gebhart/patrepeval huggingface dataset:
Reconstitution of β2‐adrenoceptor−GTP‐binding‐protein interaction in Sf9 cells (1998)

In most studies, coupling of the beta2-adrenoceptor (beta2AR) to the stimulatory, heterotrimeric GTP-binding protein of adenylyl cyclase the (Gs) is studied indirectly by measuring adenylyl cyclase activation. The aim of this study was to establish a model system in which beta2AR-Gs interactions can be studied directly at the level of the G-protein. We expressed the beta2AR alone, in combination with the alpha-subunit of Gs (G(s alpha)), and as fusion protein with G(s alpha) (beta2AR-G(s alpha)) in Sf9 insect cells. The beta2AR expressed alone couples poorly to the endogenous G(s alpha)-like G-protein of Sf9 cells since no high-affinity agonist binding could be detected, and the effects of agonist and inverse agonist on adenylyl cyclase, high-affinity GTPase and guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) binding were small. Beta2AR-G(s alpha) reconstituted high-affinity agonist binding and regulated adenylyl cyclase more effectively than the beta2AR co-expressed with a large excess of G(s alpha). In membranes expressing beta2AR-G(s alpha), highly effective agonist- and inverse agonist regulation of high-affinity GTP hydrolysis and GTP[S] binding was observed. In contrast, agonist and inverse agonist regulation of GTP hydrolysis and GTP[S] binding in membranes expressing beta2AR and G(s alpha) as separate proteins was difficult to detect. Our data show that the beta2AR interacts with G(s alpha) more efficiently when expressed as a fusion protein than when expressed with an excess of non-fused G(s alpha). The beta2AR-G(s alpha) fusion protein provides a very sensitive model system to study the regulation of Gs function by beta2AR agonists and inverse agonists directly at the level of the G-protein.
Knockdown of connexin43‐mediated regulation of the zone of polarizing activity in the developing chick limb leads to digit truncation (2002)

In the developing chick wing, the use of antisense oligodeoxynucleotides to transiently knock down the expression of the gap junction protein, connexin43 (Cx43), results in limb patterning defects, including deletion of the anterior digits. To understand more about how such defects arise, the effects of transient Cx43 knockdown on the expression patterns of several genes known to play pivotal roles in limb formation were examined. Sonic hedgehog (Shh), which is normally expressed in the zone of polarizing activity (ZPA) and is required to maintain both the ZPA and the apical ectodermal ridge (AER), was found to be downregulated in treated limbs within 30 h. Bone morphogenetic protein-2 (Bmp-2), a gene downstream of Shh, was similarly downregulated. Fibroblast growth factor-8 expression, however, was unaltered 30 h after treatment but was greatly reduced at 48 h post-treatment, when the AER begins to regress. Expressions of Bmp-4 and Muscle segment homeobox-like gene (Msx-1) were not affected at any of the time points examined. Cx43 expression is therefore involved in some, but not all patterning cascades, and appears to play a role in the regulation of ZPA activity.
Basal Cell Carcinomas in Mice Overexpressing Sonic Hedgehog (1997)

Mutations in the tumor suppressor gene PATCHED (PTC) are found in human patients with the basal cell nevus syndrome, a disease causing developmental defects and tumors, including basal cell carcinomas. Gene regulatory relationships defined in the fruit fly Drosophila suggest that overproduction of Sonic hedgehog (SHH), the ligand for PTC, will mimic loss of ptc function. It is shown here that transgenic mice overexpressing SHH in the skin develop many features of basal cell nevus syndrome, demonstrating that SHH is sufficient to induce basal cell carcinomas in mice. These data suggest that SHH may have a role in human tumorigenesis.
Identification of a functionally important sequence in the cytoplasmic tail of integrin beta 3 by using cell-permeable peptide analogs. (1996)

Integrins are major two-way signaling receptors responsible for the attachment of cells to the extracellular matrix and for cell-cell interactions that underlie immune responses, tumor metastasis, and progression of atherosclerosis and thrombosis. We report the structure-function analysis of the cytoplasmic tail of integrin beta 3 (glycoprotein IIla) based on the cellular import of synthetic peptide analogs of this region. Among the four overlapping cell-permeable peptides, only the peptide carrying residues 747-762 of the carboxyl-terminal segment of integrin beta 3 inhibited adhesion of human erythroleukemia (HEL) cells and of human endothelial cells (ECV) 304 to immobilized fibrinogen mediated by integrin beta 3 heterodimers, alpha IIb beta 3, and alpha v beta 3, respectively. Inhibition of adhesion was integrin-specific because the cell-permeable beta 3 peptide (residues 747-762) did not inhibit adhesion of human fibroblasts mediated by integrin beta 1 heterodimers. Conversely, a cell-permeable peptide representing homologous portion of the integrin beta 1 cytoplasmic tail (residues 788-803) inhibited adhesion of human fibroblasts, whereas it was without effect on adhesion of HEL or ECV 304 cells. The cell-permeable integrin beta 3 peptide (residues 747-762) carrying a known loss-of-function mutation (Ser752Pro) responsible for the genetic disorder Glanzmann thrombasthenia Paris I did not inhibit cell adhesion of HEL or ECV 304 cells, whereas the beta 3 peptide carrying a Ser752Ala mutation was inhibitory. Although Ser752 is not essential, Tyr747 and Tyr759 form a functionally active tandem because conservative mutations Tyr747Phe or Tyr759Phe resulted in a nonfunctional cell permeable integrin beta 3 peptide. We propose that the carboxyl-terminal segment of the integrin beta 3 cytoplasmic tail spanning residues 747-762 constitutes a major intracellular cell adhesion regulatory domain (CARD) that modulates the interaction of integrin beta 3-expressing cells with immobilized fibrinogen. Import of cell-permeable peptides carrying this domain results in inhibition "from within" of the adhesive function of these integrins.
Advances in FDG PET Probes in Surgical Oncology (2002)

Whole-body positron emission tomography (WB-PET) has been developed as a sensitive, cost-effective method for imaging malignant disease. WB-PET provides complete body imaging with a single scanning approach for a variety of malignancies. With increasing clinical experience, the indications for its use have broadened. This article reviews current uses of the technology and discusses some potential applications, particularly the utility of a commercially available surgical gamma probe for detecting the gamma particles emitted in the decay process of FDG.
All‐trans retinoic acid for treatment of chronic hepatitis C (2008)

The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non-responders under ATRA and PegIFN-alpha2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.
Photodestruction of fluorophores and optimum conditions for trace DNA detection by automated DNA sequencer (1992)

Although automated DNA sequencers are becoming popular, their sensitivity in detecting DNA bands is still around 10(-17) mole/band. The sensitivity of a system depends on the laser power, labeling fluorophore, and the fluorescence-collecting yield. The emission and photodestruction cross-sections of the fluorophores are critical in optimizing the irradiated laser power and the migration speeds of DNA fragments to achieve high sensitivity. We investigated photodestruction cross-sections of various fluorophores to optimize the irradiation laser power. In addition, we used a cylindrical lens system to improve the fluorescence-collecting yield of a DNA sequencer using side entry laser irradiation. Fluoresceine isothiocyanate (FITC) commonly used in fluorescence studies, is very photo-destructive, the cross-section of the destruction being about 3.8 x 10(-20) cm2 in buffer solution while that of Texas Red is 1.5 x 10(-21) cm2. When the time for DNA fragments to transit through the irradiated region is 11 s, the optimum laser powers are 0.9 mW, with an Ar laser (488 nm) for FITC-DNA, and 18 mW, with an He-Ne laser (594 nm) for Texas Red DNA. We have developed a DNA sequencer, with a cylindrical lens system which improves the fluorescence-collecting efficiency by a factor of 4, and an He-Ne laser (5 mW). Although the sequencer uses a slab gel, an ultra-high sensitivity of 5 x 10(-20) mole/band (S/N-4) was achieved under optimized conditions.
Arrhenius analysis of the thermal response of human colonic adenocarcinoma cellsin vitrousing the multi-target, single-hit and the linear-quadratic model (1997)

In order to compare the intrinsic thermal sensitivity of different malignant cell lines the multi-target, single-hit model has been widely accepted. It is even applied in clinical hyperthermia by the so-called thermal isoeffect dose (TID) concept originated from this model. The second model which is preferentially used to describe radiation survival curves is the linear-quadratic (LQ) model which can be also applied to thermal response. Interestingly, no breaking point and different activation energies are obtained with this model. In the present paper we demonstrate this discrepancy with the two human colonic adenocarcinoma cell lines WiDr and SW620. Our results further validate the already earlier published persuasion, that neither the multi-target, single-hit model, nor the LQ model are adequate to describe hyperthermic survival. Since both models give completely different results, further data aquisition of isoeffect factors, breaking points and activation enthalpies based on the multi-target, single-hit model only, is unprofitable until advanced models of thermal inactivation have been developed.
Preparation and Characterization of New Anti-PSMA Monoclonal Antibodies with Potential Clinical Use (2007)

Monoclonal antibodies with high specificity for prostate cancer tissue are of interest for diagnostic and therapeutic applications employing targeted therapy. The prostate-specific membrane antigen (PSMA) is a protein predominantly found in epithelial cells of prostate tissue origin and its expression correlates with tumor aggressiveness. Here, we report the development and characterization of new antibodies against PSMA. Murine monoclonal antibodies (MAb) were obtained by immunizing mice with a peptide corresponding to PSMA extracellular residues 490-500 -- GKSLYESWTKK (PSMA(490-500)). The MAbs react specifically to PSMA and to the prostate cancer cell line LNCaP with an affinity for PSMA in the low nanomolar range. This study also demonstrates the potential use of these antibodies for targeted drug delivery to prostate cancer cells. Nanomolar concentrations of PSMA-specific MAb in association with a molecule with cytotoxic potential were sufficient to allow for binding and uptake by LNCaP cells within minutes, leading to complete cell death within 3 days. These MAbs have potential clinical value in the development of diagnostic and therapeutic applications for prostate cancer.
Experience in designing a large-scale multiprocessor using field-programmable devices and advanced CAD tools (1996)

This paper provides a case study that shows how a demanding application stresses the capabilities of today's CAD tools, especially in the integration of products from multiple vendors. We relate our experiences in the design of a large, high-speed multiprocessor computer, using state of the art CAD tools. All logic circuitry is targeted to field-programmable devices (FPDs). This choice amplifies the difficulties associated with achieving a highspeed design, and places extra requirements on the CAD tools. Two main CAD systems are discussed in the paper: Cadence Logic Workbench (LWB) is employed for board-level design, and Altera MAX+plusII is used for implementation of logic circuits in FPDs. Each of these products is of great value for our project, but the integration of the two is less than satisfactory. The paper describes a custom procedure that we developed for integrating sub-designs realized in FPDs (via MAX+plusII) into our board-level designs in LWB. We also discuss experiences with Logic Modelling Smart Models, for simulation of FPDs and other types of chips.
Cytosolic Delivery of Macromolecules. 3. Synthesis and Characterization of Acid-Sensitive Bis-Detergents (2004)

A serious limitation that precludes utilization of single-tailed, pH-sensitive detergents for the cytosolic delivery of macromolecules is their low limit of incorporation in stable liposomal formulations. To address this issue, we have prepared two Gemini surfactants or 'bis-detergents' by cross-linking the headgroups of single-tailed, tertiary amine detergents through oxyethylene (BD1) or acid-labile acetal (BD2) moieties. The membrane-bound pK(a) of the twin tertiary amine headgroups was determined to be 6.37 +/- 0.36 using a fluorescence-based assay. As evidenced by thin-layer chromatography, BD2was hydrolyzed under acidic conditions (pH 5.0) with an approximate half-life of 3 h at 37 degrees C, while BD1 remained stable. Low pH-induced collapse of liposomes containing acid-labile BD2 into micelles was more facile than that of BD1. With BD1, the process appeared to be reversible in that aggregation of micelles was observed at basic pH. The irreversible lamellar-to-micellar transition observed with BD2-containing liposomes can possibly be attributed to acid-catalyzed hydrolysis of the acetal cross-linker, which generates two detergent monomers within the bilayer. Liposomes composed of 75 mol % bis-detergent and 25 mol % phosphatidylcholine were readily prepared and could entrap macromolecules such as polyanionic dextran of MW 40 kDa with moderate efficiency. The ability of BD2-containing liposomes to promote efficient cytosolic delivery of antisense oligonucleotides was confirmed by (a) their diffuse intracellular distribution seen in fluorescence micrographs, and (b) the up-regulation of luciferase in an antisense functional assay. The low pH-responsive, bis-detergent constructs described herein are suitable for triggered release strategies targeted to acidic intracellular or interstitial environments.
RLIP76 Transports Vinorelbine and Mediates Drug Resistance in Non–Small Cell Lung Cancer (2005)

Vinorelbine (Navelbine), an amphiphilic semisynthetic Vinca alkaloid, has displayed superior activity and decreased resistance in the treatment of advanced non-small cell lung cancer (NSCLC) compared with other members of its class. Recently, vinorelbine and cisplatin combination chemotherapy has been shown for the first time to confer a significant survival advantage in early-stage lung cancer after surgical therapy. The biological mechanisms underlying the differential response of NSCLC to cytocidal activity of vinorelbine have yet to be elucidated. Our recent findings indicate a role of RLIP76, a non-ATP binding cassette transport protein, in catalyzing the ATP-dependent efflux of structurally and functionally unrelated chemotherapeutic agents such as doxorubicin and vinblastine in NSCLC. Present studies were conducted to assess whether RLIP76 mediates vinorelbine transport and resistance. Here we show that RLIP76 catalyzes the transport of vinorelbine in a saturable manner with respect to vinorelbine (K(m) 75 nmol/L) and ATP (K(m) = 3.4 mmol/L). Three-fold overexpression of RLIP76 in NSCLC and SCLC confers increased resistance to cytotoxicity. RLIP76 overexpression causes a sustained intracellular decrease in vinorelbine concentration because of increased efflux, and anti-RLIP76 antibodies sensitize lung cancer cells to vinorelbine by inhibiting its efflux. These studies for the first time show that RLIP76 mediates vinorelbine transport and is capable of conferring drug accumulation defect and resistance to lung cancer cells.
Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs (1997)

We describe the design, fabrication, and output capabilities of a microminiature electrical stimulator that can be injected in or near nerves and muscles. Each single-channel microstimulator consists of a cylindrical glass capsule with hermetically sealed electrodes in either end (2-mm diameter x 13-mm overall length). Power and digital control data can be transmitted to multiple implants (256 unique addresses) via a 2-MHz RF field created by an external AM oscillator and inductive coil. In vitro testing demonstrated accurate control of output pulsewidth (3-258 microseconds in 1-microseconds steps) and current (0-30 mA in two linear ranges of 16 steps each, up to 8.5 V available compliance voltage). Microstimulators were used successfully for chronic stimulation in hindlimb muscles of cats. Design and fabrication issues affecting yield and reliability of the packaging and electronics are discussed.
The safety and efficacy of intravenous ferric carboxymaltose in anaemic patients undergoing haemodialysis: a multi-centre, open-label, clinical study (2010)

FCM is well-tolerated and effective in the correction of Hb levels and iron stores in patients with IDA undergoing HD. As changes in anaemia treatment other than i.v. FCM (e.g. increased ESA doses) were not permitted during the study, the clinically relevant increase in Hb in the majority of patients can be solely attributed to efficient iron utilization. The incidence of AEs was as expected for this population.
Treatment of Chronic Peripheral Arterial Disease (2003)

Peripheral arterial disease (PAD) is a common but under-recognized problem. Intermittent claudication is the most frequent symptom of PAD, although the diagnosis of PAD is often overlooked until the patient is presented with limb-threatening ischemia. Importantly, PAD is a marker of generalized atherosclerosis and is closely associated with coronary and cerebrovascular disease. The primary causes of death in patients with PAD are myocardial infarction and stroke. Reducing risk factors is an integral and aggressive part of the treatment regimen. The recognition and diagnosis of PAD, combined with its appropriate medical management, may well reduce the overall risk of cardiovascular morbidity. When diagnosed early, both exercise and pharmacotherapy can ameliorate symptoms of claudication, augment functional performance, and improve quality of life. This review focuses on the general medical management and specific therapeutic options. Because PAD is a manifestation of generalized atherosclerosis, the principal issue in medical management of PAD is a treatment plan that modifies known risk factors for atherosclerosis and its atherothrombotic complications. All patients with PAD should be receiving antiplatelet therapy to prevent ischemic events and ACE inhibitors should be used if appropriate. Medical treatment for patients with claudication includes exercise in rehabilitation and drug therapy. It is also recognized that selected patients with claudication symptoms may benefit from catheter-based interventions, and most PAD patients with critical leg ischemia require revascularization procedures. Although many therapies for claudication have been thoroughly investigated, research continues on new treatments. In contrast, more prospective, randomized trials are needed to evaluate various therapies for treating patients with PAD. Keywords: peripheral vascular disease, therapy, chronic arterial disease, critical limb ischemia
The first linkage disequilibrium (LD) maps: Delineation of hot and cold blocks by diplotype analysis (2002)

Linkage disequilibrium (LD) provides information about positional cloning, linkage, and evolution that cannot be inferred from other evidence, even when a correct sequence and a linkage map based on more than a handful of families become available. We present theory to construct an LD map for which distances are additive and population-specific maps are expected to be approximately proportional. For this purpose, there is only a modest difference in relative efficiency of haplotypes and diplotypes: resolving the latter into 2-locus haplotypes has significant cost or error and increases information by about 50%. LD maps for a cold spot in 19p13.3 and a more typical region in 3q21 are optimized by interval estimates. For a random sample and trustworthy map the value of LD at large distance can be predicted reliably from information over a small distance and does not depend on the evolutionary variance unless the sample size approaches the population size. Values of the association probability that can be distinguished from the value at large distance are determined not by population size but by time since a critical bottleneck. In these examples, omission of markers with significant Hardy-Weinberg disequilibrium does not improve the map, and widely discrepant draft sequences have similar estimates of the genetic parameters. The LD cold spot in 19p13.3 gives an unusually high estimate of time, supporting an argument that this relationship is general. As predicted for a region with ancient haplotypes or uniformly high recombination, there is no clear evidence of LD clustering. On the contrary, the 3q21 region is resolved into alternating blocks of stable and decreasing LD, as expected from crossover clustering. Construction of a genomewide LD map requires data not yet available, which may be complemented but not replaced by a catalog of haplotypes.
Direct-tunneling gate leakage current in double-gate and ultrathin body MOSFETs (2002)

The impact of energy quantization on gate tunneling current is studied for double-gate and ultrathin body MOSFETs. Reduced vertical electric field and quantum confinement in the channel of these thin-body devices causes a decrease in gate leakage by as much as an order of magnitude. The effects of body thickness scaling and channel crystallographic orientation are studied. The impact of threshold voltage control solutions, including doped channel and asymmetric double-gate structures is also investigated. Future gate dielectric thickness scaling and the use of high-/spl kappa/ gate dielectrics are discussed.