that prevents the buildup of cholesterol in membranes by converting it to cholesterol esters. Blocking ACAT1 pharmacologically or by Acat1 gene knock-out (KO) decreases amyloidopathy in mouse models for Alzheimer's disease. However, the beneficial actions of ACAT1 blockage to treat Alzheimer's disease remained not well understood. Microglia play essential roles in the proteolytic clearance of amyloid β (Aβ) peptides. Here we show that Acat1 gene KO in mouse increases phagocytic uptake of oligomeric Aβ1–42 and stimulates lysosomal Aβ1–42 degradation in cultured microglia and in vivo. Additional results show that Acat1 gene KO or a specific ACAT1 inhibitor K604 stimulates autophagosome formation and transcription factor EB-mediated lysosomal proteolysis. Surprisingly, the effect of ACAT1 blockage does not alter mTOR signaling or endoplasmic reticulum stress response but can be modulated by agents that disrupt cholesterol biosynthesis. To our knowledge, our current study provides the first example that a small molecule (K604) can promote autophagy in an mTOR-independent manner to activate the coordinated lysosomal expression and regulation network. Autophagy is needed to degrade misfolded proteins/peptides. Our results implicate that blocking ACAT1 may provide a new way to benefit multiple neurodegenerative diseases.
Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Drug treatments for HCC have been largely unsuccessful. Histone deacetylase inhibitors can reactivate tumor suppressor genes in cancer cells and serve as potential anti-cancer drugs. Two potent HDAC inhibitors OSU-HDAC42 and SAHA induced autophagy in HCC cells as revealed by transmission electron microscopy, immunofluorescence and LC3-II accumulation. We found that SAHA and OSU-HDAC42 induced autophagy through downregulation of Akt/mTOR signaling and induction of ER stress response. Inhibition of autophagy by 3-MA or Atg5 knockout reduced SAHA-induced cytotoxicity, indicating that SAHA-induced autophagy led to cell death. Our results show that the combination of autophagy inducers with SAHA might be attractive for the treatment of HCC and pharmacological targeting of autophagy provides promise for the management of cancer therapy.
Responses To Microinjections Of Endomorphin And Nociceptin Into The Medullary Cardiovascular Areas

1. Cardiovascular effects of microinjections of nociceptin and endomorphin‐2 into the following medullary areas were studied in urethane‐anaesthetized rats: chemoreceptor projection site (CPS), intermediate portion of the nucleus tractus solitarius (I‐NTS), caudal ventrolateral medullary depressor area (CVLM) and rostral ventrolateral medullary pressor area (RVLM).
A relaxation oscillator with multi-phase triangular waveform generation

This paper firstly presents a CMOS voltage-controlled oscillator (VCO) which enables octa-phase triangular waveform generation. By utilizing a cascaded relaxation oscillator core followed by a pseudo injection-locked oscillator circuit, an octa-phase differential VCO with triangular waveform outputs is realized. Simulation results show that the proposed fully differential multi-phase VCO can achieve broad tuning range with programmable timing capacitors, offering &#60;1% phase mismatch.
Cooperative Joint Localization and Clock Synchronization Based on Gaussian Message Passing in Asynchronous Wireless Networks

Localization and synchronization are very important in many wireless applications such as monitoring and vehicle tracking. Utilizing the same time of arrival (TOA) measurements for simultaneous localization and synchronization is challenging. In this paper, we present a factor graph (FG) representation of the joint localization and time synchronization problem based on TOA measurements, in which the non-line-of-sight (NLOS) measurements are also taken into consideration. On this FG, belief propagation (BP) message passing and variational message passing (VMP) are applied to derive two fully distributed cooperative algorithms with low computational requirements. Due to the nonlinearity in the observation function, it is intractable to compute the messages in closed form, and most existing solutions rely on Monte Carlo methods, e.g., particle filtering. We linearize a specific nonlinear term in the expressions of messages, which enables us to use a Gaussian representation for all messages. Accordingly, only the mean and variance have to be updated and transmitted between neighboring nodes, which significantly reduces the communication overhead and computational complexity. A message passing schedule scheme is proposed to trade off between estimation performance and communication overhead. Simulation results show that the proposed algorithms perform very close to particle-based methods with much lower complexity, particularly in densely connected networks.
Numerical simulation chaotic synchronization of Chua circuit and its application for secure communication

Abstract. The Chua circuit is among the simplest non-linear circuits that show most complex dynamical behavior, including chaos which exhibits a variety of bifurcation phenomena and attractors. In this paper, Chua attractor’s chaotic oscillator, synchronization and masking communication circuits were designed and simulated. The Chua system is addressed suitable for chaotic synchronization circuits and chaotic masking communication circuits using Matlab and MultiSIM software. Simulation results are used to visualize and illustrate the effectiveness of Chua chaotic system in synchronization and application of secure communication.
Acquiring Inductive Constraints from Self-Generated Evidence

Several recent theoretical proposals suggest that young children are rational, constructivist learners (e.g. Gopnik & Wellman, 2012; Xu & Kushnir, 2012; 2013). One of the claims made under constructive learning is that children are active learners – they selectively attend and explore their environment in order to maximize information gain (e.g., Kidd, Piantadosi, & Aslin, 2012; Schulz & Bonawitz, 2007). Most studies to date, however, have focused on how efficiently children learn when they are given evidence by an experimenter (‘teacher’), under conditions of training: children receive a restricted set of evidence, and they are subsequently tested on their learning. Yet children are not mere observers; they actively engage their environment to supplement their learning. In our experiment, 3-year-old children successfully acquired higher-order generalizations using self-generated evidence during free play, suggesting an early capacity to engage in self-directed learning.
Analysis of a 5-dof planar biped mechanism with parallelogram-type links

This paper reports the modeling, trajectory planning and control of a 5-degree-of-freedom biped robot with parallelogram-type links. The kinematic and dynamic models are obtained by using a simplified approach of the real mechanism. The model-based controller for the tracking of the proposed gait patterns, and the analysis of the Zero Moment Point, which determines the dynamic stability, are also presented. Simulation results give important information for the future practical implementation of the mechanism.
Android Anti-Virus Analysis

—The number of devices running with the Android operating system has been on the rise. By the end of 2012, it will account for nearly half of the world's smartphone market. Along with its growth, the importance of security has also risen. A proportional increase in the number of vulnerabilities is also happening to the extent that there are a limited number of security applications available to protect these devices. The efficacies of these applications have not been empirically established. This paper analyzes some of the security tools written for the Android platform to gauge their effectiveness at mitigating spyware and malware.
Burst-train Generation for Femtosecond Laser Filamentation-driven Micromachining

Bursts of femtosecond laser pulses with a repetition rate of 38.5MHz were created by integrating a purpose-built burst resonator system with a Ti: Sapphire laser system. The timing control system in this work provided flexibility for generation of any desirable pulse train profile in the burst envelope. These laser pulses further have been used for high aspect ratio hole drilling inside glass materials. High repetition rate of the pulses produces heat accumulation effects during the laser machining interaction which provided the possibility of deeper etching, increased the aspect ratio, and mitigated cracks and damages effects of single pulses. During the process, time-resolved nanosecond scale side-view images have been recorded with a time-gated intensified-CCD camera enabling the observation of transient effects during the laser machining process. These side-view images further have been used to assess the physics of burst interaction and illustrate benefits and disadvantages of high repetition rate laser pulses.
Parse, Price and Cut—Delayed Column and Row Generation for Graph Based Parsers

Graph-based dependency parsers suffer from the sheer number of higher order edges they need to (a) score and (b) consider during optimization. Here we show that when working with LP relaxations, large fractions of these edges can be pruned before they are fully scored---without any loss of optimality guarantees and, hence, accuracy. This is achieved by iteratively parsing with a subset of higherorder edges, adding higher-order edges that may improve the score of the current solution, and adding higher-order edges that are implied by the current best first order edges. This amounts to delayed column and row generation in the LP relaxation and is guaranteed to provide the optimal LP solution. For second order grandparent models, our method considers, or scores, no more than 6--13% of the second order edges of the full model. This yields up to an eightfold parsing speedup, while providing the same empirical accuracy and certificates of optimality as working with the full LP relaxation. We also provide a tighter LP formulation for grandparent models that leads to a smaller integrality gap and higher speed.
Protein Kinase CK2 Inhibition Down Modulates the NF-κB and STAT3 Survival Pathways, Enhances the Cellular Proteotoxic Stress and Synergistically Boosts the Cytotoxic Effect of Bortezomib on Multiple Myeloma and Mantle Cell Lymphoma Cells

CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.
Trust, Contract and Relationship Development

This article contributes to the debate on the relation between trust and control in the management of inter-organizational relations. More specifically, we focus on the question how trust and formal contract are related. While there have been studies on whether trust and contract are substitutes or complements, they offer little insight into the dynamic interaction between the two. They fail to answer, first, whether contract precedes trust or follows it, in other words, what causal relationship exists between the concepts; second, how and why trust and contract can substitute or complement each other; and third, how the various combinations of trust and contract affect a relationship’s development and outcome. In search of answers, we conducted longitudinal case studies to reveal the relationship between trust, contract and relationship outcome in complex inter-firm relationships. We find trust and contract to be both complements and substitutes and find that a close study of a contract’s content offers alternative insight into the presence and use of contracts in inter-firm relationships.
Chk1 promotes replication fork progression by controlling replication initiation

DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.
Clinical Pharmacokinetics of Carboplatin

The pharmacokinetics of carboplatin were investigated in cancer patients after single, IV infusion doses of 75, 150, 247.5, 300, 375, and 450 mg/m2. Total plasma and urine platinum and plasma ultrafilterable platinum concentrations were determined by atomic absorption spectrometry. Carboplatin was analyzed in plasma by a specific high‐performance liquid chromatography (HPLC) procedure. Total plasma platinum, which represented free carboplatin, protein‐bound platinum and metabolites, declined triexponentially; plasma half‐lives (t1/2Λ1, 0.2 to 0.4 hr, t1/2Λ2, 1–3 to 1.7 hr; t1/2Λ3, 22 to 40 hr) and total body clearance (CLTB 2.8 ± 0.5 L/m2/hr) were dose independent. Maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) increased proportionally with dose. Plasma ultrafilterahle platinum and carboplatin concentrations at doses of 375 and 450 mg/m2 declined in a biphasic manner. Plasma carboplatin elimination (t1/2Λ1, 0.50 hr; t1/2Λ2 2.2 hr) and CLTB (4.4 to 5.6 L/m2/hr) were also independent of dose; AUC and Cmax increased proportionally to dose. Plasma free platinum was essentially all carboplatin for 8 or 12 hours after administration. Carboplatin did not bind to plasma protein in vitro but did degrade (U1/2–26 hours) to yield a reactive intermediate that bound rapidly and irreversibly to protein. The long terminal elimination half‐life of plasma platinum was associated with irreversible binding of a platinum metabonate to plasma protein. The urinary excretion of platinum (0 to 24 hours) accounted for 58 to 72% of doses in 12 to 24 hours. The remainder of the dose is slowly excreted. The pharmacokinetics, in vivo stability, protein binding, and elimination of carboplatin are distinct from the first‐generation analog cisplatin.
Static and Dynamic Thermal Behavior of Carbon Based Nanofluids

iii DEDICATION . v ACKNOWLEDGEMENTS . vi LIST OF FIGURES . x LIST OF TABLES . xii LIST OF SYMBOLS . xiii CHAPTER I MOTIVATION . 1 CHAPTER II LITERATURE REVIEW . 6 2.
Cellular immunity of patients with malignant glioma: prerequisites for dendritic cell vaccination immunotherapy.

OBJECT Vaccination therapy that uses dendritic cells (DCs) is a promising immunotherapeutic approach. However, it relies on intact cellular immunity and efficient generation of mature DCs, both of which can be impaired in patients with glioma. Therefore, the immune status and ex vivo generation of DC in such patients were studied. METHODS The frequencies of white blood cell subsets and monocyte-derived, mature DCs in patients with high-grade gliomas and healthy control volunteers were analyzed using flow cytometry. In the patients, frequencies of lymphocytes, T cells, and B cells were reduced in comparison with the volunteers in the control group, whereas frequencies of neutrophils and monocytes were increased. There were no differences between the two groups in terms of white blood cell counts or the frequency of NK cells and the major T-cell subsets. The responsiveness of T cells to lectin stimulation was normal. For monocytes, lower frequencies of CD80+ and CD86+ cells but not of CD40+ and HLA-DR+ cells were observed in patients. Ex vivo DC generation in a two-step culture protocol in autologous plasma-supplemented medium or in serum-free medium showed only minor differences in CD80 and HLA-DR expression between the patient and control groups. Frequencies of CD83+, CD1a+, CD14-, CD40+, and CD86+ cells were comparable. Overall, the serum-free medium was superior to the plasma-supplemented medium and allowed efficient ex vivo generation of CD83+, CD1a+, and CD14- mature DCs. CONCLUSIONS Only minor defects in the immune status of patients with glioma were observed, which probably would not hamper immunotherapy. Mature DCs can be generated successfully in normal numbers and with typical immunophenotypes from monocytes of patients with glioma, particularly under serum-free conditions.
Regression with Respect to Sensing Actions and Partial States

In this paper, we present a state-based regression function for planning domains where an agent does not have complete information and may have sensing actions. We consider binary domains, and employ the 0-approximation (Son & Baral 2001) to define the regression function. In binary domains, the use of 0-approximation means using 3-valued states. Although planning using this approach is incomplete with respect to the full semantics, we adopt it to have a lower complexity. We prove the soundness and completeness of our regression formulation with respect to the definition of progression and develop a conditional planner that utilizes our regression function.
Cycloleucine blocks NMDA responses in cultured hippocampal neurones under voltage clamp: antagonism at the strychnine‐insensitive glycine receptor

1 Radioligand binding studies have demonstrated that the neutral amino acid cycloleucine may act as a competitive antagonist at the glycine modulatory site on the N‐methyl‐D‐aspartate (NMDA) receptor complex. In the present study, we examined the effects of cycloleucine on NMDA‐evoked inward current responses in dissociated hippocampal neuronal cultures using the whole cell voltage‐clamp technique. 2 In the presence of 1 μm glycine, cycloleucine caused a reversible, dose‐dependent inhibition of NMDA responses with an IC50 of 24 μm. An increase in glycine to 100 μm resulted in a shift to the right of the cycloleucine concentration‐effect curve (IC50, 1.4 mm). However, with cycloleucine concentrations ≤ 100 μm, a fraction of the block could not be overcome by glycine even at concentrations as high as 1 mm. 3 The cycloleucine block was unaffected by shifts in the holding potential (‐60 to +60mV), and there was no effect of cycloleucine on the reversal potential of the NMDA‐evoked current. 4 Cycloleucine failed to effect kainic acid‐ and quisqualic acid‐evoked currents at concentrations which inhibited NMDA responses. 5 We conclude that cycloleucine is a potent and selective antagonist of NMDA‐receptor mediated responses. Although this effect occurs in part via competitive antagonism at the glycine modulatory site, the cycloleucine block cannot be completely reversed by glycine indicating an interaction with an additional site on the receptor‐channel complex.
Determinants of Anion Permeation in the Second Transmembrane Domain of the Mouse Bestrophin-2 Chloride Channel

Bestrophins have been proposed to constitute a new family of Cl channels that are activated by cytosolic Ca. We showed previously that mutation of serine-79 to cysteine in mouse bestrophin-2 (mBest2) altered the relative permeability and conductance to SCN. In this paper, we have overexpressed various mutant constructs of mBest2 in HEK-293 cells to explore the contributions to anion selectivity of serine-79 and other amino acids (V78, F80, G83, F84, V86, and T87) located in the putative second transmembrane domain (TMD2). Residues selected for mutagenesis were distributed throughout TMD2, but mutations at all positions changed the selectivity. The effects on selectivity were rather modest. Replacement of residues 78, 79, 80, 83, 84, 86, or 87 with cysteine had similar effects: the permeability of the channel to SCN relative to Cl (PSCN/PCl) was decreased three- to fourfold and the relative SCN conductance (GSCN/GCl) was increased five- to tenfold. Side chains at positions 78 and 80 appeared to be situated close to the permeant anion, because the electrostatic charge at these positions affected permeation in specific ways. The effects of charged sulfhydryl-reactive MTS reagents were the opposite in the V78C and F80C mutants and the effects were partially mimicked by substitution of F80 with charged amino acids. In S79T, switching from Cl to SCN caused slow changes in GSCN/GCl (τ = 16.6 s), suggesting that SCN binding to the channel altered channel gating as well as conductance. The data in this paper and other data support a model in which TMD2 plays an important role in forming the bestrophin pore. We suggest that the major determinant in anion permeation involves partitioning of the permeant anion into an aqueous pore whose structural features are rather flexible. Furthermore, anion permeation and gating may be linked.