gebhart/patrepeval huggingface dataset:
Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. (1986)

Using pharmacological (Simpson, L.L., 1980, J. Pharmacol. Exp. Ther. 212:16-21) and autoradiographic techniques (Black, J.D., and J.O. Dolly, 1986, J. Cell Biol., 103:521-534), it has been shown that botulinum neurotoxin (BoNT) is translocated across the motor nerve terminal membrane to reach a postulated intraterminal target. In the present study, the nature of this uptake process was investigated using electron microscopic autoradiography. It was found that internalization is acceptor-mediated and that binding to specific cell surface acceptors involves the heavier chain of the toxin. In addition, uptake was shown to be energy and temperature-dependent and to be accelerated by nerve stimulation, a treatment which also shortens the time course of the toxin-induced neuroparalysis. These results, together with the observation that silver grains were often associated with endocytic structures within the nerve terminal, suggested that acceptor-mediated endocytosis is responsible for toxin uptake. This proposal is supported further by the fact that lysosomotropic agents, which are known to interfere with the endocytic pathway, retard the onset of BoNT-induced neuroparalysis and also affect the distribution of silver grains at nerve terminals treated with 125I-BoNT. Possible recycling of BoNT acceptors (an important aspect of acceptor-mediated endocytosis of toxins) at motor nerve terminals was indicated by comparing the extent of labeling in the presence and absence of metabolic inhibitors. On the basis of these collective results, it is concluded that BoNT is internalized by acceptor-mediated endocytosis and, hence, the data support the proposal that this toxin inhibits release of acetylcholine by interaction with an intracellular target.
Effects of Homologous Phosphoenolpyruvate-Carbohydrate Phosphotransferase System Proteins on Carbohydrate Uptake and Poly(3-Hydroxybutyrate) Accumulation in Ralstonia eutropha H16 (2011)

Seven gene loci encoding putative proteins of the phosphoenolpyruvate-carbohydrate phosphotransferase system (PEP-PTS) were identified in the genome of Ralstonia eutropha H16 by in silico analysis. Except the N-acetylglucosamine-specific PEP-PTS, an additional complete PEP-PTS is lacking in strain H16. Based on these findings, we generated single and multiple deletion mutants defective mainly in the PEP-PTS genes to investigate their influence on carbon source utilization, growth behavior, and poly(3-hydroxybutyrate) (PHB) accumulation. As supposed, the H16 ΔfrcACB and H16 ΔnagFEC mutants exhibited no growth when cultivated on fructose and N-acetylglucosamine, respectively. Furthermore, a transposon mutant with a ptsM-ptsH insertion site did not grow on both carbon sources. The observed phenotype was not complemented, suggesting that it results from an interaction of genes or a polar effect caused by the Tn5::mob insertion. ptsM, ptsH, and ptsI single, double, and triple mutants stored much less PHB than the wild type (about 10 to 39% [wt/wt] of cell dry weight) and caused reduced PHB production in mutants lacking the H16_A2203, H16_A0384, frcACB, or nagFEC genes. In contrast, mutant H16 ΔH16_A0384 accumulated 11.5% (wt/wt) more PHB than the wild type when grown on gluconate and suppressed partially the negative effect of the ptsMHI deletion on PHB synthesis. Based on our experimental data, we discussed whether the PEP-PTS homologous proteins in R. eutropha H16 are exclusively involved in the complex sugar transport system or whether they are also involved in cellular regulatory functions of carbon and PHB metabolism.
Navigation Using Signals of Opportunity in the AM Transmission Band (2006)

Maintaining a precision navigation solution both in a GPS hostile jamming environment and also in a GPS non-compatible terrain area is of great importance. To that end, this thesis evaluates the ability to navigate using signals from the AM band of the electromagnetic spectrum (520 to 1710 kHz). Navigation position estimates are done using multi-lateration techniques similar to GPS. However, pseudoranges are created using Time Difference of Arrival (TDOA) distances between a reference receiver and a mobile receiver, allowing the mobile receiver to obtain absolute position estimates over time. Four methods were developed for estimating the cross-correlation peak within a specified (sampled) portion of the cross-correlation data for use in TDOA measurement generation. To evaluate the performance of each peak locating method, a simulation environment was created to attempt to model real-world Amplitude Modulation (AM) signal characteristics. The model simulates AM transmission sources, signal receivers, propagation effects, inter-receiver frequency errors, noise addition, and multipath. When attempting to develop a data collection system for real-world signals, it became clear that selecting a proper analog front-end prior to digitization is pivotal in the success of the navigation system. Overall, this research shows that the use of AM signals for navigation appears promising. However, the characteristics of AM signal propagation, including multipath, need to be studied in greater detail to ensure the accuracy of the simulation models.
Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases (2015)

Monoclonal antibodies are being developed as therapeutics to complement drugs and vaccines or to fill the gap where no drugs or vaccines exist. These therapeutic antibodies (ThAb) may be especially important for infectious diseases in which there is antibiotic resistance, toxin-mediated pathogenesis, or for emerging pathogens. The unique structure of antibodies determines the specific nature of the effector function, so when developing ThAb, the desired effector functions need to be considered and integrated into the design and development processes to ensure maximum efficacy and safety. Antibody subclass is a critical consideration, but it is noteworthy that almost all ThAb that are licenced or currently in development utilise an IgG1 backbone. This review outlines the major structural properties that vary across subclasses, how these properties affect functional immunity, and discusses the various approaches used to study subclass responses to infectious diseases. We also review the factors associated with the selection of antibody subclasses when designing ThAb and highlight circumstances where different subclass properties might be beneficial when applied to particular infectious diseases. These approaches are critical to the future design of ThAb and to the study of naturally-acquired and vaccine-induced immunity.
DNA detection in hair of transgenic mice-a simple technique minimizing the distress on the animals (1999)

The breeding of transgenic animals requires that each individual offspring be analysed for integration of transgenic deoxyribonucleic acid (DNA), unless exclusively homozygous animals are mated. The standard protocol for identification of transgenic animals (Hogan et al. 1994) is based on tissue samples and preparation of chromosomal DNA including proteinase K digestion and phenol/chloroform extraction. The procedure described here represents a much simpler and faster method to screen offspring for the transgene DNA. It is based on the use of hair bulbs as sample material, which can be directly used for polymerase chain reaction (PCR) after alkaline lysis. This protocol allows large numbers of animals to be easily screened in a minimum amount of time. A unique advantage though, is the reduction of the distress caused to the animals. With respect to the 3Rs (Replacement, Reduction, Refinement), and because of technical advantages this method may replace ear or tail clipping.
Fungal Adherence to the Vascular Compartment: A Critical Step in the Pathogenesis of Disseminated Candidiasis (1992)

The importance of adherence of Candida albicans to the vascular structures in the pathogenesis of disseminated candidiasis is discussed. The evidence for adherence of this fungus to endothelial cells and to the subendothelial basement membrane in vivo is reviewed, as are the data documenting these events in vitro. Information on the subcellular interactions of the host's vascular structures with this pathogen is presented. For example, the C. albicans surface receptors for iC3b, laminin, and fibronectin are discussed in light of their possible ability to mediate the adherence of the fungus to vascular structures. The review is concluded with a potentially unifying concept of integrin-like receptors on Candida that bind arginine-glycine-aspartic acid-containing peptides that may account for the binding of numerous human proteins to C. albicans.
Beamforming in large-scale MIMO multiuser links under a per-node power constraint (2012)

Large-scale multiple-input multiple-output (MIMO) systems use a large array of nodes to offer high communication performance to multiple mobile users. For such systems to be economically practical, each node participating in the large-scale link likely has limited transmit power capability, and therefore properly limiting the per-node transmit power must be incorporated into the signal processing algorithm. This work generalizes an iterative beamforming algorithm for multiuser MIMO signaling, subject to such a per-node power constraint, that can accommodate nonlinear precoding and detection. Simulations using the algorithm for large-scale MIMO systems reveal that the approach can offer performance similar to that obtained with a more traditional sum-power constraint without the wide range of per-antenna transmit power distribution typical of such a constraint.
The regulation of veratridine‐stimulated electrogenic ion transport in mouse colon by neuropeptide Y (NPY), Y1 and Y2 receptors (2005)

1 Neuropeptide Y (NPY) is a prominent enteric neuropeptide with prolonged antisecretory effects in mammalian intestine. Veratridine depolarises neurons consequently causing epithelial anion secretion across mouse colon mucosa. Our aim was to characterise functionally, veratridine-stimulated mucosal responses and to determine the roles for NPY, Y(1), and Y(2) receptors in modulating these neurogenic effects. 2 Colon mucosae (with intact submucous innervation) from wild-type mice (+/+) and knockouts lacking either NPY (NPY-/-), Y(1)-/- or Y(2)-/- were placed in Ussing chambers and voltage clamped at 0 mV. Veratridine-stimulated short-circuit current (I(sc)) responses in +/+, Y(1) or Y(2) antagonist pretreated +/+ colon, Y(1)-/- and NPY-/- colon were insensitive to cholinergic blockade by atropine (At; 1 microM) and hexamethonium (Hex; 10 microM). Tetrodotoxin (TTX, 100 nM) abolished veratridine responses, but had no effect upon carbachol (CCh) or vasoactive intestinal polypeptide (VIP)-induced secretory responses. 3 To establish the functional roles for Y(1) and Y(2) receptors, +/+ tissues were pretreated with either the Y(1) or Y(2) receptor antagonist (BIBO3304 (300 nM) or BIIE0246 (1 microM), respectively) and veratridine responses were compared with those from Y(1)-/- or Y(2)-/- colon. Neither BIBO3304 nor Y(1)-/- altered veratridine-induced secretion, but Y(1) agonist responses were abolished in both preparations. In contrast, the Y(2) antagonist BIIE0246 significantly amplified veratridine responses in +/+ mucosa. Unexpectedly, NPY-/- colon exhibited significantly attenuated veratridine responses (between 1 and 5 min). 4 We demonstrate that electrogenic veratridine responses in mouse colon are noncholinergic and that NPY can act directly upon epithelia, a Y(1) receptor effect. The enhanced veratridine response observed in +/+ tissue following BIIE0246, indicates that Y(2) receptors are located on submucosal neurons and that their activation by NPY will inhibit enteric noncholinergic secretory neurotransmission. 5 We also demonstrate Y(1) and Y(2) receptor-mediated antisecretory tone in +/+ colon and show selective loss of each in Y(1) and Y(2) null colon respectively. In NPY-/- tissue, only Y(1)-mediated tone was present, this presumably being mediated by endogenous endocrine peptide YY. Y(2) tone was absent from NPY-/- (and Y(2)-/-) colon and we conclude that NPY activation of neuronal Y(2) receptors attenuates secretory neurotransmission thereby providing an absorptive electrolyte tone in isolated colon.
High-efficiency Fresnel acoustic lenses (1993)

Acoustic Fresnel lenses have emerged in recent years as an alternative to the conventional spherical lenses for focusing sound waves in applications such as acoustic microscopy. Fresnel lenses offer the advantage of near-planar geometry and, therefore, ease of fabrication compared to spherical lenses. The Fresnel acoustic lenses reported so far, however, have the disadvantage of low efficiency; only about 40% of the input signal is directed towards the focus. The design and fabrication of “binary” acoustic Fresnel lenses that offer much higher efficiencies are described. These lenses, while being still nearly planar, have multiple phase levels to achieve phase shifts other than 0 and 180 degrees as used in conventional, two phase Fresnel lenses. Acoustic Fresnel lenses were fabricated at frequencies of about 1 MHz and 170 MHz. Measurements of the focusing efficiency and point spread function have been performed to characterize the operation of these lenses. Focusing efficiencies in excess of 80% have been achieved with these lenses. The measurements compare well to theoretical simulations
A Role for Epsin N-terminal Homology/AP180 N-terminal Homology (ENTH/ANTH) Domains in Tubulin Binding (2003)

The epsin N-terminal homology (ENTH) domain is a protein module of approximately 150 amino acids found at the N terminus of a variety of proteins identified in yeast, plants, nematode, frog, and mammals. ENTH domains comprise multiple alpha-helices folded upon each other to form a compact globular structure that has been implicated in interactions with lipids and proteins. In characterizing this evolutionarily conserved domain, we isolated and identified tubulin as an ENTH domain-binding partner. The interaction, which is direct and has a dissociation constant of approximately 1 microm, was observed with ENTH domains of proteins present in various species. Tubulin is co-immunoprecipitated from rat brain extracts with the ENTH domain-containing proteins, epsins 1 and 2, and punctate epsin staining is observed along the microtubule cytoskeleton of dissociated cortical neurons. Consistent with a role in microtubule processes, the over-expression of epsin ENTH domain in PC12 cells stimulates neurite outgrowth. These data demonstrate an evolutionarily conserved property of ENTH domains to interact with tubulin and microtubules.
The relationship of the biophysical and biochemical characteristics of type VII collagen to the function of anchoring fibrils. (1990)

Type VII collagen is a major component of anchoring fibrils, which are 800-nm-long centrosymmetrically cross-banded fibrils that are believed to secure the attachment of certain epithelial basement membranes to the underlying stromal matrix. The ultrastructure of the anchoring fibrils is highly variable, suggesting that the fibrils are flexible. Flexibility measurements along the length of the triple-helical domain of type VII procollagen indicate that major flexible sites correlate well with known discontinuities in the (Gly-X-Y)n repeating sequence. Therefore, the helical disruptions may account for the tortuous shapes of anchoring fibrils observed ultrastructurally. The centrosymmetrical banding pattern observed for anchoring fibrils results from the unstaggered lateral packing of antiparallel type VII collagen dimers that form these structures. This antiparallel arrangement is specified by disulfide bonds formed at the margins of a 60-nm overlap of the amino termini. As long as these disulfide bonds remain intact, they protect the amino-terminal overlapping triple helices from collagenase digestion. This disulfide-bonded pair of triple helices is termed C-1. Large nonhelical domains (NC-1) extend from both ends of the anchoring fibrils and are believed to interact with the basement membrane or with anchoring plaques. Rotary shadowing of the NC-1 domains showed trident-like shapes, suggesting that a single alpha-chain contributed the structure of each arm and that the three arms were extended. Biochemical and biophysical analyses of NC-1 domains independently confirm these suggestions and imply that the arms of NC-1 domains are identical and individually capable of interactions with basement membrane components, potentially allowing trivalent interaction of type VII collagen with various macromolecules.
Opioid Therapy and Immunosuppression (2004)

The idea that opioids modulate the immune system is not new. By the late 19th century, Cantacuzene, used morphine to suppress cellular immunity and lower the resistance of guinea pigs to bacterial infection. While exogenous opioids mediate immunosuppression, endogenous opiates exert opposite actions. Acute and chronic opioid administration is known to have inhibitory effects on humoral and cellular immune responses including antibody production, natural killer cell activity, cytokine expression, and phagocytic activity. Opiates behave like cytokines, modulating the immune response by interaction with their receptors in the central nervous system and in the periphery. Potential mechanisms by which central opiates modulate peripheral immune functions may involve both the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. The presence of opioid receptors outside the central nervous system is increasingly recognized. Those receptors have been identified not only in peripheral nerves but also in immune inflammatory cells. The immunosuppression mediated by opiates may explain the increased incidence of infection in heroin addicts. Opiates may also promote immunodeficiency virus infection by decreasing the secretion of alpha and beta chemokines (important inhibitory cytokines for the expression of HIV) and at the same time increasing the expression of chemoreceptors CCR5 and CCR3, coreceptors for the virus. The fact that peripheral immunosupression is mediated at least in part by opioid receptors located in the central nervous system and that intrathecally administered opioids do not exert the same immunosuppressive effects may have important clinical implications for those patients receiving long-term opioid therapy for malignant and nonmalignant pain.
A neuro-evolution method for dynamic resource allocation on a chip multiprocessor (2002)

Technology-driven limitations will soon force microprocessor chips to contain multiple processing cores, as the scalability of individual cores peaks while transistor counts continue to increase. To obtain the best performance, flexible management of the on-chip resources, such as cache memory and off-chip bandwidth, is needed. However, the control for the dynamic management of these on-chip resources is difficult to design. In this paper, we propose a method for developing such a controller: evolving a recurrent neural network using the enforced sub-populations algorithm. The method is tested in a trace-based simulation that measures dynamic assignation of a pool of level-two cache banks to a set of processing cores. We present results showing that, when the chip is controlled by the neural network, we obtain a 13% performance improvement over static cache partitioning.
Novel fluorescent contrast agents for optical imaging of in vivo tumors based on a receptor-targeted dye-peptide conjugate platform (2001)

We have designed, synthesized, and evaluated the efficacy of novel dye-peptide conjugates that are receptor specific. Contrary to the traditional approach of conjugating dyes to large proteins and antibodies, we used small peptide-dye conjugates that target over-expressed receptors on tumors. Despite the fact that the peptide and the dye probe have similar molecular mass, our results demonstrate that the affinity of the peptide for its receptor and the dye fluorescence properties are both retained. The use of small peptides has several advantages over large biomolecules, including ease of synthesis of a variety of compounds for potential combinatorial screening of new targets, reproducibility of high purity compounds, diffusiveness to solid tumors, and the ability to incorporate a variety of functional groups that modify the pharmacokinetics of the peptide-dye conjugates. The efficacy of these new fluorescent optical contrast agents was evaluated in vivo in well-characterized rat tumor lines expressing somatostatin (sst(2)) and bombesin receptors. A simple continuous wave optical imaging system was employed. The resulting optical images clearly show that successful specific tumor targeting was achieved. Thus, we have demonstrated that small peptide-dye conjugates are effective as contrast agents for optical imaging of tumors.
Dysregulation of the E-Cadherin/Catenin Complex by Irreversible Mutations in Human Carcinomas (1998)

The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.