gebhart/patrepeval huggingface dataset:
Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. (1993)

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-Gal A) gene at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder-variant Fabry phenotypes, and for precise carrier detection in Fabry families, the alpha-Gal A transcripts or genomic sequences from unrelated Fabry hemizygotes were analyzed. In patients with the classical phenotype, 18 new mutations were identified: N34S, C56G, W162R, R227Q, R227X, D264V, D266V, S297F, D313Y, G328A, W340X, E398X, IVS2+2, IVS5 delta-2,3, 773 delta 2, 954 delta 5, 1016 delta 11, and 1123 delta 53. Unrelated asymptomatic or mildly affected patients with symptoms confined to the heart had a missense mutation, N215S, that expressed residual enzymatic activity. Related, moderately affected patients with late-onset cardiac and pulmonary manifestations had a small deletion, 1208 delta 3, that predicted the in-frame deletion of arginine 404 near the terminus of the 429 residue enzyme polypeptide. In addition, five small gene rearrangements involving exonic sequences were identified in unrelated classically affected patients. Two small deletions and one small duplication had short direct repeats at their respective breakpoint junctions and presumably resulted from slipped mispairing. A deletion occurred at a potential polymerase alpha arrest site, while the breakpoints of another deletion occurred at an inverted tetranucleotide repeat. Screening of unrelated Fabry patients with allele-specific oligonucleotides for seven mutations revealed that these were private, with the notable exception of N215S, R227Q, and R227X, which were each found in several unrelated families from different ethnic backgrounds. The CpG dinucleotide at codon 227 was the most common site of mutation, having been altered in 5% of the 148 unrelated Fabry alleles. These studies revealed that most alpha-Gal A lesions were private, that codon 227 was a mutational hot spot, and that certain mutations predicted a milder disease phenotype.
Diagnosis and surgical management of fractures of the orbit and optic canal (1991)

Recent advances in our ability to diagnose and treat orbital fractures have included devices to measure orbital pressure, refinement of the role of magnetic resonance scanning in the detection of intraorbital wooden foreign bodies, and further developments in alloplastic materials for orbital wall reconstruction. Surgical decision making in orbital fracture repair continues to be hampered by a lack of controlled studies to provide guidance. However, there is a growing trend in many centers towards earlier and more aggressive intervention. This swing of the pendulum towards early intervention is based on improved radiographic ability to demonstrate and quantitate the fracture-induced increase in orbital volume, combined with more delicate reconstructive capabilities provided by the new miniplate and microplate osteosynthesis systems. Indirect optic nerve trauma is a rare but potentially devastating injury in which blunt trauma to the head is transmitted through the bones of the skull to the bony optic nerve canal, causing a concussive injury to the optic nerve. The use of steroids continues to be the primary form of treatment for these injuries, although the doses originally considered “megadoses” may be too low based on data from spinal cord injury studies. Extracranial surgical decompression of the bony optic canal, performed by an ophthalmologist or otolaryngologist with special training in deep orbital surgery, has produced anecdotal reports of successful return of vision. The precise role of steroids and surgery in the treatment of this injury will be answered only by a prospective randomized trial.
Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast Cancer (2017)

Androgen receptor-targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.
Fuzzy clustering of physicochemical and biochemical properties of amino Acids (2011)

In this article, we categorize presently available experimental and theoretical knowledge of various physicochemical and biochemical features of amino acids, as collected in the AAindex database of known 544 amino acid (AA) indices. Previously reported 402 indices were categorized into six groups using hierarchical clustering technique and 142 were left unclustered. However, due to the increasing diversity of the database these indices are overlapping, therefore crisp clustering method may not provide optimal results. Moreover, in various large-scale bioinformatics analyses of whole proteomes, the proper selection of amino acid indices representing their biological significance is crucial for efficient and error-prone encoding of the short functional sequence motifs. In most cases, researchers perform exhaustive manual selection of the most informative indices. These two facts motivated us to analyse the widely used AA indices. The main goal of this article is twofold. First, we present a novel method of partitioning the bioinformatics data using consensus fuzzy clustering, where the recently proposed fuzzy clustering techniques are exploited. Second, we prepare three high quality subsets of all available indices. Superiority of the consensus fuzzy clustering method is demonstrated quantitatively, visually and statistically by comparing it with the previously proposed hierarchical clustered results. The processed AAindex1 database, supplementary material and the software are available at http://sysbio.icm.edu.pl/aaindex/ .
Short Communication. Weighting functions and data truncation in the fitting of multi-exponential functions (1974)

Artificial data were simulated by using two-exponential functions and normally distributed pseudo-random numbers. The variation corresponded to either constant or relative variance for the data error. These data were used to test (i) three different weighting functions and (ii) the effect of data truncation on the precision of estimating the parameters of two-exponential functions.
Humanization of KC4G3, an Anti-Human Carcinoma Antibody (1994)

We have previously constructed a chimeric version of KC4G3, a murine antibody that reacts with several human epithelial cancers and binds to the human breast epithelial mucin. We have now successfully humanized KC4G3 using positional consensus data, previously compiled after examining several other antibody structures, listing residues in the VH and V kappa frameworks that could influence antigen binding. We have previously showed that a fraction of the kappa chains of murine and chimeric KC4G3 migrates abnormally on SDS-PAGE most likely due to N-linked glycosylation in V kappa. The glycosylation signal has now been removed from V kappa, as a consequence of humanization. As expected, the humanized kappa chain migrates normally on SDS-PAGE. We detected no significant differences either in the affinities (1.6 x 10(9) M-1 vs. 1.4 x 10(9) M-1, respectively) or in the ability to compete for antigen binding, between the murine and the humanized antibodies. The humanized version is an IgG1, kappa immunoglobulin produced by mouse myeloma SP2/0-Ag14 cells and is designated HuKC4v2. The HuKC4v2 frameworks conform to the V kappa II and VHIII human consensus in all but six positions in V kappa and three positions in VH.
Bridging large defects in bone by demineralized bone matrix in the form of a powder. A radiographic, histological, and radioisotope-uptake study in rats. (1987)

Demineralized bone powder was used as an osteoinductive substance to bridge very large defects (more than 50 per cent of the total length of the bone) in one radius of each of thirty-three rats. An identical defect was produced in the contralateral radius of each animal for use as a control. The defect on the control side was left unbridged or was bridged by large chips of autologous bone or an autologous inlay graft. All rats showed formation of new bone throughout the length of the radial defect only on the side in which the demineralized bone powder had been implanted. The control side, in which an autologous graft in the form of chips or inlay had been implanted, showed resorption of the graft. The maximum rate of formation of bone occurred fifteen to twenty-one days after implantation of the demineralized bone powder. At thirty-five days, the experimental defect was fully bridged, forming solid bone, in 71 per cent of the rats, and the remaining 29 per cent showed bridging of 95.8 per cent of the length of the defect, with union on one side. Analysis of the sequential radiographs, technetium-99m scans, and histological findings showed that the formation of bone and bridging of the defect were superior on the side in which the demineralized bone powder had been implanted compared with the side in which pieces of autologous bone or an autologous inlay graft had been used.(ABSTRACT TRUNCATED AT 250 WORDS)
Strategies for Myocardial Repair (1995)

The therapeutic recourse for end-stage heart disease is currently limited to cardiac transplantation. The ability to augment cardiomyocyte number in an end-stage heart might facilitate myocardial function. Augmentation of cardiomyocyte number may be achievable by the targeted expression of cell cycle regulatory genes to the myocardium. Alternatively, intracardiac grafting of exogenous cardiomyocytes might also provide a viable approach to augment cardiomyocyte number. Potential strategies for heart muscle regeneration via gene therapy and cellular transplantation are discussed.
Heart rate variability features for epilepsy seizure prediction (2013)

Although refractory epileptic patients suffer from uncontrolled seizures, their quality of life (QoL) may be improved if an epileptic seizure can be predicted in advance. In the preictal period, an excessive neuronal activity of epilepsy affects the autonomic nerve system. Since the fluctuation of the R-R interval (RRI) of an electrocardiogram (ECG), called heart rate variability (HRV), reflects the autonomic nervous function, an epileptic seizure may be predicted through monitoring HRV data of an epileptic patient. In the present work, preictal and interictal HRV data of epileptic patients were analyzed for developing an epilepsy seizure prediction system. The HRV data of five patients were collected, and their HRV features were calculated. The analysis results showed that frequency HRV features, such as LF and LF/HF, changed at least one minute before seizure onset in all seizure episodes. The possibility of realizing a HRV-based seizure prediction system was shown through these analysis.
Inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) activity by suramin and suramin analogues is correlated to interaction with the GM-CSF nucleotide-binding site. (1995)

Suramin and suramin analogues strongly inhibit both nucleotide interaction with the nucleotide-binding site of granulocyte-macrophage colony-stimulating factor (GM-CSF) and bioactivity of the molecule as assessed by competition photoaffinity labeling and cell proliferation assay, respectively. The half-maximal inhibition of cell proliferation by suramin occurs at 68 +/- 2.5 microM; three suramin analogues achieved comparable activity. The degree of competitive inhibition of nucleotide-binding by these compounds and the inhibition of GM-CSF bioactivity are correlated such that the compounds show similar rank-order by both of these methods. The strong interaction of suramin and related compounds with the nucleotide-binding site may mimic nucleotide-mediated inhibition of GM-CSF bioactivity and may be an important mechanism by which suramin acts as a pharmacological anti-growth factor agent.
Molecular Characterization and Ocular Hypotensive Properties of the Prostanoid EP 2 Receptor (1995)

The cloning of the genes that encode for prostaglandin (PG) receptors has resolved much of the complexity and controversy in this area by confirming the classification proposed by Coleman, et al. Two issues that remained unresolved were (1) the inability of the EP2 agonist butaprost to interact with the cloned putative EP2 receptor and (2) molecular biological confirmation of a fourth PGE2-sensitive receptor, which was pharmacologically designated EP4. In order to provide clarification, we attempted to clone further PGE2-sensitive receptors. By using a cDNA probe that encodes for the human EP3A receptor, a cDNA clone that encoded for a novel PGE2-sensitive receptor was obtained by screening a human placenta library. This cDNA clone was transfected into COS-7 cells for pharmacological studies. The cDNA clone obtained from human placenta had only about 30% amino acid identity with cDNAs for other PG receptors, including those that encode for the previously proposed murine and human EP2 receptors. Radioligand binding studies on the novel EP receptor expressed in COS-7 cells revealed that selective EP2 agonists such as butaprost, AH 13205, AY 23626 and 19(R)-OH PGE2 all competed with 3H-PGE2 for its binding sites, whereas selective agonists for other PG receptor subtypes had minimal or no effect. This receptor was coupled to adenylate cyclase and EP2 agonists caused dose-related increases in cAMP. It appears that the cDNA described herein encodes for the pharmacologically defined EP2 receptor. Ocular studies revealed that AH 13205 decreased intraocular pressure in normal and ocular hypertensive monkeys by a mechanism that does not appear to involve inhibition of aqueous humor secretion.
Mitochondrial oxidative stress is the achille's heel of melanoma cells resistant to Braf-mutant inhibitor (2013)

Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.
Zinc Deficiency and Methylbenzylnitrosamine-lnduced Esophageal Cancer in Rats1 (1978)

Dietary zinc deficiency increases the incidence of and shortens the lag time for induction of esophageal tumors in rats by methylbenzylnitrosamine (MBN). Groups of control and zinc-deficient outbred Charles River CD rats were given 24, 17, 8, or 4 doses of MBN, administered twice weekly by intragastric intubation at doses of 2 mg/kg body weight. Between 58 and 93 days after the beginning of treatment, all rats were killed and examined. The frequency of esophageal tumors in the zinc-deficient groups was significantly higher than in the corresponding control groups. Following ip injection of [methyl-14C]MBN, DNA and RNA of esophagus and liver were more noticeably labeled than kidney, lung, and small intestine, which exhibited only modest labeling. In vitro incubation with [14C]MBN of tissue slices from esophagus, liver, kidney, and small intestine produced similar results. This pattern correlates well with the results of our studies of MBN-induced esophageal tumorigenesis.
The ankyrin repeat domains of the NF-kappa B precursor p105 and the protooncogene bcl-3 act as specific inhibitors of NF-kappa B DNA binding. (1992)

The inducible pleiotropic transcription factor NF-kappa B is composed of two subunits, p50 and p65. The p50 subunit is encoded on the N-terminal half of a 105-kDa open reading frame and contains a rel-like domain. To date, no function has been described for the C-terminal portion. We show here that the C-terminal half of p105, when expressed as a separate molecule, binds to p50 and can rapidly disrupt protein-DNA complexes of p50 or native NF-kappa B. Deletion analysis of this precursor-derived inhibitor activity indicated a domain containing ankyrin-like repeats as necessary for inhibition. The protooncogene bcl-3, which contains seven ankyrin repeats, can equally inhibit p50 DNA binding. These observations identify bcl-3 as an inhibitor of NF-kappa B and strongly suggest that the ankyrin repeats in these factors are involved in protein-protein interactions with the rel-like domain of p50. Comparison with other ankyrin repeat-containing proteins suggests that a subclass of these proteins acts as regulators of rel-like transcription factors.
Blocking OX-40/OX-40 Ligand Interaction In Vitro and In Vivo Leads to Decreased T Cell Function and Amelioration of Experimental Allergic Encephalomyelitis (1999)

The OX-40R is a member of the TNF receptor family and is expressed primarily on activated CD4+ T cells. When the OX-40R is engaged by the OX-40 ligand (OX-40L), a potent costimulatory signal occurs. We have identified a population of CD11b+ cells, isolated from the central nervous system (CNS) of mice with actively induced experimental allergic encephalomyelitis (EAE), that expresses OX-40L. Moreover, the expression of OX-40L was found to be associated with paralytic episodes of EAE and was reduced or absent at disease recovery. These CD11b+ cells also coexpressed B7 and MHC class II. Therefore, to address the relative contributions of OX-40R/OX-40L and CD28/B7 to the costimulation of myelin-specific T cells, blocking studies were performed using soluble OX-40R and/or soluble CTLA-4. CD11b+ cells isolated from the CNS of mice with actively induced EAE were able to present Ag to proteolipid protein 139-151-specific T cell lines in vitro. The addition of soluble OX-40R:Ig to CD11b+ brain microglia/macrophages inhibited T cell proliferation by 50-70%. The addition of CTLA-4:Ig inhibited T cell proliferation by 20-30%, and the combination inhibited T cell proliferation by 95%. In vivo administration of soluble OX-40R at the onset of actively induced or adoptively transferred EAE reduced ongoing signs of disease, and the mice recovered more quickly from acute disease. The data imply that OX-40L, expressed by CNS-derived APC, acts to provide an important costimulatory signal to EAE effector T cells found within the inflammatory lesions. Furthermore, the data suggest that agents designed to inhibit the OX-40L/OX-40R complex may be useful for treating autoimmune disease.
A Selective Fluorescent Sensor for Detecting Lead in Living Cells (2006)

We present the synthesis, properties, and biological applications of Leadfluor-1 (LF1), a new water-soluble, turn-on fluorescent sensor that is capable of selectively imaging Pb2+ in aqueous solution and in living cells. LF1 combines a fluorescein chromophore and a pseudocrown receptor to provide good selectivity for Pb2+ over a range of biologically and environmentally relevant metal ions in aqueous solution, with sensitivity to parts per billion EPA limits for allowable lead in drinking water. In addition to these attributes, imaging experiments further show that LF1 is the first small-molecule reagent that can be delivered into living cells and report changes in intracellular Pb2+ levels.
Microwave vector signal transmission over an optical fiber based on IQ modulation and coherent detection (2014)

A novel approach to transmitting two vector signals using a single optical carrier based on IQ modulation and coherent detection is proposed and demonstrated. In the proposed system, two quadrature phase-shift keying (QPSK) signals are IQ modulated on an optical carrier with one polarization state using a dual-parallel Mach-Zehnder modulator (DP-MZM). The optical carrier with an orthogonal polarization state is not modulated but transmitted with the modulated optical wave. At the receiver, the two orthogonally polarized light waves are separated and sent to a coherent detector, where the two QPSK signals are separated and demodulated. An experiment is performed. The transmission of two QPSK signals at 2 GHz with a data rate of 1 Gbps is implemented over a 25 km single-mode fiber. The performance of the transmission in terms of error vector magnitude is evaluated.
Hydrolysis of diadenosine polyphosphates by nucleotide pyrophosphatases/phosphodiesterases (2003)

Diadenosine polyphosphates (ApnAs) act as extracellular signaling molecules in a broad variety of tissues. They were shown to be hydrolyzed by surface-located enzymes in an asymmetric manner, generating AMP and Apn-1 from ApnA. The molecular identity of the enzymes responsible remains unclear. We analyzed the potential of NPP1, NPP2, and NPP3, the three members of the ecto-nucleotide pyrophosphatase/phosphodiesterase family, to hydrolyze the diadenosine polyphosphates diadenosine 5',5"'-P1,P3-triphosphate (Ap3A), diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A), and diadenosine 5',5"'-P1,P5-pentaphosphate, (Ap5A), and the diguanosine polyphosphate, diguanosine 5',5"'-P1,P4-tetraphosphate (Gp4G). Each of the three enzymes hydrolyzed Ap3A, Ap4A, and Ap5A at comparable rates. Gp4G was hydrolyzed by NPP1 and NPP2 at rates similar to Ap4A, but only at half this rate by NPP3. Hydrolysis was asymmetric, involving the alpha,beta-pyrophosphate bond. ApnA hydrolysis had a very alkaline pH optimum and was inhibited by EDTA. Michaelis constant (Km) values for Ap3A were 5.1 micro m, 8.0 micro m, and 49.5 micro m for NPP1, NPP2, and NPP3, respectively. Our results suggest that NPP1, NPP2, and NPP3 are major enzyme candidates for the hydrolysis of extracellular diadenosine polyphosphates in vertebrate tissues.