gebhart/patrepeval huggingface dataset:
FUNCTIONAL AND STRUCTURAL COMPLEXITY OF SIGNAL TRANSDUCTION VIA G-PROTEIN-COUPLED RECEPTORS (1997)

A prerequisite for the maintenance of homeostasis in a living organism is fine-tuned communication between different cells. The majority of extracellular signaling molecules, such as hormones and neurotransmitters, interact with a three-protein transmembrane signaling system consisting of a receptor, a G protein, and an effector. These single components interact sequentially and reversibly. Considering that hundreds of G-protein-coupled receptors interact with a limited repertoire of G proteins, the question of coupling specificity is worth considering. G-protein-mediated signal transduction is a complex signaling network with diverging and converging transduction steps at each coupling interface. The recent realization that classical signaling pathways are intimately intertwined with growth-factor-signaling cascades adds another level of complexity. Elaborate studies have significantly enhanced our knowledge of the functional anatomy of G-protein-coupled receptors, and the concept has emerged that receptor function can be modulated with high specificity by coexpressed receptor fragments. These results may have significant clinical impact in the future.
Mutation of a ligand binding domain of beta 3 integrin. Integral role of oxygenated residues in alpha IIb beta 3 (GPIIb-IIIa) receptor function. (1994)

A single amino acid substitution in beta 3 (Asp119 --> Tyr) abrogates the ligand binding function of beta 3 integrins and alters the divalent cation conformation of the platelet integrin alpha IIb beta 3 (GPIIb-IIIa). This aspartic acid residue resides within a conserved cluster of oxygenated residues that may provide ligands for the coordination of divalent cations. To assign function to the other oxygenated residues in this group (Ser121, Ser123, Asp126, Asp127, and Ser130), each of these amino acids in beta 3 was individually substituted by alanine. None of these amino acid substitutions altered heterodimer formation or surface expression. However, the substitutions had differential effects on receptor function. Substitution at positions Asp119 or Ser121 produced a complete loss of receptor function. Cells expressing these mutants failed to adhere to fibrinogen, failed to bind activation-independent ligand-mimetic peptides, and did not bind the ligand-mimetic mAb PAC1 following activation of the receptor. Similarly, cells expressing beta 3 with a substitution at Ser123 also failed to adhere to fibrinogen and did not bind RGD peptide or mAb PAC1. These cells did retain the capacity to bind an alpha IIb beta 3-specific, high affinity peptidomimetic, but occupancy did not induce the conformational change from resting to activated state observed following occupancy of the wild type receptor. Substitution at positions Asp126, Asp127, or Ser130 had no effect on ligand binding function. These data indicate that Asp119, along with Ser121 and Ser123, plays an integral role in the ligand binding function of alpha IIb beta 3.
A peptide encoded by human gene MAGE‐3 and presented by HLA‐A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE‐3 (1994)

The human MAGE-3 gene is expressed in many tumors of several histological types but it is silent in normal tissues, with the exception of testis. Antigens encoded by MAGE-3 may, therefore, be useful targets for specific anti-tumor immunization of cancer patients. We reported previously that MAGE-3 codes for an antigenic peptide recognized on a melanoma cell line by autologous cytolytic T lymphocytes (CTL) restricted by HLA-A1. Here we report that the MAGE-3 gene also codes for another antigenic peptide that is recognized by CTL restricted by HLA-A2. MAGE-3 peptides bearing consensus anchor residues for HLA-A2 were synthesized and tested for binding. T lymphocytes from normal individuals were stimulated with autologous irradiated lymphoblasts pulsed with each of three peptides that showed strong binding to HLA-A2. Peptide FLWGPRALV was able to induce CTL. We obtained CTL clones that recognized not only HLA-A2 cells pulsed with this peptide but also HLA-A2 tumor cell lines expressing the MAGE-3 gene. The proportion of melanoma tumors expressing this antigen should be approximately 32% in Caucasian populations, since 49% of individuals carry the HLA-A2 allele and 65% of melanomas express MAGE-3.
A Versatile Method for Tuning the Chemistry and Size of Nanoscopic Features by Living Free Radical Polymerization (2003)

A novel approach is presented for manipulating the size and chemistry of nanoscopic features using a combination of contact molding and living free radical polymerization. In this approach a highly cross-linked photopolymer, based on a methacrylate/acrylate mixture, was patterned into submicrometer-sized features on a silicon wafer using a contact-molding technique. A critical component of the monomer mixture was the incorporation of an initiator containing monomer into the network structure, which provides sites for functional group amplification. Features ranging in size from 5 microm to <60 nm were accurately replicated by this process and living free radical polymerizations, both atom transfer radical and nitroxide-mediated polymerization (NMP), could be conducted from these initiating sites to yield polymer brushes which represent a grafted layer of linear chains attached to the original network polymer. Grafts consisting of polystyrene, poly(methyl methacrylate), and poly(2-hydroxyethyl)methacrylate were grown with controlled thicknesses ranging from 10 to 143 nm and graft molecular weights of between 18 000 to 290 000 amu. As a result of this secondary graft process, feature sizes could be tuned from the original 100 nm down to 20 nm, and the surface chemistry varied from hydrophilic to hydrophobic starting from the same initial master pattern. The thin films and patterned features were characterized by contact angle, ellipsometry, optical, and atomic force microscopies.
Oriented Speckle Reducing Anisotropic Diffusion (2007)

Ultrasound imaging systems provide the clinician with noninvasive, low-cost, and real-time images that can help them in diagnosis, planning, and therapy. However, although the human eye is able to derive the meaningful information from these images, automatic processing is very difficult due to noise and artifacts present in the image. The speckle reducing anisotropic diffusion filter was recently proposed to adapt the anisotropic diffusion filter to the characteristics of the speckle noise present in the ultrasound images and to facilitate automatic processing of images. We analyze the properties of the numerical scheme associated with this filter, using a semi-explicit scheme. We then extend the filter to a matrix anisotropic diffusion, allowing different levels of filtering across the image contours and in the principal curvature directions. We also show a relation between the local directional variance of the image intensity and the local geometry of the image, which can justify the choice of the gradient and the principal curvature directions as a basis for the diffusion matrix. Finally, different filtering techniques are compared on a 2-D synthetic image with two different levels of multiplicative noise and on a 3-D synthetic image of a Y-junction, and the new filter is applied on a 3-D real ultrasound image of the liver.
Collagenolytic enzymes in human neoplasms. (1972)

A variety of human neoplasms were examined for their ability to produce collagenolytic enzymes in culture. Some types of tumors of epithelial origin demonstrated a very high frequency of collagenolytic activity, while neoplasms of mesenchymal origin, nonneoplastic tissues, and other types of epithelial neoplasms only rarely produced collagenase. In particular, tumors of the colon and carcinomas of both squamous and basal cell origin displayed a high frequency of activity.

Tumor collagenases from several different sources were isolated and examined for their mode of attack on native collagen, pH optima, and inhibition of activity by EDTA, cysteine, and pooled human serum. Tumor enzymes appear to be similar to the collagenases isolated from normal human skin by these criteria.
Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. (1992)

von Willebrand factor (vWf) is synthesized as a large precursor that dimerizes in the endoplasmic reticulum and forms multimers in the trans- and post-Golgi compartments of megakaryocytes and endothelial cells. The disulfide-bonded multimers are stored in alpha granules of platelets and Weibel-Palade bodies of endothelial cells. The prosequence, composed of two homologous D domains, is required for vWf multimerization and storage. Each D domain contains vicinal cysteines (159Cys-Gly-Leu-162Cys and 521Cys-Gly-Leu-524Cys) that are similar to those at the active site of disulfide isomerases that catalyze thiol protein disulfide interchange. As in disulfide isomerases, a positively charged amino acid (lysine) is also found in close proximity to the vicinal cysteines. Although conserved, the lysine present in thioredoxin was shown not to be essential for its redox activity. We investigated the role of the vicinal cysteines and the lysine residue in the vWf propolypeptide by site-directed mutagenesis and expression of the resulting constructs in mammalian cells. Insertion of an extra glycine between the vicinal cysteines in either D domain inhibited multimerization of dimers, whereas alteration of lysine to glycine in both domains (residues 157 and 519) had no effect. This suggests the importance of the vicinal cysteines but not the lysines in vWf multimerization. Expression of the mutant with an additional glycine in the D1 domain in AtT-20 cells, a mouse pituitary cell line that can store vWf, led to the storage of the resulting dimers. This demonstrates that the mutation did not effect the capacity of the propolypeptide to direct vWf storage while its ability to promote interchain disulfide bonding was eliminated.
Photonic nanojet-enhanced nanometer-scale germanium photodiode (2013)

A design challenge for photodiodes yielding both high speed and responsivity is the necessity to concentrate incident light into a subwavelength active volume region. Photonic nanojets have been reported in the literature as a means to focus an incident plane wave to a subwavelength-waist propagating beam with applications ranging from next-generation DVDs to characterizing subwavelength features within dielectric targets. In the present work, a new application of photonic nanojets is proposed, focusing electromagnetic energy into a photodiode. Three-dimensional finite-difference time-domain solutions are conducted to determine the advantages of photonic nanojet-enhanced photodiodes at near-infrared wavelengths (1310 nm). We find that photonic nanojets provide a factor of 26 increase in the volume-integrated electric field within the subwavelength active volume of the photodiode of size 0.0045 μm³. Furthermore, this increase is achieved independent of the incident polarization and over a broad bandwidth. Photonic nanojets may thus serve as an attractive alternative to plasmonics for some applications.
Maximum oxidative phosphorylation capacity of the mammalian heart (1997)

It is difficult to estimate the maximum in vivo aerobic ATP production rate of the intact heart independent of limitations imposed by blood flow, oxygen delivery, and maximum mechanical power. This value is critical for establishing the kinetic parameters that control oxidative phosphorylation, as well as for providing insights into the limits of myocardial performance. In this study, the maximum ADP-P(i)-driven heart mitochondrial respiratory rate (MV(O2 mito)) was determined with saturating levels of oxygen, substrates, and cofactors at 37 degrees C. These rates were normalized to cytochrome alpha1 alpha3 (cytochrome oxidase; Cyt a) content. To extrapolate this rate to the intact heart, the Cyt a content of the myocardium (nmol Cyt a/g wet wt myocardium) was determined in the same hearts. The maximum ADP-P(i)-driven mitochondrial respiratory rates were 676 +/- 31 and 665 +/- 65 nmol O2 x min(-1) x nmol Cyt a(-1) in the dog and pig, respectively. The Cyt a content in the two species was 43.6 +/- 2.4 and 36.6 +/- 3.1 nmol Cyt a/g wet wt, respectively. With these values, the MV(O2 mito) was calculated to be 29.5 (dog) and 24.3 (pig) micromol O2 x min(-1) x g wet wt myocardium(-1). Comparison with in vivo studies shows that the exercising heart can utilize 80-90% of its maximum oxidative capacity, implying there is little aerobic ATP production reserve in the mammalian heart.
Specificity of the immune response to the group B polysaccharide of Neisseria meningitidis. (1991)

A panel of monoclonal antibodies (mAb) and polyclonal sera of murine, human and equine origin, of IgM isotype and with specificity for Neisseria meningitidis group B polysaccharide, an alpha(2----8)-linked homopolymer of sialic acid, were examined for their antigenic and biological specificities. The nature of the antigenic determinants on B polysaccharide was investigated using a series of N-acyl derivatives of B polysaccharide, two sialic acid polymers containing alpha(2----9)-linkages and a series of polynucleotides. The panel of antibodies recognized an array of unrelated antigenic determinants on the B polysaccharide, despite its structural simplicity, and all but one were highly effective in an in vitro bactericidal assay and/or in an in vivo murine passive protection model. There was no evidence that B polysaccharide induced antibody capable of blocking biological activity (blocking antibody).
In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients. (1979)

The cytotoxic nucleoside 2'-deoxyadenosine is excreted in excessive amounts by individuals with genetic deficiency of adenosine deaminase, and may be in part responsible for the severe combined immune dysfunction from which they suffer. Earlier studies from this laboratory showed that 2'-deoxyadenosine causes the irreversible inactivation of the enzyme S-adenosylhomocysteine hydrolase by an active site-directed, "suicide-like" process. In this communication we have demonstrated similar inactivation of S-adenosylhomocysteine hydrolase in hemolysate and in intact erythrocytes, as well as a striking deficiency of S-adenosylhomocysteine hydrolase activity in the erythrocytes of three adenosine deaminase-deficient patients. In vivo suicide-like inactivation of S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine may contribute to the cytotoxicity of 2'-deoxyadenosine and to the immune dysfunction in adenosine deaminase deficiency.
RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases (2018)

In conclusion, this study showed a genetic intra- and intertumor heterogeneity in MTC, But in only 20% of CASES These results could justify the relatively moderate level of aggressiveness of the disease with respect to more aggressive human tumors that are characterized by a high rate of mutation and heterogeneity.
Association of Protamine IgE and IgG Antibodies with Life-Threatening Reactions to Intravenous Protamine (1989)

Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery. Retrospective studies have shown that such reactions are more common in diabetic patients receiving daily subcutaneous injections of protamine-insulin preparations. To determine whether anti-protamine IgE or IgG antibodies might explain the increased risk for protamine reactions among patients with protamine-insulin-dependent diabetes, we conducted a case-control study of 27 patients (diabetic and nondiabetic) who had acute reactions to intravenous protamine and 43 diabetic patients who tolerated protamine without a reaction during diagnostic or surgical procedures. Cases and controls were grouped according to previous exposure to protamine-insulin preparations. In diabetic patients who had received protamine-insulin injections, the presence of serum antiprotamine IgE antibody was a significant risk factor for acute protamine reactions (relative risk, 95; P = 1.0 X 10(-5), as was antiprotamine IgG (relative risk, 38; P = 1.2 X 10(-5). No patients without previous exposure to protamine-insulin injections had serum protamine IgE antibodies. In this group, anti-protamine IgG antibody was a risk factor for protamine reactions (relative risk, 25; P = 0.0062). We conclude that in protamine-insulin-dependent diabetics, the increased risk of serious reactions when intravenous protamine was given appeared to be caused largely by antibody-mediated mechanisms. In nondiabetic subjects, the presence of protamine IgG was significantly associated with an increased risk of acute protamine reactions, although many nondiabetic subjects who had reactions had no IgG antibodies.
Concepts and targets in triple-negative breast cancer: recent results and clinical implications (2016)

Triple-negative breast cancer (TNBC) is a heterogeneous disease in which tumors are defined by lack of expression of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) receptor. No targeted therapies are available for the treatment of TNBC, and chemotherapy remains the standard of care. Gene expression profiling has identified six distinct molecular subtypes of TNBC. The identification of novel targets, coupled with the development of therapies for different subsets of TNBC, holds great promise for the future treatment of this aggressive form of breast cancer. This review focuses on novel therapies in development for the treatment of TNBC.
Pelvic Electrical Neuromodulation for the Treatment of Overactive Bladder Symptoms (2011)

Overactive bladder syndrome negatively affects the daily life of many people. First-line conservative treatments, such as antimuscarinics, do not always lead to sufficient improvement of the complaints and/or are often associated with disabling adverse effects leading to treatment failure. Electrical stimulation of the sacral nerves has emerged as an alternative and attractive treatment for refractory cases of bladder overactivity. Few theories attempted to explain its mechanism of action which remains elusive. It involves percutaneous posterior tibial nerve stimulation and more commonly sacral neuromodulation. For the latter, temporary sacral nerve stimulation is the first step. If the test stimulation is successful, a permanent device is implanted. The procedure is safe and reversible. It carries a durable success rate. The technique should be combined with careful followup and attentive adjustments of the stimulation parameters in order to optimize the clinical outcomes. This paper provides a review on the indications, possible mechanisms of action, surgical aspects and possible complications, and safety issues of this technique. The efficacy of the technique is also addressed.
Yin Yang 1 expression in human tumors (2010)

The Yin Yang 1 (YY1) transcription factor has been identified to target a plethora of potential target genes, the products of which are important for proliferation and differentiation. The mechanisms of YY1 action are related to its ability to initiate, activate or repress transcription depending on the context in which it binds. This article sheds a light on the role that YY1 plays in different human types of cancer, through the context of its expression levels. Moreover, we concentrate on the most relevant studies that have focused on YY1 regulation. we performed computational analysis on thirty-six publicly available Gene expression Omnibus (GeO) datasets, to further understand whether differences in YY1 transcript levels occur in different cancer types when compared with relative normal tissue, benign tumor or its metastatic counterpart. Our results suggest a dual role of YY1 in cancer development, either through overexpression or under-expression, depending on the tumor type.
Rac inhibits thrombin-induced Rho activation: evidence of a Pak-dependent GTPase crosstalk (2006)

The strict spatio-temporal control of Rho GTPases is critical for many cellular functions, including cell motility, contractility, and growth. In this regard, the prototypical Rho family GTPases, Rho, Rac, and Cdc42 regulate the activity of each other by a still poorly understood mechanism. Indeed, we found that constitutively active forms of Rac inhibit stress fiber formation and Rho stimulation by thrombin. Surprisingly, a mutant of Rac that is unable to activate Pak1 failed to inhibit thrombin signaling to Rho. To explore the underlying mechanism, we investigated whether Pak1 could regulate guanine nucleotide exchange factors (GEFs) for Rho. We found that Pak1 associates with P115-RhoGEF but not with PDZ-RhoGEF or LARG, and knock down experiments revealed that P115-RhoGEF plays a major role in signaling from thrombin receptors to Rho in HEK293T cells. Pak1 binds the DH-PH domain of P115-RhoGEF, thus suggesting a mechanism by which Rac stimulation of Pak1 may disrupt receptor-dependent Rho signaling. In agreement, expression of a dominant-negative Pak-Inhibitory Domain potentiated the activation of Rho by thrombin, and prevented the inhibition of Rho by Rac. These findings indicate that Rac interferes with receptor-dependent Rho stimulation through Pak1, thus providing a mechanism for cross-talk between these two small-GTPases.
Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. (1990)

Respiratory distress and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. More than 30 yr ago it was suggested that the large amounts of DNA in purulent secretions contribute to its viscosity and that bovine pancreatic DNase I could reduce the viscosity. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of cystic fibrosis, we have cloned, sequenced, and expressed rhDNase. Catalytic amounts of rhDNase greatly reduce the viscosity of purulent cystic fibrosis sputum, transforming it within minutes from a nonflowing viscous gel to a flowing liquid. The reduction in viscosity is associated with a decrease in size of DNA in the sputum. Inhalation of a rhDNase aerosol may be a simple direct approach that will help individuals with cystic fibrosis and other patients with pneumonia or bronchitis to clear their airways of purulent secretions.
Hypoxic neuropathy Does hypoxia play a role in diabetic neuropathy? (1989)

In this report I review: (1) the blood supply and endoneurial microenvironment of nerve; (2) the class, type, and spatial distribution of nerve fiber degeneration as a function of number, site, and class of vessels occluded; (3) the putative mechanisms of nerve hypoxia; and (4) the role of hypoxia in diabetic polyneuropathy.