gebhart/patrepeval huggingface dataset:
Immunohistochemical Demonstration of Enzymatically Modified Human LDL and Its Colocalization With the Terminal Complement Complex in the Early Atherosclerotic Lesion (1998)

Treatment of low density lipoprotein (LDL) with degrading enzymes transforms the molecule to a moiety that is micromorphologically indistinguishable from lipoproteinaceous particles that are present in atherosclerotic plaques, and enzymatically modified LDL (E-LDL), but not oxidized LDL (ox-LDL), spontaneously activates the alternative complement pathway, as do lesion lipoprotein derivatives. Furthermore, because E-LDL is a potent inducer of macrophage foam cell formation, we propose that enzymatic degradation may be the key process that renders LDL atherogenic. In this article, we report the production of two murine monoclonal antibodies recognizing cryptic epitopes in human apolipoprotein B that become exposed after enzymatic attack on LDL. One antibody reacted with LDL after single treatment with trypsin, whereas recognition by the second antibody required combined treatment of LDL with trypsin and cholesterol esterase. In ELISAs, both antibodies reacted with E-LDL produced in vitro and with lesion complement activator derived from human atherosclerotic plaques, but they were unreactive with native LDL or ox-LDL. The antibodies stained E-LDL, but not native LDL or ox-LDL, that had been artificially injected into arterial vessel walls. With the use of these antibodies, we have demonstrated that early human atherosclerotic coronary lesions obtained at autopsy as well as lesions examined in freshly explanted hearts always contain extensive extracellular deposits of E-LDL. Terminal complement complexes, detected with a monoclonal antibody specific for a C5b-9 neoepitope, colocalized with E-LDL within the intima, which is compatible with the proposal that subendothelially deposited LDL is enzymatically transformed to a complement activator at the earliest stages in lesion development.
MLL-SEPTIN gene fusions in hematological malignancies (2011)

The mixed lineage leukemia (MLL) locus is involved in more than 60 different rearrangements with a remarkably diverse group of fusion partners in approximately 10% of human leukemias. MLL rearrangements include chromosomal translocations, gene internal duplications, chromosome 11q deletions or inversions and MLL gene insertions into other chromosomes, or vice versa. MLL fusion partners can be classified into four distinct categories: nuclear proteins, cytoplasmatic proteins, histone acetyltransferases and septins. Five different septin genes (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) have been identified as MLL fusion partners, giving rise to chimeric fusion proteins in which the N terminus of MLL is fused, in frame, to almost the entire open reading frame of the septin partner gene. The rearranged alleles result from heterogeneous breaks in distinct introns of both MLL and its septin fusion partner, originating distinct gene fusion variants. MLL-SEPTIN rearrangements have been repeatedly identified in de novo and therapy related myeloid neoplasia in both children and adults, and some clinicopathogenetic associations are being uncovered. The fundamental roles of septins in cytokinesis, membrane remodeling and compartmentalization can provide some clues on how abnormalities in the septin cytoskeleton and MLL deregulation could be involved in the pathogenesis of hematological malignancies.
Do single enantiomers have something special to offer? (2001)

Single enantiomers have a significant role to play in enhancing drug discovery and development. Researchers are overcoming the technical limitations associated with developing single enantiomers, and the growth in targeted drug development already means that more single enantiomers are developed ab initio. Moreover, as pharmaceutical companies decide whether to progress a single enantiomer, rather than a racemate, early in development, increasingly fewer racemates will reach the market. Developing a single enantiomer as a line extension of a profitable drug is of growing importance and is reflected in the increasing number of speculative patents on chiral switches. The implications are that single enantiomers will eventually touch every area of clinical medicine. As the number of chiral drugs launched onto the market increases, so clinicians need to be aware of the key issues surrounding enantiomers. This review examines some of the issues arising from the growing importance of enantiomers in medicine. Copyright 2001 John Wiley & Sons, Ltd.
Activation of the lac Operon of Escherichia coli by a mutant FNR protein (1987)

The FNR protein of E. coli is a transcriptional activator required for the expression of genes involved in anaerobic respiratory pathways. Site-directed mutagenesis was used to alter three amino acids in the recognition helix of the putative DNA-binding domain of FNR, with the aim of changing its specificity to that of the cyclic AMP receptor protein (CRP). In the presence of the mutant protein (FNR-215) expression of the lac operon was activated during anaerobiosis and unaffected by glucose. FNR-215 did not have a uniform effect on the expression of other cAMP-CRP-dependent genes, but the results demonstrate the fundamental similarity between FNR- and CRP-mediated transcriptional activation.
CMOS RF Integrated Circuits: Past, Present and Future (Invited) (1999)

CMOS RF ICs continue their transition from academic curiosities to practical devices. Recent milestones at the device- and building block-level include: Noise figures for single-ended LNAs of ~ldB in the low-GHz range; fully integrated oscillators with phase noise compliant with GSM specifications at under lOmW power consumption; 5GHz injection-locked frequency dividers with sub-mW power consumption and large (~30%) tuning range; MOSFET ring mixers with over lOdBm 11P3 and "zero" power consumption; shielded spiral and helical inductors with improved Q; accumulation-mode MOS varactors with Q-frequency products in excess of 100-200GHz and tuning ratios approaching 2:1; fixed lateral flux capacitors with still higher Q-f products; coplanar transmission lines with <0.3dB/mm attenuation at 50GHz; microwave-compatible ESD structures; and constant-gm biasing for process independence. These advances have combined to enable a single-chip GPS receiver in 0.5μm to exhibit 2.8dB overall NF, 57dB SFDR at 115mW, and a 5GHz HIPERLAN receiver to exhibit 5dB NF at <45mW using a 0.25μm technology. Scaling forces that are already firmly in place will continue to drive still greater improvements in performance.
Diabetes and Endocrinology market analysis. (2021)

In 2012 there were 1.5 million deaths worldwide directly caused by diabetes. It was the eighth leading cause of death among both sexes and the fifth leading cause of death in women in 2012. Blood glucose levels that are higherthan-optimal, even if below the diagnostic threshold for diabetes, are a major source of mortality and morbidity. The diagnostic criterion for diabetes is fasting plasma glucose ≥ 7.0 mmol/L – a diagnostic point selected on the basis of micro-vascular complications such as diabetic retinopathy. The risk of macro-vascular disease, such as heart attack or stroke, however, starts increasing well before this diagnostic point. To better understand the full impact of blood glucose levels on mortality therefore requires a look at mortality related to blood glucose as a risk factor. The total burden of deaths from high blood glucose1 in 2012 has been estimated to amount to 3.7 million. This number includes 1.5 million diabetes deaths, and an additional 2.2 million deaths from cardiovascular diseases, chronic kidney disease, and tuberculosis related to higher-than-optimal blood glucose. Its magnitude highlights that high blood glucose causes a large burden of mortality beyond those deaths directly caused by diabetes. The largest number of deaths resulting from high blood glucose occur in upper-middle income countries (1.5 million) and the lowest number in low-income countries (0.3 million). After the age of 50, middle-income countries have the highest proportion of deaths attributed to high blood glucose, for both men and women.
Heavy chain position 50 is a determinant of affinity and specificity for the anti-digoxin antibody 26-10. (1993)

Antibody produced by a variant of the murine antidigoxin hybridoma 26-10 has reduced affinity for digoxin but enhanced recognition of the digoxin 12-hydroxyl due to a Tyr to His substitution at heavy chain position 50 (Schildbach, J. F., Panka, D. J., Parks, D. R., Jager, G. C., Novotny, J., Herzenberg, L. A., Mudgett-Hunter, M., Bruccoleri, R. E., Haber, E., and Margolies, M. N. (1991) J. Biol. Chem. 266, 4640-4647). Consistent with these data, the 26-10 Fab-digoxin x-ray crystal structure (Jeffrey, P. D., Strong, R. K., Sieker, L. C., Chang, C. Y., Campbell, R. L., Petsko, G. A., Haber, E., Margolies, M. N., and Sheriff, S. (1993) Proc. Natl. Acad. Sci. U. S. A., in press) reveals that Tyr-50 contacts a region of digoxin that includes the hapten-12 carbon. To determine the effects of other heavy chain position 50 substitutions, mutant antibodies were engineered, and their affinities for digoxin and digoxin analogues were measured. The affinity of the mutant antibodies for digoxin roughly correlates with the size of the position 50 side chain. Substitutions of Trp or Phe have no effect on affinity, whereas substitutions of Asn, His, Leu, Ala, Gly, and Asp confer progressively lower affinities. Although Trp and Phe mutants exhibit wild-type specificity, Asn and Asp mutants have improved affinity for digoxin relative to digitoxin (12-deshydroxydigoxin). Leu, Ala, and Gly mutants have improved affinity for 12-acetyldigoxin relative to digoxin as compared with 26-10. These results indicate that position 50 is a determinant of both antibody affinity and fine specificity for antibody 26-10 and that single-amino acid substitutions can alter antibody fine specificity. Models of the mutants were computationally constructed, and haptens were docked into the modeled binding sites. The results suggest that 12-acetyldigoxigenin occupies different orientations in the 26-10 and in the Ala mutant binding sites, resulting in altered binding.
Histórias orais: relato de experiências em pesquisas geográficas (2011)

A historia oral pode ser utilizada como historia de vida, de empresas, de instituicoes e de comunidades. Objetivamos, em nossa analise, discutir as possibilidades de encontro com a historia oral em nossa trajetoria academica a partir dos primeiros anos de formacao ate a pesquisa atual como professor da Universidade de Sao Paulo. Inicialmente, valemo-nos da historia oral para a discussao da urbanizacao de Rondonopolis. Posteriormente, trouxemos a discussao das memorias das comunidades tradicionais como mediacao para evidenciar a importância da historia oral na formacao social. Finalmente, utilizamos as lembrancas para a compreensao da formacao de instituicoes universitarias brasileiras com base em historias de vida de professores.
New frontiers in medical sciences : redefining hyaluronan : proceedings of the symposium held in Padua, Italy, 17-19 June 1999 (2000)

Hardbound. Although hyaluronan was discovered nearly 70 years ago and has been investigated by thousands of scientists, it is very appropriate that as we enter a new millennium, the study of the biology and chemistry of hyaluronan has entered a renaissance period. The driving force behind the symposium was to redefine the properties and complex biological roles of hyaluronan, its interactions with other molecules of the extracellular matrix and its increasing use to treat various pathologies. For many decades hyaluronan was considered to be merely a structural component of many tissues, certainly important for the normal function of our eyes and joints, but of relatively little interest to scientists trying to understand complex multicellular processes. That view has been dramatically changed by several unexpected discoveries: that several cell surface receptors specifically recognize hyaluronan; that small hyaluronan oligosaccharides stimulate angiogenes
Potential Role of Purinergic Signalling in Cochlear Pathology (2002)

Adenosine triphosphate (ATP) is a major intercellular signalling molecule that is involved in neurotransmission in the central and autonomic nervous systems, regulation of blood flow, and neuroendocrine function. It is also a key signalling molecule involved in normal cochlear homoeostasis, regulating hearing sensitivity, controlling vascular tone and acting as a candidate neurotransmitter at the hair cell afferent synapses. It has also been established that extracellular ATP mediates some pathological processes such as inflammation, apoptosis and cell proliferation. Evidence for a profound influence of extracellular ATP on normal cochlear function offers the tantalizing possibility that extracellular purine nucleotides may play a role in disease processes in the inner ear. This review draws on the current understanding of the pathophysiological role of extracellular ATP in tissues, and the evidence for the functional expression of purinergic signalling elements in the inner ear, to speculate on the potential role of purine nucleotides in cochlear pathology.
An Efficient Encryption and Key Management Scheme for Layered Access Control of H.264/Scalable Video Coding (2009)

This paper proposes a new selective encryption scheme and a key management scheme for layered access control of H.264/SVC. This scheme encrypts three domains in hierarchical layers using different keys: intra prediction modes, motion vector difference values and sign bits of texture data. The proposed scheme offers low computational complexity, low bit-overhead, and format compliance by utilizing the H.264/SVC structure. It provides a high encryption efficiency by encrypting domains selectively, according to each layer type in the enhancement-layer. It also provides confidentiality and implicit authentication using keys derived in the proposed key management scheme for encryption. Simulation results show the effectiveness of the proposed scheme.
Purification, Cloning, Expression, and Mechanism of Action of a Novel Platelet Aggregation Inhibitor from the Salivary Gland of the Blood-sucking Bug, Rhodnius prolixus (2000)

Rhodnius prolixus aggregation inhibitor 1 (RPAI-1), a 19-kDa protein isolated from the salivary gland of R. prolixus, was purified by strong cation exchange and reverse-phase high performance liquid chromatographies. Based on 49 amino-terminal amino acid sequences of RPAI-1, primers were produced to generate probes to screen an R. prolixus salivary gland cDNA library. A phage containing the full-length clone of RPAI-1 codes for a mature protein of 155 amino acids. RPAI-1 shows sequence homology to triabin and pallidipin, lipocalins from Triatoma pallidipennis. The cDNA sequence was cloned in Pet17B Escherichia coli expression vector, producing an active peptide. RPAI-1 inhibits human platelet-rich plasma aggregation triggered by low concentrations of ADP, collagen, arachidonic acid, thromboxane A(2) mimetics (U46619), and very low doses of thrombin and convulxin. Here we show that ADP is the target of RPAI-1 since (i) RPAI-1 inhibits ADP-dependent large aggregation formation and secretion triggered by U46619, without affecting Ca(2+) increase and shape change; (ii) ADP restored the inhibition of U46619-induced platelet aggregation by RPAI-1, (iii) PGE(1)-induced increase of cAMP (which is antagonized by U46619 in an ADP-dependent manner) was restored by RPAI-1, (iv) RPAI-1 inhibits low concentrations of ADP-mediated responses of indomethacin-treated platelets, and (v) RPAI-1 binds to ADP, as assessed by large zone chromatography. RPAI-1 affects neither integrin alpha(2)beta(1)- nor glycoprotein VI-mediated platelet responses. We conclude that RPAI-1 is the first lipocalin described that inhibits platelet aggregation by a novel mechanism, binding to ADP.
A model for the origin of the anomalous and very bright UV lines of Fe II in gaseous condensations of the star $\mathsf{\eta}$ Carinae (2001)

We present a qualitative physical model of the origin of two very bright UV lines of Fe II at 2507-2509 Å, present in high-resolution spectra of gaseous condensations (blobs) close to the central star of η Carinae. The spectra have been obtained with the Hubble Space Telescope (HST). The model is based on a type of Bowen mechanism with selective photoexcitation of Fe II by a broad HLyα profile, generated in the HII region and diffusely transferred to the optically thick HI region. The frequency distribution by large Doppler diffusion into the HI region provides a substantial broadening of HLyα, which makes it possible to selectively photo-excite short-lived (≈1 ns) states at 11.2 eV in Fe II. Within the frame of the present model the intense HLyα radiation induces a depletion of the lower, long-lived (≈1 ms) level of the strong UV lines by photoionization. The subsequent recombination of Fe III explains the appearance of the "forest" of narrow Fe II lines. The possibility of a cyclic process is also discussed, where HLyα induces depletion to bound states, which have fast decays in the far-UV to the lower state of the Bowen pumping channel.
Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element (1991)

Abstract A patient with homozygous beta thalassemia of German/Italian descent was found to be doubly heterozygous for the common IVS1–110 G----A mutation of the beta globin gene and for a novel C----T mutation of the proximal CACCC-box of the beta globin gene promoter at position -87 relative to the transcription start site (cap). Transcription analysis in an HeLa cell transfection assay indicated a 45% to 51% residual activity of the gene with the -87 C----T mutation relative to normal, further underlining the physiologic role of the affected promoter element. The finding of an only moderately reduced transcriptional activity of the beta globin gene with the -87 C----T mutation corresponds well with the clinical phenotype of the reported patient, which is characterized by a late onset of symptoms, moderate anemia, and normal physical development. The ethnically German mother of the propositus has minimal anemia with only slightly changed red blood cell indices, which can also be explained by the relatively high residual activity of the gene with the -87 C----T mutation.
The Membrane-proximal Region of the Thrombopoietin Receptor Confers Its High Surface Expression by JAK2-dependent and -independent Mechanisms (2006)

Janus tyrosine kinase 2 (JAK2) is essential for signaling by the thrombopoietin (TpoR) and erythropoietin (EpoR) receptors. In the absence of JAK2 most EpoR molecules are retained in the endoplasmic reticulum in an Endo H-sensitive form. In contrast, we show that in the absence of JAK2 a large fraction of the TpoR is processed to the mature Endo H-resistant form and reaches the cell surface. By studying chimeras of the TpoR and EpoR we show that high surface expression of the TpoR is entirely conferred by the membrane-proximal region of the intracellular domain that includes the juxtamembrane, Box 1, and Box 2 regions. The TpoR intracellular domain shows similar effects on receptor endocytosis rate as that of the EpoR, but does stabilize the mature receptor isoform from degradation. Co-expression of JAK2 further stabilizes mature TpoR and thus further increases its surface expression. This JAK2 effect depends on the Box 1 region, the only JAK2 interacting site in the TpoR. By contrast, EpoR requires Box 1 as well as the flanking 20 residues on the C-terminal side for JAK2 interaction and JAK2-dependent surface expression. Our study suggests that whereas cell surface expression of type I cytokine receptors requires their cognate JAKs, the mechanisms governing receptor-JAK interactions differ among receptors interacting with the same JAK protein.
A Phase II Trial of Vinorelbine and Cisplatin in Previously Untreated Inoperable Non—Small-Cell Lung Cancer (2000)

Weekly vinorelbine injection with cisplatin had been used in treatment of non-small-cell lung cancer. We performed a phase II trial to evaluate the efficacy and toxicity of a new schedule of vinorelbine and cisplatin in patients with previously untreated, inoperable (stage IIIB or stage IV) non-small-cell lung cancer. From April 1996 to May 1997, 52 patients were enrolled for study, and 50 patients were eligible and evaluable for both response and toxicity assessment. Therapy consisted of vinorelbine, 30 mg/m2, intravenously on days 1 and 5 of a 21-day cycle, and cisplatin 100 mg/m2 (reduced to 80 mg/m2 after the first seven patients) given on day 1. A total of 211 treatment courses were administered; the median number of cycles administered per patient was 4.5 (range: 1-6), the median dose intensity for vinorelbine was 16.9 mg/m2/week (84.4%), whereas that of cisplatin was 22.8 mg/m2/week (84.7%). Twenty-five patients responded to therapy for an overall response rate of 50%; one patient attained a complete response (2%). The main toxicities were vomiting, myelosuppression, and diarrhea, which included World Health Organization grade 3 or 4 nausea/vomiting (58% patients), anemia (41% patients), neutropenia (12% patients), and diarrhea (14%). The median duration of responses was 9 months. The median time to disease progression was 6.8 months (range 0.4-18.1 months). Median survival was 13 months, and 54% of patients were alive at 1 year. We conclude that this new schedule of vinorelbine and cisplatin achieves a high response with acceptable toxicity profile in patients with advanced non-small-cell lung cancer.
Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice (2001)

Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, appears to be an effective means for achieving protection against a variety of carcinogens in animals and humans. Transcriptional control of the expression of these enzymes is mediated, at least in part, through the antioxidant response element (ARE) found in the regulatory regions of their genes. The transcription factor Nrf2, which binds to the ARE, appears to be essential for the induction of prototypical phase 2 enzymes such as glutathione S -transferases (GSTs) and NAD(P)H:quinone oxidoreductase (NQO1). Constitutive hepatic and gastric activities of GST and NQO1 were reduced by 50–80% in nrf2 -deficient mice compared with wild-type mice. Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2 -deficient mice. In parallel with the enzymatic changes, nrf2 -deficient mice had a significantly higher burden of gastric neoplasia after treatment with benzo[ a ]pyrene than did wild-type mice. Oltipraz significantly reduced multiplicity of gastric neoplasia in wild-type mice by 55%, but had no effect on tumor burden in nrf2 -deficient mice. Thus, Nrf2 plays a central role in the regulation of constitutive and inducible expression of phase 2 enzymes in vivo and dramatically influences susceptibility to carcinogenesis. Moreover, the total loss of anticarcinogenic efficacy of oltipraz in the nrf2 -disrupted mice highlights the prime importance of elevated phase 2 gene expression in chemoprotection by this and similar enzyme inducers.
Rational Design of a Monoclonal Antibody (mAb) Inhibiting Calcitonin Gene-Related Peptide (CGRP), ALD403, Intended for the Prevention of Migraine (P2.155) (2017)

To describe the rational design objectives and results supporting optimized pharmacokinetics, efficacy, safety, and ease of use for ALD403, a mAb CGRP inhibitor for the prevention of migraine.