gebhart/patrepeval huggingface dataset:
Mechanisms of heterogeneous distribution of monoclonal antibodies and other macromolecules in tumors: significance of elevated interstitial pressure. (1988)

The therapeutic efficacy of monoclonal antibodies (MAbs), bound to radionuclides, chemotherapeutic agents, toxins, growth factors, or effector antibodies, depends upon their ability to reach their target in vivo in adequate quantities. Despite the high vascular permeability and interstitial transport coefficients in tumor tissue compared to several normal tissues, MAbs and their fragments do not distribute homogeneously in a tumor. Heterogeneity of tumor-associated antigen expression alone cannot explain this maldistribution of MAbs in tumors. We propose that in addition to the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MAbs, elevated interstitial pressure is responsible for the poor penetration of MAbs into tumors. Elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and also leads to an experimentally verifiable, radially outward convection which opposes the inward diffusion. We present here mathematical models for transport of fluid and macromolecules in a tumor. To illustrate the significance of elevated interstitial pressure, these models are used to describe the interstitial pressure, interstitial fluid velocity, and concentration of nonbinding macromolecules as a function of radial position in a uniformly perfused tumor. The key result of these models is that the filtration of fluid from blood vessels in a uniformly perfused tumor is (a) spatially heterogeneous, (b) a result of elevated interstitial pressure, and (c) sufficient to explain the heterogeneous distribution of macromolecules in tumors. Nonuniform blood flow, and extravascular binding would enhance this heterogeneity in the solute distribution considerably. The results of the models also agree with the following experimental data: (a) tumor interstitial pressure is low in the periphery and it increases toward the center of the tumor; (b) the radially outward fluid velocity at the tumor periphery predicted by the model is of the same order of magnitude as measured in tissue-isolated tumors; and (c) immediately after bolus injection, the concentration of macromolecules is higher in the periphery than in the center; however, at later time periods the peripheral concentration is lower than in the center. These results have significant implications not only for MAbs and their fragments, but for other biologically useful macromolecules (e.g., cytokines) produced by genetic engineering for cancer diagnosis and treatment.
A recurrent neural network model for generation of humanlike reaching movements (2018)

We constructed a recurrent neural network model that can generate human reaching motion. Given a target position, the neural network model is capable of producing muscular activation signals that move the hand to the target endpoint, while solving the problem of musculoskeletal redundancy by dynamic relaxation of the energy functions embedded in the network. The proposed neural network model was integrated with a two-dimensional three-link eight muscle musculoskeletal model of the human arm to simulate arm reaching movements in the horizontal and sagittal planes. Our results demonstrate that the model is capable of generating natural arm movements that have spatiotemporal features, such as a slightly curved hand path and the characteristic bell-shaped velocity profile, that are similar to those of actual human movements. Some aspects of the proposed computational framework might be utilized in the central nervous system for generation of reaching movements.
A 10-b 70-MS/s CMOS D/A converter (1991)

A 10-b 70-MS/s CMOS D/A converter fabricated in a 1- mu m CMOS technology is described. An integral linearity error caused by error distributions of current sources is reduced by a new switching sequence called hierarchical symmetrical switching. A differential linearity error caused by an off-axis drain-source implantation is reduced by the layout technique of current sources. The D/A converter is fabricated by using a single-polycide double-metal standard digital process. Both the integral and the differential linearity errors are less than +or-0.5 LSB. The settling time to +or-0.1 % is less than 14 ns. The worst-case glitch energy is approximately 60 pV-s. This D/A converter has a single power supply of 5 V and dissipates 170 mW at 70 MS/s. The chip size is 2.02 mm*1.87 mm.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand (2004)

The objective of this study was to investigate whether the immunostimulatory properties of human monocyte-derived dendritic cells (DCs) could be enhanced by triggering OX40/OX40L signaling. Since monocyte-derived DCs possess only low-cell surface levels of OX40L in the absence of CD40 signaling, OX40L was expressed by transfection of DCs with the corresponding mRNA. We show that OX40L mRNA transfection effectively enhanced the immunostimulatory function of DCs at multiple levels: OX40L mRNA transfection augmented allogeneic and HLA class II epitope-specific CD4+ T-cell responses, improved the stimulation of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without interfering with the prostaglandin E2 (PGE2)-mediated migratory function of the DCs, and facilitated interleukin 12 p70 (IL-12p70)-independent T helper type 1 (Th1) polarization of naive CD4+ T-helper cells. Furthermore, vaccination of tumor-bearing mice using OX40L mRNA-cotransfected DCs resulted in significant enhancement of therapeutic antitumor immunity due to in vivo priming of Th1-type T-cell responses. Our data suggest that transfection of DCs with OX40L mRNA may represent a promising strategy that could be applied in clinical immunotherapy protocols, while circumventing the current unavailability of reagents facilitating OX40 ligation.
Phase I Study of Antisense Oligonucleotide Against Vascular Endothelial Growth Factor: Decrease in Plasma Vascular Endothelial Growth Factor With Potential Clinical Efficacy (2006)

VEGF-AS was well tolerated, with biologic effects and preliminary evidence of clinical efficacy.
New Therapeutics for Chronic Heart Failure (2002)

Traditionally, clinicians have viewed heart failure either as a problem of excessive salt and water retention caused by abnormalities of renal blood flow, or as a hemodynamic problem associated with a reduced cardiac output and excessive peripheral vasoconstriction. Recently, clinicians have begun to adopt a neurohormonal model in which heart failure progresses because of the toxic effects of endogenous biological systems that become activated in heart failure. We review the rationale for existing heart failure therapies and discuss the reasoning behind the development of some emerging therapies.
Furin-mediated Processing of Pro-C-type Natriuretic Peptide (2003)

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family that is involved in a variety of homeostatic processes. Here we characterize the processing essential for the conversion of the precursor, human pro-CNP, to the biologically active hormone. In human embryonic kidney 293 and chondrosarcoma SW 1353 cells, recombinant pro-CNP was converted into a mature peptide intracellularly as detected by Western analysis. Expression of recombinant human corin, a proatrial natriuretic peptide convertase, did not enhance the processing of pro-CNP in these cells. The processing of pro-CNP was inhibited in the presence of an inhibitor of the endoprotease furin but was not affected by inhibitors of matrix metalloproteinases and tumor necrosis factor-alpha convertase. In furin-deficient human colon adenocarcinoma LoVo cells, no conversion of recombinant pro-CNP to CNP was detected. Expression of recombinant human furin in LoVo cells restored the ability of these cells to process pro-CNP. Furthermore, incubation of purified recombinant human furin with LoVo cell lysate containing pro-CNP led to the conversion of the precursor to a mature peptide. The furin-processed CNP was shown to be biologically active in a cell-based cGMP assay. These results demonstrate that furin is a critical enzyme for the processing of human pro-CNP.
The Study of the Cultivation of Chinese Hamster Ovary and Bows Cell Lines (1993)

Abstract Sixteen poly(organophosphazenes) were prepared by reaction between polydichlorophosphazene and nucleophilic reagents such as phenoxides and amino compounds. Adhesive and colony formation percent were investigated using V-79 Chinese hamster cells on poly(organophosphazene) films. It was found that [NP(OC6H5)2-x(NHBu-n)x]n(x=0.2, 1.8) gave the best percent adhesiveness. This value was similar to that of FalconR. On the other hand, [NP(OC6H5) (NHBu-n)] film showed best colony percent formation. This was of a higher value than that of Falcon. The [NP(OC6H5)2]n properties were poor for cultivation of useful Bowes and chinese hamster ovary cell lines in comparison with Cytodex III.
In-vitro platform to study ultrasound as source for wireless energy transfer and communication for implanted medical devices (2010)

A platform to study ultrasound as a source for wireless energy transfer and communication for implanted medical devices is described. A tank is used as a container for a pair of electroacoustic transducers, where a control unit is fixed to one wall of the tank and a transponder can be manually moved in three axes and rotate using a mechanical system. The tank is filled with water to allow acoustic energy and data transfer, and the system is optimized to avoid parasitic effects due to cables, reflection paths and cross talk problems. A printed circuit board is developed to test energy scavenging such that enough acoustic intensity is generated by the control unit to recharge a battery loaded to the transponder. In the same manner, a second printed circuit board is fabricated to study transmission of information through acoustic waves.
Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis (2006)

These results suggest that the Hh signaling pathway may play an important role in myogenic differentiation and the malignant potential of human intestinal stromal tumors.
Surgical options in the management of groin hernias. (1999)

Inguinal and femoral hernias are the most common conditions for which primary care physicians refer patients for surgical management. Hernias usually present as swelling accompanied by pain or a dragging sensation in the groin. Most hernias can be diagnosed based on the history and clinical examination, but ultrasonography may be useful in differentiating a hernia from other causes of groin swelling. Surgical repair is usually advised because of the danger of incarceration and strangulation, particularly with femoral hernias. Three major types of open repair are currently used, and laparoscopic techniques are also employed. The choice of technique depends on several factors, including the type of hernia, anesthetic considerations, cost, period of postoperative disability and the surgeon's expertise. Following initial herniorrhaphy, complication and recurrence rates are generally low. Laparoscopic techniques make it possible for patients to return to normal activities more quickly, but they are more costly than open procedures. In addition, they require general anesthesia, and the long-term hernia recurrence rate with these procedures is unknown.
Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein (2008)

Human interleukin-18 (hIL-18) is a cytokine that plays an important role in inflammation and host defense against microbes. Its activity is regulated in vivo by a naturally occurring antagonist, the human IL-18-binding protein (IL-18BP). Functional homologs of human IL-18BP are encoded by all orthopoxviruses, including variola virus, the causative agent of smallpox. They contribute to virulence by suppressing IL-18-mediated immune responses. Here, we describe the 2.0-A resolution crystal structure of an orthopoxvirus IL-18BP, ectromelia virus IL-18BP (ectvIL-18BP), in complex with hIL-18. The hIL-18 structure in the complex shows significant conformational change at the binding interface compared with the structure of ligand-free hIL-18, indicating that the binding is mediated by an induced-fit mechanism. EctvIL-18BP adopts a canonical Ig fold and interacts via one edge of its beta-sandwich with 3 cavities on the hIL-18 surface through extensive hydrophobic and hydrogen bonding interactions. Most of the ectvIL-18BP residues that participate in these interactions are conserved in both human and viral homologs, explaining their functional equivalence despite limited sequence homology. EctvIL-18BP blocks a putative receptor-binding site on IL-18, thus preventing IL-18 from engaging its receptor. Our structure provides insights into how IL-18BPs modulate hIL-18 activity. The revealed binding interface provides the basis for rational design of inhibitors against orthopoxvirus IL-18BP (for treating orthopoxvirus infection) or hIL-18 (for treating certain inflammatory and autoimmune diseases).
Dynamics of RNA-protein interactions in the HIV-1 Rev-RRE complex visualized by 6-thioguanosine-mediated photocrosslinking. (1997)

Expression of the structural proteins of human immunodeficiency virus type 1 (HIV-1) requires the direct interaction of multiple copies of the viral protein Rev with its target RNA, the Rev response element (RRE). RRE is a complex 351-nt RNA that is highly structured and located within the viral env gene. During initial Rev-RRE recognition, Rev binds with high affinity to a bubble structure located within the RRE RNA stem-loop II. We have used a site-specific photocrosslinking method based on 6-thioguanosine (6-thioG) photochemistry to probe the conformation of the high-affinity binding site of RRE RNA and its interactions with Rev protein under physiological conditions. A minimal duplex RNA containing the bubble region of RRE and 12 flanking base pairs was synthesized chemically. Two different RRE constructs with a single photoactive nucleoside (6-thio-dG or 6-thioG) at position 47 or 48 were synthesized. Upon UV irradiation, 6-thioG at both positions formed interstrand covalent crosslinks in RRE RNA. Mapping of crosslink sites by RNA sequencing revealed that 6-thioG at position 47 or 48 crosslinked to A73. In the presence of Rev, both RNA-RNA and RNA-protein crosslinks were observed, however, the RNA-RNA crosslink site was unchanged. Our results provide direct evidence that, during RNA-protein recognition, Rev is in close proximity to O6 of G47 and G48 in the major groove of RRE RNA. Our results also show that the bubble region of RRE RNA has a biologically relevant structure where G47 and G48 are in close proximity to A73 and this RNA structure is not changed significantly upon Rev binding. We propose that Rev protein recognizes and binds to specific structural elements of RRE RNA containing non-Watson-Crick base pairs and such structures could be a determinant for recognition by other RNA-binding proteins. Our site-specific crosslinking methods provide a general approach to capture dynamic states of biologically relevant RNA structures that are otherwise missed by NMR and X-ray crystallographic studies.
Modeling antibody hypervariable loops: a combined algorithm. (1989)

To be of any value, a predicted model of an antibody combining site should have an accuracy approaching that of antibody structures determined by x-ray crystallography (1.6-2.7 A). A number of modeling protocols have been proposed, which fall into two main categories--those that adopt a knowledge-based approach and those that attempt to construct the hypervariable loop regions of the antibody ab initio. Here we present a combined algorithm requiring no arbitrary decisions on the part of the user, which has been successfully applied to the modeling of the individual loops in two systems: the anti-lysozyme antibody HyHel-5, the crystal structure of which is as a complex with lysozyme [Sheriff, S., Silverton, E. W., Padlan, E. A., Cohen, G. H., Smith-Gill, S. J., Finzel, B. C. & Davies, D. R. (1987) Proc. Natl. Acad. Sci. USA 84, 8075-8079], and the free antigen binding fragment (Fab) of the anti-lysozyme peptide antibody, Gloop2. This protocol may be used with a high degree of confidence to model single-loop replacements, insertions, deletions, and side-chain replacements. In addition, it may be used in conjunction with other modeling protocols as a method by which to model particular loops whose conformations are predicted poorly by these methods.
The reactions of hetero‐allenes RN=C=X with phosphine derivatives containing a PH bond (1980)

Abstract Phosphine derivatives containing a PH bond can add to the C=N double bond of a hetero‐allene molecule RN=C=X. Ph 2 PH gives Ph 2 PC(X)NHR (X = O, S: R = Ph; X = N‐ p ‐tol: R = p ‐tol), cy‐C 6 H 11 PH 2 gives cy‐C 6 H 11 P[C(X)NHPh] 2 (X = O, S) And Ph 2 P(Q)H gives Ph 2 P(Q)C(X)NHR (Q = O: X = S and R = Ph; Q = S: X = O,S and R = Ph, X = N‐ p ‐tol and R = N‐ p ‐tol). The preparation of the new compounds, Ph 2 PC(N‐ p ‐tol)NH‐ p ‐tol, Ph 2 P(S)C(N‐ p ‐tol)NH‐ p ‐tol, Ph 2 P(O)C(O)NPhC(O)NHPh, cy‐C 6 H 11 P[C(S)NHPh] 2 and cy‐C 6 H 11 P[C(O)NHPh] 2 , is reported.
Malaria mimicry with tumor necrosis factor. Contrasts between species of murine malaria and Plasmodium falciparum. (1992)

Because Plasmodium berghei ANKA induces cerebral malaria and P. vinckei does not, the former has often been studied as a model for human falciparum malaria. It lacks, however, many of the systemic changes seen in the human disease. Because both of these murine models and the human disease have now been defined in terms of excess tumor necrosis factor (TNF) production, the authors have more closely examined the two murine models in this light to see which provides the better overall model for falciparum malaria. Administering TNF to malaria-infected mice did not cause cerebral symptoms nor breakdown of the blood-brain barrier, which is the hallmark of P. berghei ANKA cerebral malaria and is generally absent in human cerebral malaria. Tumor necrosis factor did, however, induce hypoglycemia and liver injury, pathology that is seen in terminal P. vinckei and falciparum malaria, but is absent in terminal P. berghei ANKA malaria. Plasma TNF and interleukin-6 (IL-6) also were found to be consistently higher in infections caused by P. vinckei than in those caused by P. berghei ANKA. The pathology of P. vinckei malaria is thus consistent with raised systemic levels of TNF and other cytokines, as is falciparum malaria. The authors therefore conclude that P. vinckei malaria, although lacking a cerebral component, is the better model for the human disease.
Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. (1998)

Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine.
Effects of calcium ions on proteolytic processing of HIV‐1 gp160 precursor and on cell fusion (1994)

Complete activation of human immunodeficiency virus type 1 (HIV-1) requires the endoproteolytic cleavage by cellular protease of the envelope glycoprotein precursor (gp160) into the external glycoprotein gp120, and the transmembrane glycoprotein gp41. We report here the effect of depletion of cellular calcium ions on maturation of precursor gp160 and its concomitant effect on syncytium formation. We show that the cellular endoprotease activity responsible for gp160 maturation and the capacity for HIV-1 to induce syncytium formation are calcium-dependent. In addition, we show that endoproteolytic maturation is a key step in syncytium formation induced by HIV-1.
Chemical Modification of Crude Timothy Grass Pollen Extract (1976)

The effects have been studied of three different chemical modifications of timothy grass pollen extract on various immunological properties. The ability to induce IgG antibody with specificity for native antigen was least affected by glutaraldehyde treatment; IgE antibody production was reduced to a similar extent by all three modifications; there was no increase in IgM production; delayed reactions were reduced. New antigenic determinants were introduced by all the modifications, but the effect was minimal following glutaraldehyde treatment. The significance of these results and the potential application of modified allergen in hyposensitisation therapy are discussed.
A Review on Deep Learning Techniques Applied to Semantic Segmentation (2017)

Image semantic segmentation is more and more being of interest for computer vision and machine learning researchers. Many applications on the rise need accurate and efficient segmentation mechanisms: autonomous driving, indoor navigation, and even virtual or augmented reality systems to name a few. This demand coincides with the rise of deep learning approaches in almost every field or application target related to computer vision, including semantic segmentation or scene understanding. This paper provides a review on deep learning methods for semantic segmentation applied to various application areas. Firstly, we describe the terminology of this field as well as mandatory background concepts. Next, the main datasets and challenges are exposed to help researchers decide which are the ones that best suit their needs and their targets. Then, existing methods are reviewed, highlighting their contributions and their significance in the field. Finally, quantitative results are given for the described methods and the datasets in which they were evaluated, following up with a discussion of the results. At last, we point out a set of promising future works and draw our own conclusions about the state of the art of semantic segmentation using deep learning techniques.
Using design based binning to improve defect excursion control for 45nm production (2007)

For advanced device (45 nm and below), we proposed a novel method to monitor systematic and random excursion. By integrating design information and defect inspection results into automated software (DBB), we can identify design/process marginality sites with defect inspection tool. In this study, we applied supervised binning function (DBC) and defect criticality index (DCI) to identify systematic and random excursion problems on 45 nm SRAM wafers. With established SPC charts, we will be able to detect future excursion problem in manufacturing line early.