gebhart/patrepeval huggingface dataset:
Sublethal Concentrations of Pleurocidin-Derived Antimicrobial Peptides Inhibit Macromolecular Synthesis in Escherichia coli (2002)

Cationic bactericidal peptides are components of natural host defenses against infections. While the mode of antibacterial action of cationic peptides remains controversial, several targets, including the cytoplasmic membrane and macromolecular synthesis, have been identified for peptides acting at high concentrations. The present study identified peptide effects at lower, near-lethal inhibitory concentrations. An amidated hybrid of the flounder pleurocidin and the frog dermaseptin (P-Der), two other pleurocidin derivatives, and pleurocidin itself were studied. At 2 microg/ml, the MIC, P-Der inhibited Escherichia coli growth in a broth dilution assay but did not cause bacterial death within 30 min, as estimated by viable count analysis. Consistent with this, P-Der demonstrated a weak ability to permeabilize membranes but was able to translocate across the lipid bilayer of unilamellar liposomes. Doses of 20 microg/ml or more reduced bacterial viable counts by about 2 log orders of magnitude within 5 min after peptide treatment. Abrupt loss of cell membrane potential, observed with a fluorescent dye, dipropylthiacarbocyanine, paralleled bacterial death but did not occur at the sublethal, inhibitory concentrations. Both lethal and sublethal concentrations of P-Der affected macromolecular synthesis within 5 min, as demonstrated by incorporation of [3H]thymidine, [3H]uridine, and [3H]histidine, but the effects were qualitatively distinct at the two concentrations. Variations of the inhibition pattern described above were observed for pleurocidin and two other derivatives. Our results indicate that peptides at their lowest inhibitory concentrations may be less capable of damaging cell membranes, while they maintain their ability to inhibit macromolecular synthesis. Better understanding of the effects of peptides acting at their MICs will contribute to the design of new peptides effective at lower, less toxic concentrations.
Selective inhibition of the growth of human erythroid bursts by monoclonal antibodies against transferrin or the transferrin receptor (1986)

The relative requirements of colonies derived from erythroid (BFU-E) and myeloid (CFU-c) progenitors for transferrin were examined using monoclonal antibodies directed against the transferrin molecule (TF-6) or its cell surface receptor (TFR-A12, TFR1-2B). Growth of erythroid bursts was profoundly reduced at concentrations of all three antibodies that had no effect on CFU-c-derived colonies. When TFR1-2B was layered over cultures established one to seven days previously, further burst development was inhibited, and degeneration of early erythroid colonies was observed. Addition of erythropoietin augmented transferrin receptor expression on cells harvested after 1 to 2 weeks in culture and analyzed by flow cytometry. Recombinant human erythropoietin gave results comparable to those obtained in experiments using human urinary erythropoietin. Analysis of erythroblasts plucked directly from culture plates confirmed the presence of transferrin receptors on BFU-E-derived colonies. Thymidine incorporation was maximal early in the second week of culture and coincided with high transferrin receptor expression. These data demonstrate that transferrin must be available into the second week of culture to support the growth and differentiation of BFU-E-derived erythroid bursts, that the generation of erythroid colonies from BFU-E is more dependent on transferrin than myeloid colony formation from CFU-c, and that erythropoietin modulates the expression of transferrin receptors on growing bursts.
Natural orifice transluminal endoscopic surgery with a snake‐mechanism using a movable pulley (2017)

The suggested snake mechanism using movable pulleys has the advantages of stiffness and maneuverability. This new mechanism can be an alternative platform for natural orifice surgery.
Faculty Opinions recommendation of A directional switch of integrin signalling and a new anti-thrombotic strategy. (2014)

Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbβ3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin β3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding. PMID: 24162846 Funding information This work was supported by: NHLBI NIH HHS, United States Grant ID: HL080264 NHLBI NIH HHS, United States Grant ID: HL109439 NHLBI NIH HHS, United States Grant ID: T32 HL007829 NHLBI NIH HHS, United States Grant ID: R01 HL109439 NHLBI NIH HHS, United States Grant ID: R01 HL062350 NHLBI NIH HHS, United States Grant ID: R01 HL080264 NHLBI NIH HHS, United States Grant ID: HL062350 More Less keyboard_arrow_down
TCP/IP and Mobile IP over asymmetric wireless links (2000)

The issues related to implementation of the Transmission Control Protocol/Internet Protocol (TCP/IP) in the fixed and mobile environments are being investigated for a variety of commercial and military applications. Specific issues are the effects of disadvantaged links associated with bandwidth, latency, and traffic asymmetries, high bit error rates, quality of services, and security requirements on network operation. We set up a ‘TCP/IP and Mobile IP Networks Testbed for Mobile Platforms’, which allowed us to simulate a wide range of network topologies such as asymmetric satellite links, mobile IP links, and Institute of Electrical and Electronics Engineers (IEEE) 802.11B wireless local area networks (WLAN). In this paper, the segmented TCP (i.e., TCP Splitting) performance with SkyX™ Gateways is described over asymmetric satellite links. Compatibility test of mobile IP mobile clients (mobile nodes) software is performed with mobile agents (home and foreign agents) software. Finally, the mobile IP network/router mobility currently under development will be also briefly described.
Lead Evaluation of Tetrahydroquinolines as Nonsteroidal Selective Androgen Receptor Modulators for the Treatment of Osteoporosis (2013)

Tetrahydroquinoline (THQ) was deemed to be a suitable scaffold for our nonsteroidal selective androgen receptor modulator (SARM) concept. We adapted the strategy of switching the antagonist function of cyano-group-containing THQ (CN-THQ) to the agonist function and optimized CN-THQ as an orally available drug candidate with suitable pharmacological and ADME profiles. Based on binding mode analyses and synthetic accessibility, we designed and synthesized a compound that possesses a para-substituted aromatic ring attached through an amide linker. The long-tail THQ derivative 6-acetamido-N-(2-(8-cyano-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-4-yl)-2-methylpropyl)nicotinamide (1 d), which bears a para-acetamide-substituted aromatic group, showed an appropriate in vitro biological profile, as expected. We considered that the large conformational change at Trp741 of the androgen receptor (AR) and the hydrogen bond between 1 d and helix 12 of the AR could maintain the structure of the AR in its agonist form; indeed, 1 d displays strong AR agonistic activity. Furthermore, 1 d showed an appropriate in vivo profile for use as an orally available SARM, displaying clear tissue selectivity, with a separation between its desirable osteoanabolic effect on femoral bone mineral density and its undesirable virilizing effects on the uterus and clitoral gland in a female osteoporosis model.
Molecular characterization of Porcine circovirus type 2 isolates from post-weaning multisystemic wasting syndrome-affected and non-affected pigs (2004)

Porcine circovirus type 2 (PCV2) is recognized as a primary cause in post-weaning multisystemic wasting syndrome (PMWS). In this study, both PCV1 and PCV2 types were studied in pigs originating from PMWS-affected (+) and non-affected (-) herds from Brittany. PCV2 was identified by PCR in 100 % of animals from PMWS(+) herds and in 76 % from PMWS(-) herds, while PCV1 was not detected. The complete sequences of 38 PCV2 isolates were determined and 23 new variants were identified, displaying between 94.6 and 99.9 % nucleotide identity with one another. Although highly related to all the PCV2 sequences available in databases, the isolates from France gathered in a distinct subcluster. Compared with the 13 PCV2 from PMWS(+) farms, the 10 PMWS(-) sequences exhibited a slightly higher variability. No viral molecular marker specific to a pathogenic state could be identified, even by including other PCV2 variants isolated from PMWS-suffering animals from other countries. We concluded that the PMWS outbreaks in Brittany are most likely not due to the emergence of a new genotype of circovirus.
A Coordinated Proteomic Approach for Identifying Proteins that Interact with the E. coli Ribosomal Protein S12 (2013)

The bacterial ribosomal protein S12 contains a universally conserved D88 residue on a loop region thought to be critically involved in translation due to its proximal location to the A site of the 30S subunit. While D88 mutants are lethal this residue has been found to be post-translationally modified to β-methylthioaspartic acid, a post-translational modification (PTM) identified in S12 orthologs from several phylogenetically distinct bacteria. In a previous report focused on characterizing this PTM, our results provided evidence that this conserved loop region might be involved in forming multiple proteins-protein interactions ( Strader , M. B. ; Costantino , N. ; Elkins , C. A. ; Chen , C. Y. ; Patel , I. ; Makusky , A. J. ; Choy , J. S. ; Court , D. L. ; Markey , S. P. ; Kowalak , J. A. A proteomic and transcriptomic approach reveals new insight into betamethylthiolation of Escherichia coli ribosomal protein S12. Mol. Cell. Proteomics 2011 , 10 , M110 005199 ). To follow-up on this study, the D88 containing loop was probed to identify candidate binders employing a two-step complementary affinity purification strategy. The first involved an endogenously expressed S12 protein containing a C-terminal tag for capturing S12 binding partners. The second strategy utilized a synthetic biotinylated peptide representing the D88 conserved loop region for capturing S12 loop interaction partners. Captured proteins from both approaches were detected by utilizing SDS-PAGE and one-dimensional liquid chromatography-tandem mass spectrometry. The results presented in this report revealed proteins that form direct interactions with the 30S subunit and elucidated which are likely to interact with S12. In addition, we provide evidence that two proteins involved in regulating ribosome and/or mRNA transcript levels under stress conditions, RNase R and Hfq, form direct interactions with the S12 conserved loop, suggesting that it is likely part of a protein binding interface.
Micromethods for the determination of metabolic characteristics in individual nephron segments. (1994)

Since a single nephron is a functional unit of the kidney, individual microdissected segments from the nephron would be ideal tissue samples for investigations on renal pharmacology. Several micromethods have enabled researchers to analyze the biochemical and pharmacological characteristics of these nephron segments. Miniaturized cuvettes containing microliter volumes of samples can be applied for general procedures of photometry like Lowry's protein determination. Fluorometry becomes a more sensitive method when enzymatic cycling systems of NAD/NADH or NADP/NADPH are combined, which have been used for assays of enzyme activities or substrate contents in minute biological samples having tissue proteins less than 1 microgram. The microchemiluminescence procedure has been successfully utilized for cellular ATP content or oxygen radical generation. Radioimmunoassay can be used to determine endogenous components such as cyclic nucleotides, eicosanoids, etc. Continuous gradient polyacrylamide microgels prepared in 5- to 10-microliters capillaries have made it possible to quantify the intranephron distribution of cytochrome P-450, xanthine oxidase and superoxide dismutase. As an example of the modern techniques, microscopic fluorometry using Fura-2AM has been established to identify agonist-induced cytosolic free calcium transients.
Theory and Direct Measurement of Boron Segregation in SiO2 during Dry, Near Dry, and Wet  O 2 Oxidation (1978)

A theory of B segregation is developed which accounts for the differences in observed in, for example, diffusion from a highly doped source as compared to oxidation of B‐doped Si in wet and dry oxidizing ambients. We have found that most dry oxidations are really only partially dry and that the presence of as little as results in an essentially the same as oxidation in 100% steam, i.e., at 1200°C with an "effective" activation energy of 0.64 eV. However, in a truly dry oxidation, the B segregation coefficient at 1200°C is ∼1 with an effective activation energy of 0.33 eV. We propose that these differences as well as the observed in high concentration diffusion source oxidations are determined by the formation thermodynamics of the B compounds that are created during segregation. Quantitative agreement with values obtained from directly measured B distributions across the interface are obtained (SIMS measurements with oxygen leak). Also, through‐oxide B implants were observed to have segregation coefficients equal to the pure dry case even though the subsequent oxidations were performed in ambients with trace amounts of . Examples are presented which illustrate the effect of trace amounts of on B diffusion during oxidation.
Nematic Phase Behaviour of Inorganic-Organic Hybrid Systems Based on Dendritic Carbosilazane Cores (2001)

The synthesis of the first inorganic-organic hybrid liquid crystal dendrimers, which exhibit enantiotropic nematic phase behaviour, is presented.
Enhancement of insulin signaling through inhibition of tissue lipid accumulation by activation of peroxisome proliferator-activated receptor (PPAR) alpha in obese mice. (2004)

The present results suggest that inhibition of lipid accumulation by hepatic PPARalpha activation leads to an improvement in impaired insulin signaling in muscle tissue as well as in the liver of insulin-resistant mice.
Virtual photons in imaginary time: Computing exact Casimir forces via standard numerical electromagnetism techniques (2007)

We describe a numerical method to compute Casimir forces in arbitrary geometries, for arbitrary dielectric and metallic materials, with arbitrary accuracy (given sufficient computational resources). Our approach, based on well-established integration of the mean stress tensor evaluated via the fluctuation-dissipation theorem, is designed to directly exploit fast methods developed for classical computational electromagnetism, since it only involves repeated evaluation of the Green's function for imaginary frequencies (equivalently, real frequencies in imaginary time). We develop the approach by systematically examining various formulations of Casimir forces from the previous decades and evaluating them according to their suitability for numerical computation. We illustrate our approach with a simple finite-difference frequency-domain implementation, test it for known geometries such as a cylinder and a plate, and apply it to new geometries. In particular, we show that a pistonlike geometry of two squares sliding between metal walls, in both two and three dimensions with both perfect and realistic metallic materials, exhibits a surprising nonmonotonic ``lateral'' force from the walls.
Optical computing and related microoptic devices (1990)

We investigate scaling with the cross-sectional area of energy and speed for optical devices and of optical design, speed, and thermal dissipation for device arrays. Theory and experiments clearly point to lower energy and faster speed for smaller devices and to simpler optical design, smaller propagation time delays, and higher thermal dissipation capability for smaller array sizes. We conclude that the development of high speed digital optical processors will depend on small devices interconnected by microoptic systems.
On the applicability of the surface equivalence theorem inside enclosures (2012)

A scenario of a generic printed circuit board (PCB) representing an electronic module inside a metallic enclosure is studied numerically. Following the surface equivalence theorem, the PCB is replaced with surface currents running on a Huygens box (HB) inside the enclosure and near-field errors with respect to the full model are observed. In concordance with previous work it is found that leaving the HB empty leads to significant errors. This time, however, countermeasures in the form of including the ground plane or substrate of the PCB inside the HB have the desired effect of reducing the errors at only some of the investigated frequencies.
Advances in the production and handling of encoded microparticles (2014)

Here we highlight emerging technologies in the synthesis, handling, and application of encoded microparticles for multiplexed assays. Traditionally, in drug discovery and life sciences research, multiple reactions will be conducted in parallel using microwell plate formats or microfluidic implementations, in which volumes are confined and reactions annotated by knowledge of what reagents were added to each volume. Microparticle-based information carriers provide an alternative approach to performing such multiplexed reactions, in which reactions and events are instead annotated with unique codes associated with the solid-phase particle. One challenge has been in creating a unique and large enough code set that is also easily readout, and we highlight two approaches that have brought orthogonal optical tagging techniques to bear. Another challenge has been that in such approaches, reactions have usually been confined to the surface of, or within the bulk of the specifically-tagged particle. We also highlight a creative approach and strategy for multiplexing - called "partipetting"- in which the coded particle can be a carrier of a unique fluid reagent.
Therapies Targeting Innate Immunity for Fighting Inflammation in Atherosclerosis (2014)

Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.
AIC649 Induces a Bi-Phasic Treatment Response in the Woodchuck Model of Chronic Hepatitis B (2015)

AIC649 has been shown to directly address the antigen presenting cell arm of the host immune defense leading to a regulated cytokine release and activation of T cell responses. In the present study we analyzed the antiviral efficacy of AIC649 as well as its potential to induce functional cure in animal models for chronic hepatitis B. Hepatitis B virus transgenic mice and chronically woodchuck hepatitis virus (WHV) infected woodchucks were treated with AIC649, respectively. In the mouse system AIC649 decreased the hepatitis B virus titer as effective as the "gold standard", Tenofovir. Interestingly, AIC649-treated chronically WHV infected woodchucks displayed a bi-phasic pattern of response: The marker for functional cure--hepatitis surface antigen--first increased but subsequently decreased even after cessation of treatment to significantly reduced levels. We hypothesize that the observed bi-phasic response pattern to AIC649 treatment reflects a physiologically "concerted", reconstituted immune response against WHV and therefore may indicate a potential for inducing functional cure in HBV-infected patients.
Intramuscular Transplantation of Muscle-Derived Stem Cells Accelerates Skeletal Muscle Healing After Contusion Injury via Enhancement of Angiogenesis (2011)

These findings could contribute to the development of biologic treatments to aid in muscle healing after muscle injury.