gebhart/patrepeval huggingface dataset:
Crystal structures of TAFI elucidate the inactivation mechanism of activated TAFI: a novel mechanism for enzyme autoregulation (2008)

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-metallocarboxypeptidase that can be proteolytically activated (TAFIa). TAFIa is unique among carboxypeptidases in that it spontaneously inactivates with a short half-life, a property that is crucial for its role in controlling blood clot lysis. We studied the intrinsic instability of TAFIa by solving crystal structures of TAFI, a TAFI inhibitor (GEMSA) complex and a quadruple TAFI mutant (70-fold more stable active enzyme). The crystal structures show that TAFIa stability is directly related to the dynamics of a 55-residue segment (residues 296-350) that includes residues of the active site wall. Dynamics of this flap are markedly reduced by the inhibitor GEMSA, a known stabilizer of TAFIa, and stabilizing mutations. Our data provide the structural basis for a model of TAFI auto-regulation: in zymogen TAFI the dynamic flap is stabilized by interactions with the activation peptide. Release of the activation peptide increases dynamic flap mobility and in time this leads to conformational changes that disrupt the catalytic site and expose a cryptic thrombin-cleavage site present at Arg302. This represents a novel mechanism of enzyme control that enables TAFI to regulate its activity in plasma in the absence of specific inhibitors.
Advanced 3D inverse method for designing turbomachine blades (1995)

To meet the goal of 60% plant-cycle efficiency or better set in the ATS Program for baseload utility scale power generation, several critical technologies need to be developed. One such need is the improvement of component efficiencies. This work addresses the issue of improving the performance of turbo-machine components in gas turbines through the development of an advanced three-dimensional and viscous blade design system. This technology is needed to replace some elements in current design systems that are based on outdated technology.
Isoform Selective Phosphoinositide 3-Kinase &#947; and &#948; Inhibitors and Their Therapeutic Potential (2008)

Phosphoinositide 3-kinases (PI3Ks) represent a family of dual specificity kinases that by acting as both lipid and protein kinases regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. The availability of genetically modified mice has recently allowed the functional characterization of class I PI3Ks, which are the most well studied PI3Ks. Whereas PI3Kalpha and PI3Kbeta are ubiquitously expressed, PI3Kdelta and PI3Kgamma are mainly restricted to leukocytes and represent key modulators of innate and adaptive immune responses. Therefore, PI3Kdelta and PI3Kgamma have become attractive drug targets for the treatment of disorders of both innate and adaptive immune system, causing inflammatory and allergic diseases. The lack of specificity, isoform selectivity and biopharmaceutical properties of the initially available pharmacological inhibitors have provided impetus to the development of novel compounds that, by exhibiting improved isoform selectivity, potency and pharmacokinetic profile, might be more safely employed. Here, we describe recently published patent specifications disclosing new PI3K inhibitors, with a main focus on compounds displaying some selectivity for PI3Kdelta and gamma isoforms and their potential therapeutic applications.
Plasticizer-Free Polymer Containing a Covalently Immobilized Ca2+-Selective Ionophore for Potentiometric and Optical Sensors (2003)

A derivative of a known Ca2+-selective ionophore, ETH 129, was synthesized to contain a polymerizable acrylic moiety (AU-1) and covalently grafted into a methyl methacrylate-co-decyl methacrylate polymer matrix. The polymer containing AU-1 was prepared via a simple one-step homogeneous polymerization method. It exhibited mechanical properties suitable for the fabrication of plasticizer-free ion-selective membrane electrodes and bulk optode films by solvent-casting and spin-coating techniques, respectively. The segmented sandwich membrane technique was utilized to assess the binding constant of free and covalently bound ionophores to calcium and to study their diffusion coefficients in the membrane phase. Diffusion was greatly diminished for the bound ionophore. This was confirmed in ion-selective electrode membranes containing no calcium ions in the inner solution, which should normally show apparent super-Nernstian response slopes in dilute calcium solutions. The response slope was Nernstian down to submicromolar concentration levels, indicating slow mass transport of calcium in the membrane. Optical-sensing films with the new copolymer matrix, unblended and blended with PVC-DOS, also confirmed that covalently bound ionophores are fully functional for maintaining selective ion extraction and binding properties of the sensing membrane.
Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. (1998)

CEA, CK-19, GA733.2, and MUC-1 show no diagnostic value as mRNA markers for the detection of micrometastases by the RT-PCR assay because they are expressed in the blood and lymph nodes of patients without cancer. Further studies are needed to assess the sensitivity of CK-20 to detect micrometastases by the RT-PCR assay in the blood and frozen-section SNs of patients with breast cancer.
Mathematical modeling and analysis of glucose and glutamine utilization and regulation in cultures of continuous mammalian cells (1995)

A number of factors have been shown to affect the metabolism of glucose and glutamine in mammalian cells and their mechanisms have been partially elucidated. Despite these efforts, a quantitative knowledge of the significance of these factors, the regulation of glucose and glutamine utilization, and particularly the interactions of these two nutrients is still lacking. Controversies exist in the literature. To clarify some of these controversies, mathematical models are proposed in this work which enable to separate and identify the effects of individual factors. Experimental data from five cell lines obtained in batch, fed-batch, and continuous cultures, both under steady-state and transient conditions, were used to verify the model formulations. The resulting kinetic models successfully describe all these cultures. According to the models, the specific consumption rate of glucose (Q(Glc)) of continuous animal cells under normal culture conditions can be expressed as a sum of three parts: a part owing to cell growth; a part owing to glucose excess; and a part owing to glutamine regulation. The specific consumption rate of glutamine (q(Glc)7) can be expressed as a sum of only two parts: a part owing to cell growth; and a part owing to glutamine excess. Using the kinetic models the interaction and regulation of glucose and glutamine utilizations are quantitatively analyzed. The results indicate that, whereas q(Glc) is affected by glutamine, q(Gln) appears to be not or less significantly affected by glucose. It is also shown that the relative utilizations of glucose and glutamine by anabolism and catabolism are mainly affected by the residual concentrations of the respective compounds and are less sensitive to growth rate and the nature of growth limitation.(c) 1995 John Wiley & Sons, Inc.
Study of HSV-1 DNA species from trigeminal ganglia of rabbits during acute and latent infections (1987)

Recurrent herpetic keratitis remains a major cause of corneal blindness in developed countries. A fundamental unanswered question regarding herpes simplex virus infection concerns the relationship between the virus and host cell DNA during latency. In the present study DNA was extracted from trigeminal ganglia during both acute and latent infection following ocular inoculation. Extracted, purified DNA was utilized for transfection and for hybridization studies using a 32P-labeled HSV-1 DNA probe. DNA extracted during acute infection was complete, linear and non-integrated. Autoradiographic patterns of DNA isolated during latent infection were suggestive of two separate DNA species.
Targeted expression of Cre recombinase to adipose tissue of transgenic mice directs adipose-specific excision of loxP-flanked gene segments (1997)

Functional analysis of mammalian genes relies, in part, on targeted mutations generated by homologous recombination in mice. We have developed a strategy for adipose-specific inactivation of loxP-floxed gene segments. Transgenic mice have been established that express Cre recombinase under the control of the adipose-specific aP2 enhancer/promoter. Crossing of the aP2/ Cre mice with any loxP-floxed gene will facilitate its functional analysis in adipose tissue.
( Mn ,  Sb) doped-Pb(Zr, Ti)O3 infrared detector arrays (2000)

( Mn , Sb) doped Pb(Zr, Ti)O3 (PMSZT) thin film infrared (IR) detectors were integrated with Si substrates. The epitaxial PMSZT thin films, deposited on c-axis oriented YBa2Cu3O7−y (YBCO) bottom electrodes, show good ferroelectric properties with a remnant polarization Pr of 31 μC/cm2, a spontaneous polarization Ps of 38 μC/cm2, and a coercive field Ec of 21 kV/cm under an electric field of 76 kV/cm. Doping with Mn and Sb into Pb(Zr, Ti)O3 (PZT) not only decreased the Curie temperature TC from 350 °C for PZT to 175 °C for PMSZT, but also enhanced IR responsivity significantly. PMSZT thin films show high figures of merit, Fi of 15.5×10−9 C cm/J, Fv of 1758 cm2/C and Fd of 5×10−5 Pa−1/2 at 25 °C. IR detector arrays, fabricated with PMSZT films deposited on YBCO microbridges with an air gap between them and the substrate for reduced thermal mass, show a higher IR voltage responsivity compared to those without an air gap.
Regulation of the gadd45β Promoter by NF-κB (2002)

In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. The NF-kappaB antiapoptotic function is crucial to oncogenesis, cancer chemoresistance, and to antagonize tumor necrosis factor (TNF) receptor-induced killing. Recently, we have shown that the suppression of the c-Jun-N-terminal kinase (JNK) cascade is a pivotal protective mechanism by NF-kappaB, and that this suppression involves the upregulation of gadd45beta/myd118. Induction of gadd45beta by stress and cytokines requires NF-kappaB; however, the regulatory mechanisms underlying this induction are not known. Here, we report that, in HeLa cells, the NF-kappaB subunit RelA is sufficient to activate gadd45beta expression, whereas Rel and p50 are not. Activation of gadd45beta by RelA depends on three kappaB elements at positions -447/-438 (kappaB-1), -426/-417 (kappaB-2), and -377/-368 (kappaB-3) of the gadd45beta promoter. Each of these sites binds to NF-kappaB complexes in vitro, and is required for optimal promoter transactivation. The data establish the direct participation of NF-kappaB in the regulation of Gadd45beta, thereby providing important mechanistic insights into the control of apoptosis by the transcription factor.
Synthesis and Hybridization Studies of 2‘-Amino-α-L-LNA and Tetracyclic “Locked LNA” (2006)

A convergent route to a new class of locked nucleic acids, i.e., 2'-amino-alpha-L-LNA, has been developed. The optimized synthetic route to the corresponding phosphoramidite building block of thymine proceeds in 4% overall yield over 15 steps from the starting diol. Crucial synthetic steps include (a) introduction of a C2-azido group prior to nucleobase coupling, (b) Vorbrüggen glycosylation primarily affording the desired alpha-anomer, (c) separation of alpha-L-ribo- and beta-L-ribo-configured bicyclic nucleosides, and (d) selection of a suitable protecting group to avoid intramolecular Michael addition of the C2'-amino group onto the C6-position. Incorporation of a 2'-amino-alpha-L-LNA monomer into oligodeoxyribonucleotides results in modest changes in thermal stability with complementary DNA, whereas significant increases in thermal stability are observed with RNA complements along with excellent Watson-Crick discrimination. These results, along with the flexibility of the synthetic strategy allowing chemoselective N2'-functionalization at a late stage, render 2'-amino-alpha-L-LNA a promising building block for nucleic acid based nanobiotechnology and therapeutics. A slight modification in strategy facilitated the synthesis of the corresponding phosphoramidite building blocks of Michael adducts, which due to their tetracyclic skeletons exhibit a conformationally restricted furanose ring and glycosidic torsion angle (anti-range). Incorporation of such a "locked LNA" monomer into oligodeoxyribonucleotides results in large decreases in thermal affinity toward DNA/RNA complements.
Signal generation using pulsed semiconductor lasers for application in millimeter-wave wireless links (1995)

We investigate the generation of signals using pulsed semiconductor lasers for application in millimeter-wave (mm-wave) wireless links. The generation of mm wave harmonic frequencies in both mode-locked and gain-switched lasers is considered and a method to generate mm-wave modulated optical signals with modulation depths approaching 100% is implemented. The technique uses optical filtering to select only two optical modes in the pulsed laser spectrum that beat together in a highspeed photodiode. The application of this method to the feeding of mm-wave wireless links incorporating microstrip patch antennas is demonstrated. These optically fed links have application in indoor wireless LAN's and optical fiber microcellular systems.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The presence of smooth muscle actin in fibroblasts in the torn human rotator cuff (2001)

The rotator cuff frequently sustains athletic and occupational injury, often resulting in chronic pain and disability. However, despite the high incidence of such shoulder problems, the pathophysiology of rotator cuff injury and healing has not yet been fully elucidated. The notable finding of this study was the presence of a contractile actin isoform, alpha-smooth muscle actin (SMA), in nonvascular cells in all of the seven torn human rotator cuff specimens evaluated immunohistochemically. Up to 95% of cells in any one region, and over 95% of elongated cells found in association with crimped collagen, contained SMA. Most of the cells staining positive for SMA in these sections had morphological features of the fibroblast, though a small number were chondrocyte-like. Treatment of cells growing out from human rotator cuff explants with TGF-beta1 significantly increased the amount of SMA evaluated by Western blot analysis. PDGF-BB and IFN-gamma had no effect on the cell content of SMA. This is the first documentation of the presence of SMA-positive cells in the human rotator cuff tendon. SMA has been found in a number of other healing connective tissues including skin, ligament, meniscus, cartilage, and other types of tendon. Of importance are previous findings that SMA-positive cells can contract a collagen-glycosaminoglycan analog of extracellular matrix in vitro. The results of the present study thus suggest that SMA-containing cells could contribute to the retraction of the torn ends of a ruptured rotator cuff and play an important role in healing.
Brain Response to Injury and Neurodegeneration: Endogenous Neuroprotective Signaling (2005)

Synaptic activity and ischemia/injury promote lipid messenger formation through phospholipase-mediated cleavage of specific phospholipids from membrane reservoirs. Lipid messengers modulate signaling cascades, contributing to development, differentiation, function (e.g., memory), protection, regeneration, and repair of neurons and overall regulation of neuronal, glial, and endothelial cell functional integrity. Oxidative stress disrupts lipid signaling and promotes lipid peroxidation and neurodegeneration. Lipid signaling at the neurovascular unit (neurons, astrocytes, oligodendrocytes, microglia, and cells of the microvasculature) is altered in early cerebrovascular and neurodegenerative disease. We discuss how lipid signaling regulates critical events in neuronal survival. Aberrant synaptic plasticity (e.g., epileptogenesis) is highlighted to show how gene expression may drive synaptic circuitry formation in the "wrong" direction. Docosahexaenoic acid has been implicated in memory, photoreceptor cell biogenesis and function, and neuroprotection. Free docosahexaenoic acid released in the brain during experimental stroke leads to the synthesis of stereospecific messengers through oxygenation pathways. One messenger, 10,17S-docosatriene (neuroprotectin D1; NPD1), counteracts leukocyte infiltration and proinflammatory gene expression in brain ischemia-reperfusion. In retina, photoreceptor survival depends on retinal pigment epithelial (RPE) cell integrity. NPD1 is synthesized in RPE cells undergoing oxidative stress, potently counteracts oxidative stress-triggered apoptotic DNA damage in RPE, upregulates antiapoptotic proteins Bcl-2 and Bcl-x(L), and decreases proapoptotic Bax and Bad expression. These findings expand our understanding of how the nervous system counteracts redox disturbances, mitochondrial dysfunction, and proinflammatory conditions. The specificity and potency of NPD1 indicate a potential target for therapeutic intervention for stroke, age-related macular degeneration, spinal cord injury, and other neuroinflammatory or neurodegenerative diseases.
Endothelin-1 in chronic renal failure and hypertension (2003)

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.
Elementos de hermenêutica constitucional - Caráter especial da norma constitucional: necessidade de teoria hermenêutica própria (2006)

NOGUEIRA, Vanessa Fabiula Pancioni. Elementos de Hermeneutica Constitucional - Carater especial da norma constitucional: necessidade de teoria hermeneutica propria. Toda norma juridica exige interpretacao para seu posterior aplicacao. A norma constitucional necessita de uma teoria hermeneutica propria, pois possui caracteristicas diferenciadas em relacao as demais normas do sistema: e a norma de maior hierarquia do ordenamento juridico, rigida, conserva eminente carater politico, iniciante e aberto, assim como possui normas de diferentes graus de eficacia. Consideracoes acerca de hermeneutica constitucional e seus reflexos nas normas infra-constitucionais.
Klotho: A Major Shareholder in Vascular Aging Enterprises (2019)

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched.
Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. (1987)

Insulin secretion is controlled by a complex set of factors. Although blood glucose levels serve as the major stimulus of insulin secretion in mammals, insulin release is also modulated by amino acids, catecholamines, glucagon, and other, intestinal hormones. The identification of factors that modulate insulin production has engendered much interest because of their potential importance in the altered dynamics of insulin secretion in response to glucose characteristic of maturity-onset diabetes mellitus. Decoding of the glucagon gene has uncovered two additional glucagon-like peptides encoded in proglucagon, the polypeptide precursor of glucagon. One of these peptides, glucagon-like peptide I, is processed from proglucagon in two forms, of 31 and 37 amino acids. We report that the smaller of the two glucagon-like peptides potently increases cAMP levels, insulin mRNA transcripts, and insulin release in cultured rat insulinoma cells. These results indicate that glucagon-like peptide I may be a physiologic modulator of insulin gene expression.