gebhart/patrepeval huggingface dataset:
Structure of the cystic fibrosis transmembrane conductance regulator in the inward-facing conformation revealed by single particle electron microscopy (2015)

The most common inherited disease in European populations is cystic fibrosis. Mutations in the gene lead to loss of function of the cystic fibrosis transmembrane conductance regulator protein (CFTR). CFTR is a member of the ATP-binding cassette family of membrane proteins that mostly act as active transporters using ATP to move substances across membranes. These proteins undergo large conformational changes during the transport cycle, consistent with an inward-facing to outward-facing translocation mechanism that was originally proposed by Jardetzky. CFTR is the only member of this family of proteins that functions as an ion channel, and in this case ATP and phosphorylation of a regulatory domain controls the opening of the channel. In this article we describe the inward-facing conformation of the protein and show it can be modulated by the presence of a purified recombinant NHERF1-PDZ1 domain that binds with high affinity to the CFTR C-terminal PDZ motif <em>(-QDTRL</em>). ATP hydrolysis activity of CFTR can also be modulated by glutathione, which we postulate may bind to the inward-facing conformation of the protein. A homology model for CFTR, based on a mitochondrial ABC transporter of glutathione in the inward-facing configuration has been generated. The map and the model are discussed with respect to the biology of the channel and the specific relationship between glutathione levels in the cell and CFTR. Finally, disease-causing mutations are mapped within the model and discussed in terms of their likely physiological effects.
Passive security intelligence to analyze the security risks of mobile/BYOD activities (2016)

As enterprises embrace mobile technologies and enable their employees to bring their own devices, traditional security mechanisms are challenged by the col-location of personal and business activities on employee-owned mobile devices on the enterprise network. This presents a new risk to enterprises as employee-owned devices can now be used as stepping stones for bypassing traditional enterprise perimeter security. Current Bring Your Own device (BYOD) programs usually either do not manage employee-owned devices or are limited by self-enrollment and device heterogeneity challenges. In this paper, we introduce a novel, nonintrusive big data analytics methodology to obtain visibility into mobile device usage. At the heart of the methodology is an inference algorithm that uses a dynamic decision tree in near real-time to fingerprint mobile devices and their usage by analyzing passively collected network data. Information, such as device type, device model, and operating systems/versions, as well as applications and their patch level, can be inferred—all without an agent installed on the devices. We correlate such information with supplemental security intelligence (e.g., vulnerability information) to discover previously unknown mobile devices on an organization's network and to establish their security posture and risk. Our evaluation on a major corporate network indicates that mobile devices can be reliably identified while mitigating their potential threats, thus demonstrating that our methodology provides valuable insights to enterprise security administrators
Abstract 24: Bone Marrow Cells Transdifferentiate into Cardiomyocytes and Repair the Infarcted Heart (2014)

A major controversy concerns whether c-kit-positive bone marrow cells (c-kit-BMCs) can acquire cell lineages different from their organ of origin. Technical challenges and variability in the protocols employed for cell isolation and detection of donor-derived structures may account only in part for the conflicting results obtained in different laboratories. We raised the hypothesis that c-kit-BMCs are functionally heterogeneous and possess distinct transdifferentiation potential. To address this issue, two methodologies were employed to label individual c-kit-BMCs and define their clonal fate in vivo: viral gene-tagging and fluorescent protein-based multicolor cell marking. c-kit-BMCs were infected with EGFP lentiviruses and injected in infarcted hearts. At 2 weeks, the regenerated myocardium was enzymatically digested and EGFP-labeled myocytes, endothelial cells, fibroblasts, and c-kit-cells were sorted. By employing a PCR-based method of detection of viral integrants, we searched for sites of viral insertion in the isolated cells. Common insertion sites were found in the DNA of c-kit-BMCs and specialized cells, documenting that single c-kit-BMCs transdifferentiated into multiple cell lineages. However, only specific subsets of c-kit-BMCs generated cardiomyocytes in vivo, strongly indicating that the c-kit-BMC pool is composed of myogenic and non-myogenic cells. To strengthen these observations, FACS-sorted c-kit-BMCs were simultaneously transduced with 3 lentiviruses, each encoding red, green or blue (RGB) fluorescent proteins. Different combinations of inserted vectors in individual c-kit-BMCs resulted in a variety of mixed colors, each indicative of the development of clonal populations. RGB-infected c-kit-BMCs were delivered to infarcted rats and gave rise to homogeneously colored colonies containing fluorescently labeled myocytes and vascular cells. The homogenous pattern of expression of the fluorescent proteins documented that the regenerated structures derived from the expansion and transdifferentiation of single c-kit-BMCs. Our findings demonstrate that c-kit-BMCs are functionally heterogeneous and have a different ability to survive, engraft, and transdifferentiate in the ischemic heart.
Modular Tapered Implants for Severe Femoral Bone Loss in Revision Total Hip Arthroplasty (2012)

Introduction Modular tapered implants have been suggested as the optimal treatment in patients with severe femoral bone loss undergoing revision total hip arthroplasty (THA). The purpose of this study is to describe minimum 2 year follow up of patients treated with modular tapered prostheses for Paprosky type IIIB and IV femoral bone loss in revision THA. Methods 44 Consecutive patients with Paprosky type IIIB (23) or IV (21) femurs undergoing revision total hip arthroplasty to cementless modular tapered prostheses were studied. Harris Hip Scores were obtained prior to revision on all patients except those presenting with acute implant failure or periprosthetic fracture. 10 Patients were deceased within 2 years of surgery; the remaining 18 were followed for an average of 42 months (range 25-69 months). Clinical outcomes were measured using the Harris Hip Score, and radiographs were assessed for signs of stem loosening or subsidence >4mm. Results No further revisions were required in patients who were deceased within 2 years. In those with >2 year follow up, there were 4 additional revisions: 1 for infection, 2 for instability, and 1 for periprosthetic fracture. In patients with surviving implants, the mean Harris Hip Score improved from 33 (range 11-49) pre-operatively to 77 (range 55-100), and there was no radiographic evidence of loosening or subsidence at time of final follow up. Conclusions These outcomes support the use of modular tapered implants as a safe and effective option for revision arthroplasty of type IIIB and IV femurs.
Design and Materials for Long-Life Spark Plugs (2006)

&lt;div class="htmlview paragraph"&gt;Durability of spark plug electrodes is mainly determined by spark gap widening, caused by electrode wear. The performance of a spark plug strongly depends on the electrode material, the electrode design, and the operating conditions, i.e. temperature, atmosphere, spark energy, and current.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;The knowledge about erosion mechanisms of spark plug materials and their dependence on spark plug parameters is of fundamental interest for the development of materials with a high resistance against electrode erosion. Endurance tests were carried out in a compression chamber to study the spark erosion behavior of different electrode materials in the temperature range between 200 and 900°C. The experiments were carried out in pure nitrogen and synthetic dry air. The pressure in the chamber was 7 bar. In pure nitrogen no erosion was observed which suggests that oxidation is the principal mechanism.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;The ignitability relies both on the electrode gap and the electrode diameter. Their influence on spark erosion was studied for pure platinum and nickel. Furthermore, the effect of atmospheric pressure and the contribution of different spark discharge phases to the electrode wear were determined. It was found that platinum and nickel show a completely different behavior due to different oxidation mechanisms. This affects both design and material development of new spark plugs.&lt;/div&gt;
Supplementary Figure S1 from A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors (2023)

&lt;p&gt;C vs t plot of 3A following 40 μmol/kg IP administration in mice.&lt;/p&gt;
A Massively Parallel Digital Learning Processor (2008)

We present a new, massively parallel architecture for accelerating machine learning algorithms, based on arrays of vector processing elements (VPEs) with variable-resolution arithmetic. Groups of VPEs operate in SIMD (single instruction multiple data) mode, and each group is connected to an independent memory bank. The memory bandwidth thus scales with the number of VPEs, while the main data flows are local, keeping power dissipation low. With 256 VPEs, implemented on two FPGAs (field programmable gate array) chips, we obtain a sustained speed of 19 GMACS (billion multiply-accumulate per sec.) for SVM training, and 86 GMACS for SVM classification. This performance is more than an order of magnitude higher than that of any FPGA implementation reported so far. The speed on one FPGA is similar to the fastest speeds published on a Graphics Processor for the MNIST problem, despite a clock rate that is an order of magnitude lower. Tests with Convolutional Neural Networks show similar compute performances. This massively parallel architecture is particularly attractive for embedded applications, where low power dissipation is critical.
On Evaluating and Comparing Open Domain Dialog Systems (2018)

Conversational agents are exploding in popularity. However, much work remains in the area of non goal-oriented conversations, despite significant growth in research interest over recent years. To advance the state of the art in conversational AI, Amazon launched the Alexa Prize, a 2.5-million dollar university competition where sixteen selected university teams built conversational agents to deliver the best social conversational experience. Alexa Prize provided the academic community with the unique opportunity to perform research with a live system used by millions of users. The subjectivity associated with evaluating conversations is key element underlying the challenge of building non-goal oriented dialogue systems. In this paper, we propose a comprehensive evaluation strategy with multiple metrics designed to reduce subjectivity by selecting metrics which correlate well with human judgement. The proposed metrics provide granular analysis of the conversational agents, which is not captured in human ratings. We show that these metrics can be used as a reasonable proxy for human judgment. We provide a mechanism to unify the metrics for selecting the top performing agents, which has also been applied throughout the Alexa Prize competition. To our knowledge, to date it is the largest setting for evaluating agents with millions of conversations and hundreds of thousands of ratings from users. We believe that this work is a step towards an automatic evaluation process for conversational AIs.
Solution Processing of GaAs Thin Films for Photovoltaic Applications (2014)

In this article we present a novel route to high quality GaAs thin films via a solution processing technique (aerosol assisted chemical vapor deposition) using a novel single source precursor [Me2GaAs(H)tBu]2. The thin films, grown on inexpensive glass substrates, were polycrystalline in nature with a Ga to As ratio of 1:1. The morphology studied via SEM showed the films to be smooth and consisting of compact domes. High-resolution transmission electron microscopy (HRTEM) revealed the films to have columnar growth and an average crystallite size of 90 nm. The films also contained low levels of contaminants as determined via energy dispersive X-ray spectroscopy (EDX) mapping, X-ray photoelectron spectroscopy (XPS) depth profiling, and secondary ion mass spectrometry (SIMS).
Doubly Stimulated Corrole for Organelle-Selective Antitumor Cytotoxicity (2022)

Balancing between safety and efficacy of cancer chemotherapeutics is achievable by relying on internal and/or external stimuli for selective and on-demand antitumor cytotoxicity. We now introduce the difluorophosphorus(V) corrole <b>PC-Im</b>, a theranostic agent with a pH-sensitive <i>N</i>-methylimidazole moiety. Structure/activity relationships, via comparison with the permanently charged <b>PC-ImM</b><b>+</b> and the lipophilic <b>PC</b>, uncovered the exceptional features of <b>PC-Im</b>: nanoparticular and monomeric at neutral and low pH, respectively, 10-fold increased light-induced singlet oxygen production at acidic pH, internalization into malignant cells within minutes, and selective accumulation within lysosomes. Submillimolar <b>PC-Im</b> concentrations are tolerable in the dark, while illumination induces nanomolar cytotoxic effects due to a multiplicity of cellular deleterious events: endoplasmic reticulum fragmentation, lysosome fusion and exocytosis, calcium leakage, mitochondrial fission, and swelling. <b>PC-Im</b> emerges as an antitumor agent, whose potency is triggered by endogenous and exogenous stimuli, assuring its cytotoxicity will occur selectively upon lysosomal accumulation and solely upon light activation.
ChemInform Abstract: PREPARATION AND REACTIVITY OF THE (CYCLOHEXADIENE)MANGANESE TRICARBONYL ANION. POTENTIALLY USEFUL METHODS OF ARENE AND CARBON‐HYDROGEN BOND ACTIVATION (1981)

Abstract Überschüssiges Li‐triethylhydridoborat oder K‐triisopropoxyhydridoborat reagieren mit dem Benzol‐ Mn‐Komplex (I) zu dem Titelkomplexion (II), das auch quantitativ durch Hydridreduktion der Cyclohexadienylverbindung (III) dargestellt werden kann, die IR‐ spektroskopisch als Intermediärprodukt bei der Reaktion von (I) zu (II) nachgewiesen wurde.
Pheromone binding by polymorphic mouse major urinary proteins (2002)

Mouse major urinary proteins (MUPs) have been proposed to play a role in regulating the release and capture of pheromones. Here, we report affinity measurements of five recombinant urinary MUP isoforms (MUPs-I, II, VII, VIII, and IX) and one recombinant nasal isoform (MUP-IV) for each of three pheromonal ligands, (+/-)-2-sec-butyl-4,5-dihydrothiazole (SBT), 6-hydroxy-6-methyl-3-heptanone (HMH), and (+/-)dehydro-exo-brevicomin (DHB). Dissociation constants for all MUP-pheromone pairs were determined by isothermal titration calorimetry, and data for SBT were corroborated by measurements of intrinsic protein fluorescence. We also report the isolation of MUP-IV protein from mouse nasal extracts, in which MUP-IV mRNA has been observed previously. The affinity of each MUP isoform for SBT (K(d) approximately 0.04 to 0.9 micro M) is higher than that for DHB (K(d) approximately 26 to 58 micro M), which in turn is higher than that for HMH (K(d) approximately 50 to 200 micro M). Isoforms I, II, VIII, and IX show very similar affinities for each of the ligands. MUP-VII has approximately twofold higher affinity for SBT but approximately twofold lower affinity for the other pheromones, whereas MUP-IV has approximately 23-fold higher affinity for SBT and approximately fourfold lower affinity for the other pheromones. The variations in ligand affinities of the MUP isoforms are consistent with structural differences in the binding cavities of the isoforms. The data indicate that the concentrations of available pheromones in urine may be influenced by changes in the expression levels of urinary MUPs or the excretion levels of other MUP ligands. The variation in pheromone affinities of the urinary MUP isoforms provides only limited support for the proposal that MUP heterogeneity plays a role in regulating profiles of available pheromones. However, the binding data support the proposed role of nasal MUPs in sequestering pheromones and possibly transporting them to their receptors.
LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins (2014)

Large glycosylating toxins are major virulence factors of various species of pathogenic Clostridia. Prototypes are Clostridium difficile toxins A and B, which cause antibiotics-associated diarrhea and pseudomembranous colitis. The current model of the toxins' action suggests that receptor binding is mediated by a C-terminal domain of combined repetitive oligopeptides (CROP). This model is challenged by the glycosylating Clostridium perfringens large cytotoxin (TpeL toxin) that is devoid of the CROP domain but still intoxicates cells. Using a haploid genetic screen, we identified LDL receptor-related protein 1 (LRP1) as a host cell receptor for the TpeL toxin. LRP1-deficient cells are not able to take up TpeL and are not intoxicated. Expression of cluster IV of LRP1 is sufficient to rescue toxin uptake in these cells. By plasmon resonance spectroscopy, a KD value of 23 nM was determined for binding of TpeL to LRP1 cluster IV. The C terminus of TpeL (residues 1335-1779) represents the receptor-binding domain (RBD) of the toxin. RBD-like regions are conserved in all other clostridial glycosylating toxins preceding their CROP domain. CROP-deficient C. difficile toxin B is toxic to cells, depending on the RBD-like region (residues 1349-1811) but does not interact with LRP1. Our data indicate the presence of a second, CROP-independent receptor-binding domain in clostridial glycosylating toxins and suggest a two-receptor model for the cellular uptake of clostridial glycosylating toxins.
Inhibition of αvβ5 Integrin Attenuates Vascular Permeability and Protects against Renal Ischemia-Reperfusion Injury (2017)

Ischemia-reperfusion injury (IRI) is a leading cause of AKI. This common clinical complication lacks effective therapies and can lead to the development of CKD. The αvβ5 integrin may have an important role in acute injury, including septic shock and acute lung injury. To examine its function in AKI, we utilized a specific function-blocking antibody to inhibit αvβ5 in a rat model of renal IRI. Pretreatment with this anti-αvβ5 antibody significantly reduced serum creatinine levels, diminished renal damage detected by histopathologic evaluation, and decreased levels of injury biomarkers. Notably, therapeutic treatment with the αvβ5 antibody 8 hours after IRI also provided protection from injury. Global gene expression profiling of post-ischemic kidneys showed that αvβ5 inhibition affected established injury markers and induced pathway alterations previously shown to be protective. Intravital imaging of post-ischemic kidneys revealed reduced vascular leak with αvβ5 antibody treatment. Immunostaining for αvβ5 in the kidney detected evident expression in perivascular cells, with negligible expression in the endothelium. Studies in a three-dimensional microfluidics system identified a pericyte-dependent role for αvβ5 in modulating vascular leak. Additional studies showed αvβ5 functions in the adhesion and migration of kidney pericytes in vitro Initial studies monitoring renal blood flow after IRI did not find significant effects with αvβ5 inhibition; however, future studies should explore the contribution of vasomotor effects. These studies identify a role for αvβ5 in modulating injury-induced renal vascular leak, possibly through effects on pericyte adhesion and migration, and reveal αvβ5 inhibition as a promising therapeutic strategy for AKI.
Ionic Strength Influences on Biofunctional Au-Decorated Microparticles for Enhanced Performance in Multiplexed Colorimetric Sensors (2020)

The rising development of biosensors offers a great potential for health, food, and environmental monitoring. However, in many colorimetric platforms, there is a performance limitation stemming from the tendency of traditional Au nanoparticles toward nonspecific aggregation in response to changing ionic strength (salt concentration). This work puts forward a new type of colorimetric aptamer-functionalized labeling of microparticles, which allows to leverage an increase in ionic strength as a positive driver of enhanced detection performance of analytical targets. The resulting device is a cost-effective, instrument-free, portable, and reliable aptasensor that serves as basis for the fabrication of universal paper-based colorimetric platforms with the capability of multiplex, multireplicates and provides quantitative colorimetric detection. A controlled fabrication process was demonstrated by keeping 90% of the signal obtained from the as-fabricated devices (<i>n</i> = 40) within ± 1 standard deviation (SD) (relative SD = 5.69%) and following a mesokurtic normal-like distribution (<i>p</i> = 0.385). We propose for the first time a salt-induced aggregation mechanism for highly stable multilayered label particles (ssDNA-PEI-Au-PS) as the basis of the detection scheme. The use of DNA aptamers as capture biomolecules and PEI as an encapsulating agent allows for a sensitive and highly specific colorimetric response. As a proof of concept, multiplexed detection of mercury (Hg<sup>2+</sup>) and arsenic (As<sup>3+</sup>) was demonstrated. In addition, we introduced a robust image analysis algorithm for testing zone segmentation and color signal quantification that allowed for analytical detection, reaching a limit of detection of 1 ppm for both targeted analytes, with enough evidence (<i>p</i> > 0.05) to prove the high specificity of the fabricated device versus a pool of possible interferent ions.
Vasopressin Type 1A Receptor Up-regulation by Cyclosporin A in Vascular Smooth Muscle Cells Is Mediated by Superoxide (2003)

Based on our previous results, we investigated whether cyclosporin A (CsA)-induced vasopressin type 1A receptor up-regulation was mediated by free radicals. We report that CsA analogues with different affinities for cyclophilin and calcineurin were able to up-regulate vasopressin type 1A receptor and to generate free radicals in smooth muscle cells independently of calcineurin. Further, we demonstrate that the antioxidant N-acetyl-L-cysteine blocked the increase in vasopressin type 1A receptor mRNA and protein levels induced by CsA and that low concentrations of prooxidants were able to directly increase vasopressin type 1A receptor mRNA and protein levels. In addition, short exposure to CsA or pro-oxidants was sufficient to significantly increase vasopressin type 1A receptor mRNA and protein levels. Using cell-permeable forms of superoxide dismutase and catalase, we finally show that superoxide mediates the CsA-induced effects on vasopressin type 1A receptor. These results provide strong evidence that CsA-induced superoxide generation is causally involved in vasopressin type 1A receptor expression and demonstrate for the first time that low physiological concentrations of radicals, most probably superoxide, are able to directly affect cellular signaling to increase vasopressin type 1A receptor expression in rat aortic smooth muscle cells.