gebhart/patrepeval huggingface dataset:
Prolyl Oligopeptidase Is Involved in Release of the Antifibrotic Peptide Ac-SDKP (2004)

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a ubiquitous tetrapeptide hydrolyzed almost exclusively by angiotensin-converting enzyme (ACE). Chronic treatment with Ac-SDKP decreases cardiac and renal fibrosis and inflammatory cell infiltration in hypertensive rats. However, very little is known about endogenous synthesis of Ac-SDKP, except that thymosin-beta4 may be the most likely precursor. Two enzymes are potentially able to release Ac-SDKP from thymosin-beta4: prolyl oligopeptidase (POP) and endoproteinase asp-N. POP is widely present and active in several tissues and biological fluids, whereas endoproteinase asp-N appears to be lacking in mammals. Therefore, we hypothesized that POP is the main enzyme involved in synthesizing the antifibrotic peptide Ac-SDKP. We investigated in vitro and in vivo production of Ac-SDKP. Using kidney cortex homogenates, we observed that Ac-SDKP was generated in a time-dependent manner in the presence of exogenous thymosin-beta4, and this generation was significantly inhibited by several POP inhibitors (POPi), Z-prolyl-prolinal, Fmoc-prolyl-pyrrolidine-2-nitrile, and S17092. Long-term administration of S17092 in rats significantly decreased endogenous levels of Ac-SDKP in the plasma (from 1.76+/-0.2 to 1.01+/-0.1 nM), heart (from 2.31+/-0.21 to 0.83+/-0.09 pmol/mg protein), and kidneys (from 5.62+/-0.34 to 2.86+/-0.76 pmol/mg protein). As expected, ACE inhibitors significantly increased endogenous levels of Ac-SDKP in the plasma, heart, and kidney, whereas coadministration of POPi prevented this increase. We concluded that POP is the main enzyme responsible for synthesis of the antifibrotic peptide Ac-SDKP.
1.6 W continuous-wave coherent power from large-index-step (Δn≈0.1) near-resonant, antiguided diode laser arrays (2000)

Near-diffraction-limited-beam continuous-wave (cw) operation has been achieved to high powers from antiguided arrays with a large effective-index step between element and interelement regions. InGaAs/InGa(As)P/GaAs 40-element arrays (λ=0.985 μm) emit in beams 2×diffraction-limit (0.67°) at 1.6 W and 9×threshold in cw operation. 1 W of the coherent cw power resides in the central lobe. The external differential quantum efficiency and the threshold current are 40% and 0.4 A, respectively, for 1-mm-long devices of 191 μm emitting aperture. The overall electrical to optical power conversion efficiency at 1.6 W output power is 23%. Modeling of the thermal effects in cw operation on the array modes reveals that for high-index-step (∼0.1) near-resonant antiguided arrays thermal lensing hardly affects high-order modes, and as a consequence, 2×diffraction-limited beams can be maintained to watt-range cw powers.
An expandable error-protected 4800 bps CELP coder (US Federal Standard 4800 bps voice coder) (2003)

The authors describe a code-excited linear predictive (CELP) coder that was recently selected as the US government standard 4800-b/s voice coder. The coder has the capability for future expansion and is robust to channel errors and noisy environments. Listening tests and DRT (diagnostic rhyme test) and DAM (diagnostic acceptability measure) scores show that the decoder exceeds the performance of all government standard speech coders operating at rates below 16 kb/s and is comparable to 32-kb/s continuously-variable-slope delta modulated coders.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Retainers of the Scandinavian Kings: An Alternative Interpretation of Salin's Style II (Sixth-Seventh Centuries AD) (1997)

In recent research, the interpretation of the Scandinavian early Medieval period has changed to emphasise increasingly the leading role of South Scandinavia. Comparisons have been made between the South-Scandinavian kingdom and the early Frankish empire, including the probable existence of royal retinues. The territorial organisation of Scandinavia is discussed and used as the basis for a re-assessment of Style II as an indication of the movement of South-Scandinavian royal retainers. The organisation of retinues is discussed with reference to comparative Continental analyses, Beowulf, and later Nordic sources. They all seem to describe the same system: young warriors following a lord in order to achieve honour and wealth. Ring-swords and helmets are suggested by Continental scholars to betoken the Frankish royal retinue, and it is here suggested that ring-swords and Style II on weaponry and horse-equipment indicate the same in Scandinavia. On the basis of a regional and chronological analysis of Style II and its context, the assumed distribution of the probable retainers is studied. This reveals a clear structure in alliances, as well as the targets for military activities organised by the South-Scandinavian kings. It results in a conquest of Oland, Sweden, in the late sixth century AD and at least threats against Vestfold, Norway, in the seventh century AD.
A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma (2006)

This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.
Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions (2018)

Abstract: The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post- and predocetaxel setting, due to the significant improvement in overall survival. More recently, enzalutamide also showed impressive results in the treatment of men with nonmetastatic CRPC. Unfortunately, not all patients with CRPC are responsive to enzalutamide, and even in responders, benefits are limited by the development of drug resistance. Adaptive resistance of metastatic prostate cancer to enzalutamide treatment can be due to the activation of both androgen receptor (AR)-dependent pathways (expression of constitutively active AR splice variants, AR point mutations, gene amplification and overexpression) and mechanisms independent of AR signaling pathway (altered steroidogenesis, upregulation of the glucocorticoid receptor, epithelial–mesenchymal transition, neuroendocrine transformation, autophagy and activation of the immune system). In this review, we focus on resistance mechanisms to enzalutamide, exploring how we could overcome them through novel therapeutic options. Keywords: prostate cancer, enzalutamide, hormonal treatment, mechanisms of resistance, castration-resistant prostate cancer, androgen receptor
Analysis, design, and optimization of spiral inductors and transformers for Si RF ICs (1998)

Silicon integrated circuit spiral inductors and transformers are analyzed using electromagnetic analysis. With appropriate approximations, the calculations are reduced to electrostatic and magnetostatic calculations. The important effects of substrate loss are included in the analysis. Classic circuit analysis and network analysis techniques are used to derive two-port parameters from the circuits. From two-port measurements, low-order, frequency-independent lumped circuits are used to model the physical behavior over a broad-frequency range. The analysis is applied to traditional square and polygon inductors and transformer structures as well as to multilayer metal structures and coupled inductors. A custom computer-aided-design tool called ASITIC is described, which is used for the analysis, design, and optimization of these structures. Measurements taken over a frequency range from 100 MHz to 5 GHz show good agreement with theory.
Advances in catalytic metal-free reductions: from bio-inspired concepts to applications in the organocatalytic synthesis of pharmaceuticals and natural products (2011)

This review focuses on recent advances in catalytic metal-free transfer hydrogenations. In recent years dihydropyridines have been widely used as reducing agents in organocatalytic reductions. Analogous to nature's co-factor nicotinamide adenine dinucleotide (NADH), Hantzsch esters serve as efficient hydride donors. In combination with chiral organocatalysts, including chiral secondary amines, hydrogen bond donors or Brønsted acids, efficient catalytic asymmetric reductions have been developed which provide a diverse set of biologically active compounds, synthetic building blocks and natural products. These recent advances in developing green and sustainable reductions employing organocatalytic strategies are promising and important alternatives to conventional metal- and bio-catalyzed reductions.
Point mutations in segment I-S6 render voltage-gated Na + channels resistant to batrachotoxin (1998)

Batrachotoxin (BTX) is a steroidal alkaloid that causes Na+ channels to open persistently. This toxin has been used widely as a tool for studying Na+ channel gating processes and for estimating Na+ channel density. In this report we used point mutations to identify critical residues involved in BTX binding and to examine if such mutations affect channel gating. We show that a single asparagine --> lysine substitution of the rat muscle Na+ channel alpha-subunit, mu1-N434K, renders the channel completely insensitive to 5 microM BTX when expressed in mammalian cells. This mutant channel nonetheless displays normal current kinetics with minimal changes in gating properties. Another substitution, mu1-N434A, yields a partial BTX-sensitive mutant. Unlike wild-type currents, the BTX-modified mu1-N434A currents continue to undergo fast and slow inactivation as if the inactivation processes remain functional. This finding implies that the mu1-N434 residue upon binding with BTX is critical for subsequent changes on gating; alanine at the mu1-434 position apparently diminishes the efficacy of BTX on eliminating Na+ channel inactivation. Mutants of two adjacent residues, mu1-I433K and mu1-L437K, also were found to exhibit the identical BTX-resistant phenotype. We propose that the mu1-I433, mu1-N434, and mu1-L437 residues in transmembrane segment I-S6 probably form a part of the BTX receptor.
Molecular cloning of the human α6 integrin subunit (1991)

We have isolated cDNAs encoding the alpha 6 subunit from a lambda gt11 expression library from human keratinocytes by combined screening with a rabbit polyclonal anti-alpha 6 antibody and the polymerase chain reaction. The alpha 6 subunit encoded by this cDNA consists of 1050 amino acids with a 991-amino-acid extracellular, a 23-amino-acid transmembrane and a 36-amino-acid cytoplasmic domain. The extracellular domain contains three putative divalent cation-binding sites and nine potential N-linked glycosylation sites. From a cDNA library from normal human mammary gland cells two different cDNAs for alpha 6 were isolated, one of which is identical to the above cDNA. The two alpha 6 subunits, called alpha 6A and alpha 6B, encoded by the two cDNAs each have a unique cytoplasmic domain, that of alpha 6B being 18 amino acids longer than that of alpha 6A. Different carcinoma cell lines contain transcripts for both alpha 6 subunits. K562 leukemic cells have little alpha 6A or alpha 6B mRNAs. The overall level of expression varies in the carcinoma cell lines, but reflects alpha 6 cell surface expression. In A375 melanoma cells, however, cell surface expression of alpha 6 was low in spite of a high level of mRNA. This suggest that other mechanisms may be involved in regulating the expression of alpha 6 on the surface of these cells. The mRNA for both alpha 6 subunits is around 6 kb. The alpha 6 subunits are similar to other alpha subunits (26-31% identity with cleaved alpha subunits) of the integrin family but they are more similar to the alpha 3 subunit (40% identity). This high degree of similarity may be the basis for their functional resemblance since both alpha 3 and alpha 6 subunits, when associated with beta 1, function as laminin receptors and bind to the long arm of laminin. The genes for alpha 6 and beta 4, the alternative beta subunit with which alpha 6 combines on certain epithelial cells, were mapped to chromosome 2 and 17q11-qter, respectively.
Transport Diffusion of Gases Is Rapid in Flexible Carbon Nanotubes (2006)

Molecular dynamics simulations of rigid, defect-free single-walled carbon nanotubes have previously suggested that the transport diffusivity of gases adsorbed in these materials can be orders of magnitude higher than any other nanoporous material (A. I. Skoulidas et al., Phys. Rev. Lett. 2002, 89, 185901). These simulations must overestimate the molecular diffusion coefficients because they neglect energy exchange between the diffusing molecules and the nanotube. Recently, Jakobtorweihen et al. have reported careful simulations of molecular self-diffusion that allow nanotube flexibility (Phys. Rev. Lett. 2005, 95, 044501). We have used the efficient thermostat developed by Jakobtorweihen et al. to examine the influence of nanotube flexibility on the transport diffusion of CH4 in (20,0) and (15,0) nanotubes. The inclusion of nanotube flexibility reduces the transport diffusion relative to the rigid nanotube by roughly an order of magnitude close to zero pressure, but at pressures above about 1 bar the transport diffusivities for flexible and rigid nanotubes are very similar, differing by less than a factor or two on average. Hence, the transport diffusivities are still extremely large compared to other known materials when flexibility is taken into account.
Multiple Sclerosis as a By-Product of the Failure to Sustain Protective Autoimmunity: A Paradigm Shift (2002)

Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.
Regression of Microalbuminuria in Type 1 Diabetes (2003)

Frequent regression of microalbuminuria in patients with type 1 diabetes indicates that elevated urinary albumin excretion does not imply inexorably progressive nephropathy. Identification of the multiple determinants of the regression of microalbuminuria has implications for current theories about the mechanisms of early diabetic nephropathy.
Diagnosis of rotavirus infection with cloned cDNA copies of viral genome segments (1985)

The diagnostic potential of cloned cDNA copies of human rotavirus (strain WA) genome segments for the detection of rotavirus in clinical specimens has been determined. A hybridization assay in which a mixture of 32P-labeled cDNAs representing the 11 rotavirus segments was used as a probe compared favorably with three frequently used diagnostic tests for rotavirus in terms of both specificity and sensitivity. Significantly, clinical isolates could be readily distinguished when cloned cDNA copies of individual genome segments were used independently as a probe. In assays in which genome RNA from rotaviruses of known subgroups and serotypes were tested, cloned probes that encode nonstructural viral proteins hybridized efficiently to genome RNAs of all strains, whereas cloned probes corresponding to genome segments 6 and 9 exhibited the potential for differentiating strains of different subgroups and serotypes. Cloned cDNA copies of rotavirus genome segments therefore offer considerable potential for improved general diagnosis of rotavirus in clinical specimens, as well as for epidemiological studies in which virus isolates can be distinguished on the basis of nucleotide sequence homology of individual genome segments.
Adipsin, the adipocyte serine protease: gene structure and control of expression by tumor necrosis factor (1986)

We have isolated, mapped and sequenced adipsin, the adipocyte differentiation-dependent serine protease gene. This gene, which is present in a single form in the mouse, spans 1.7 kilobases and contains five exons. While the basic exon structure characteristic of serine protease genes is conserved in adipsin, there is also a fusion of two exons that are separate in other serine proteases. The sequence data also suggests a mechanism of alternative splicing which appears to account for the generation of two adipsin mRNA species differing by only three nucleotides and encoding two different signal peptides. To investigate the control of adipsin expression we have examined the effects of tumor necrosis factor (TNF) on adipocytes. The level of adipsin RNA is dramatically decreased by hormone treatment, but the change occurs more slowly than for other fat cell mRNAs, such as glycerophosphate dehydrogenase. These results show that adipsin is a novel serine protease gene whose expression is regulated by a macrophage-derived factor which modulates expression of other adipocyte-specific RNAs.
The oxidant stress hypothesis of atherogenesis (2001)

Atherosclerosis is the commonest lesion of blood vessels and is responsible for life-threatening events such as myocardial infarction and stroke. In the last two decades a series of excellent studies unraveled biochemical mechanisms that provided the background for a theory of atherogenesis. This theory is centered on foam cells and on free radical-mediated modification of low density lipoprotein (LDL). Foam cells are the main cell type of atherosclerotic lesions and originate from monocytes migrated from blood and from smooth muscle cells of the arterial wall. Foam cells are engulfed of lipids taken from LDL. Paradoxically, accumulation of LDL in developing foam cells does not occur via the classic LDL receptor. Incubation of macrophages with even very high concentrations of LDL does not appreciably increase cholesterol content. Chemically modified LDL easily enter the cells of atherosclerotic plaque via an unregulated receptor, the scavenger receptor. The most studied chemical modification of LDL is that induced by free radicals.
Peginterferon alfa‐2a (40kDa) and ribavirin: comparable rates of sustained virological response in sub‐sets of older and younger HCV genotype 1 patients (2009)

The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alpha-2a (40 KDa) 180 microg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients <or=50 was greater than those >50 years (52%vs 39%; P = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alpha-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P < 0.0001). Higher relapse rates were observed in older patients (41%vs 25%; P = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level (P = 0.0067), higher ALT-ratio (P = 0.0113) and absence of cirrhosis (P = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates.