gebhart/patrepeval huggingface dataset:
Activation of Signal Transducer and Activator of Transcription 5 in Human Prostate Cancer Is Associated with High Histological Grade (2004)

We have recently identified signal transducer and activator of transcription 5 (Stat5) as a critical survival factor for prostate cancer cells. We now report that activation of Stat5 is associated with high histological grade of human prostate cancer. Specifically, immunohistochemical analysis demonstrated a strong positive correlation with activation of Stat5 and high Gleason score in 114 human prostate cancers. To investigate the mechanisms underlying constitutive activation of Stat5 in prostate cancer, a dominant-negative mutant of Janus kinase 2 (Jak2) was delivered by adenovirus to CWR22Rv cells. Dominant-negative-Jak2 effectively blocked the activation of Stat5 whereas wild-type Jak2 enhanced activation, indicating that Jak2 is the main kinase that phosphorylates Stat5 in human prostate cancer cells. A ligand-induced mechanism for activation of Stat5 in prostate cancer was suggested by the ability of prolactin (Prl) to stimulate activation of both Jak2 and Stat5 in CWR22Rv human prostate cancer cells and in CWR22Rv xenograft tumors. In addition, Prl restored constitutive activation of Stat5 in five of six human prostate cancer specimens in ex vivo long-term organ cultures. Finally, Prl protein was locally expressed in the epithelium of 54% of 80 human prostate cancer specimens with positive correlation with high Gleason scores and activation of Stat5. In conclusion, our data indicate that increased activation of Stat5 was associated with more biologically aggressive behavior of prostate cancer. The results further suggest that Jak2 is the principal Stat5 tyrosine kinase in human prostate cancer, possibly activated by autocrine/paracrine Prl.
Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling (2011)

Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogues of itraconazole with greater potency and to understand the structure-activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogues were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this analysis, we have identified analogues with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR analysis of these activities revealed that potent activity of the analogues against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in composition with branching at the α or β position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-butyl side chain can lead to enhancement of the biological activity of itraconazole.
Development and Validation of a Semiquantitative, Multitarget PCR Assay for Diagnosis of Bacterial Vaginosis (2012)

Quantitative PCR assays were developed for 4 organisms reported previously to be useful positive indicators for the diagnosis of bacterial vaginosis (BV)--Atopobium vaginae, Bacterial Vaginosis-Associated Bacterium 2 (BVAB-2), Gardnerella vaginalis, and Megasphaera-1--and a single organism (Lactobacillus crispatus) that has been implicated as a negative indicator for BV. Vaginal samples (n = 169), classified as positive (n = 108) or negative (n = 61) for BV based on a combination of the Nugent Gram stain score and Amsel clinical criteria, were analyzed for the presence and quantity of each of the marker organisms, and the results were used to construct a semiquantitative, multiplex PCR assay for BV based on detection of 3 positive indicator organisms (A. vaginae, BVAB-2, and Megasphaera-1) and classification of samples using a combinatorial scoring system. The prototype BV PCR assay was then used to analyze the 169-member developmental sample set and, in a prospective, blinded manner, an additional 227 BV-classified vaginal samples (110 BV-positive samples and 117 BV-negative samples). The BV PCR assay demonstrated a sensitivity of 96.7% (202/209), a specificity of 92.2% (153/166), a positive predictive value of 94.0%, and a negative predictive value of 95.6%, with 21 samples (5.3%) classified as indeterminate for BV. This assay provides a reproducible and objective means of evaluating critical components of the vaginal microflora in women with signs and symptoms of vaginitis and is comparable in diagnostic accuracy to the conventional gold standard for diagnosis of BV.
Establishment of Human Embryonic Stem Cell Line Stably Expressing Epstein-Barr Virus-Encoded Nuclear Antigen 1 (2005)

Human embryonic stem (hES) cells have the capability of unlimited undifferentiated proliferation, yet maintain the potential to form perhaps any cell type in the body. Based on the high efficiency of the Epstein-Barr virus-based episomal vector in introducing exogenous genes of interest into mammalian cells, we applied this system to hES cells, expecting that this would resolve the problem of poor transfection efficiency existing in current hES cell research. Therefore, the first step was to establish EBNA1-positive hES cells. Using the Fugene 6 transfection reagent, we transfected hES cells with the EBNA1 expression vector and subsequently generated hES cell clones that stably expressed EBNA1 under drug selection. These clones were confirmed to express EBNA1 mRNA by RT-PCR and to express EBNA1 protein by Western blotting. Furthermore, luciferase reporter gene analysis was performed on the EBNA1 clones and revealed that the expressed EBNA1 protein was functional. When the EBNA1-positive cells were injected into severe combined immunodeficient (SCID) mice, they formed teratoma tissues containing all three embryonic germ layers and EBNA1 protein was detected in these teratoma tissues by Western blotting. All the results show that we have successfully created stable EBNA1-hES cells, thus laying a good foundation for further research.
Cloning of the Human Prolyl 4-Hydroxylase α Subunit Isoform α(II) and Characterization of the Type II Enzyme Tetramer (1997)

Prolyl 4-hydroxylase (proline hydroxylase, EC 1.14.11.2) catalyzes the formation of 4-hydroxyproline in collagens. The vertebrate enzyme is an alpha2beta2 tetramer, the beta subunit of which is identical to protein disulfide-isomerase (PDI, EC 5.3.4.1). We report here on cloning of the recently discovered alpha(II) subunit from human sources. The mRNA for the alpha(II) subunit was found to be expressed in a variety of human tissues, and the presence of the corresponding polypeptide and the (alpha(II))2beta2 tetramer was demonstrated in cultured human WI-38 and HT-1080 cells. The type II tetramer was found to represent about 30% of the total prolyl 4-hydroxylase in these cells and about 5-15% in various chick embryo tissues. The results of coexpression in insect cells argued strongly against the formation of a mixed alpha(I)alpha(II)beta2 tetramer. PDI/beta polypeptide containing a histidine tag in its N terminus was found to form prolyl 4-hydroxylase tetramers as readily as the wild-type PDI/beta polypeptide, and histidine-tagged forms of prolyl 4-hydroxylase appear to offer an excellent source for a simple large scale purification of the recombinant enzyme. The properties of the purified human type II enzyme were very similar to those of the type I enzyme, but the Ki of the former for poly(L-proline) was about 200-1000 times that of the latter. In agreement with this, a minor difference, about 3-6-fold, was found between the two enzymes in the Km values for three peptide substrates. The existence of two forms of prolyl 4-hydroxylase in human cells raises the possibility that mutations in one enzyme form may not be lethal despite the central role of this enzyme in the synthesis of all collagens.
Apoptosis and nuclear shapes in benign prostate hyperplasia and prostate adenocarcinoma: Comparison with and relation to Gleason score (1999)

The present study clearly shows the presence of apoptosis in BPH and PCA and shows an increasing number of apoptotic bodies with higher cellular malignancy. The nuclear shapes in PCA were more irregular and larger in size with increasing cellular malignancy. As expected, nuclei in BPH were smaller in size and rounder than those of cancer nuclei.
The 2004 Genetics Society of America Medal Trudy F. C. Mackay (2004)

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Trudy F. C. Mackay



THE 2004 GSA Medal is awarded to Trudy F. C. Mackay for her substantial contributions to quantitative genetics. Much of what we now know about the genetic basis of variation in quantitative traits follows from Trudy’s meticulous experiments on bristle
Perimetric Defects and Ganglion Cell Damage: Interpreting Linear Relations Using a Two-Stage Neural Model (2004)

Pooling by second-stage spatial filters can account for empiric findings of linear relations between perimetric defects and measures of ganglion cell loss.
Slotless PM Motor Design for Hard Disk Drives (1997)

Slotted motors are presently used in all hard disk drives (HDDs). However, the advantages of a slotless spindle providing low static cogging torque and negligible torque ripples would be required to meet the demands of the HDD industry, as indicated by the trends in increased capacity and smaller formats. The location of the windings in the airgap of a slotless machine resulting in an extended airgap produces lower inductance values, which will provide the drive with better dynamics. These features are discussed in this article. Aspects of the design and construction of a slotless permanent magnet (PM) motor are described and, where appropriate, comparisons are made with a slotted motor. Both motors are intended for use in a 3.5-inch, half-height HDD. The design of the slotless motor meets all the specifications for application in the HDD. The test and performance of the motor show that the slotless motor is superior in performance in comparison with the slotted motor.
Effects of oxidative stress on red blood cell rheology in sickle cell patients (2014)

Sickle cell anaemia (SS) and sickle cell-haemoglobin C disease (SC) patients exhibit severe red blood cell (RBC) rheological alterations involved in the development of several complications. The contribution of oxidative stress in these haemorheological abnormalities is still unknown. We compared RBC reactive oxygen species (ROS) and glutathione (GSH) content, and the haemorheological profile of SS (n = 11), SC (n = 11) and healthy subjects (n = 12) at baseline and after in-vitro treatment with t-butyl hydroperoxide (TBHP). We showed: (i) higher RBC ROS content in SS and SC patients, with the highest level observed in SS patients; (ii) lower RBC GSH content in sickle syndrome patients, especially in SS patients; (iii) TBHP increased RBC ROS production and decreased RBC GSH content in all groups; (iv) TBHP decreased RBC aggregation and increased the strength of RBC aggregates in all groups but the increase in RBC aggregates strength was greater in sickle cell patients; (v) TBHP decreased RBC deformability in the three groups but with a higher magnitude in sickle cell patients. These data suggest that RBCs from sickle cell patients have an exaggerated response to oxidative stress, which is accompanied by a profound abnormal haemorheological profile, with greater alterations in SS than in SC patients.
Increase in cytochrome oxidase capacity of BAT and other tissues in cold-acclimated gerbils (1990)

To determine the effects of cold acclimation on the oxidative capacity of different tissues and their possible role in nonshivering thermogenesis (NST) in a desert rodent, the gerbil (Gerbillus campestris), measurements of cytochrome oxidase activity (COX) were performed on homogenates of liver, brown adipose tissue (BAT), and subsarcolemmal (SS) and intermyofibrillar (IMF) fractions of skeletal muscle. Total organ mass was also measured. Gerbils were maintained either at thermoneutrality (TN) or cold [4 degrees C, ambient temperature (Ta)] for 4 (CA4) or 8 (CA8) wk. A comparative study was made with mice (Mus musculus). Total and relative masses of BAT increased significantly in both gerbils and mice during cold acclimation, whereas muscle mass decreased in CA4 gerbils. Specific and total COX (TCOX) increased in the three tissues. A considerable increase (+170%, P less than 0.05) of TCOX and protein content in liver of CA4 gerbils compared with controls was observed, whereas no significant changes occurred in liver of CA4 mice. In muscle, an increase of TCOX in SS and a reduction in IMF cell compartments were noted. The increase in BAT oxidative capacity in CA4 gerbils represented only a small portion of that in liver (36%) and in SS fraction of muscle (41%) at the same stage of acclimation. The ability of the three tissues to contribute to components of thermogenesis in vivo was evaluated. The sum of oxidative capacity of the three tissues was largely above the peak metabolic rate (PMR), whereas that of muscle exceeded maximum shivering thermogenesis, which developed both in TN and CA4 gerbils.(ABSTRACT TRUNCATED AT 250 WORDS)
Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels (1994)

1. We used the tested fiber method to record from single myelinated afferents axons ending in a chronic nerve injury site (neuroma) in the rat sciatic nerve or L4,5 dorsal root. Axons were chosen for study that fired spontaneously with a stable tonic or interrupted (bursty) autorhythmic firing pattern. 2. Agents that block voltage-sensitive Na+ channels [tetrodotoxin (TTX), lidocaine], voltage-sensitive Ca2+ channels (Cd2+, Co2+, Ni2+, verapamil, D600, nifedipine, and fluarizine), volt-age-sensitive K+ channels [tetraethylammonium (TEA), 4-aminopyridine (4-AP)], and Ca(2+)-activated K+ channels (gK+Ca2+;quinidine, apamine) were applied topically to the neuroma. Effects on baseline rhythmogenesis and on the duty cycle of bursting were documented. Spike pattern analysis was used to determine whether changes in firing frequency were associated with changes in impulse initiation (electrogenesis), or resulted from (partial) block of impulse propagation downstream from the site of electrogenesis. Effects of veratridine were also noted. 3. Na+ channel blockers consistently quenched neuroma firing, and they did so by suppressing the process of impulse initiation. Only rarely was propagation block the dominant process. In bursty fibers the duration of on-periods shortened as the duration of off-periods lengthened, without a significant change in the baseline interspike interval (ISI). Veratridine accelerated firing, also via the impulse generating process. 4. Ca2+ channel blockers had essentially no effect on baseline firing rate (i.e., ISI). 5. Ca2+ channel blockers, as well as blockers of gK+Ca2+, had substantial, but inconsistent effects on burst pattern. It is not clear whether this reflects variability in the experimental conditions, or heterogeneity among the fibers sampled. 6. Blockade of K+ channels failed to evoke rhythmogenesis in acutely cut axons as it does in chronically injured axons, even in the presence of veratridine. This is consistent with other evidence that ectopic neuroma firing depends on postinjury remodeling of membrane electrical properties. 7. The data indicate that, in chronically injured axons, the inward currents that underly electrogenicity, enable ectopic discharge, and, together with outward K+ currents, set the fundamental firing rhythm (ISI), operate primarily with the use of voltage-sensitive Na+ rather than Ca2+ channels. 8. The on-off duty cycle in bursty fibers was affected by Na+ channel ligands and also, although less so, and less consistently by, Ca2+ channel ligands. This indicates that both may play a role in the slow modulations of membrane potential that presumably underly interrupted autorhythmicity.
In vitro Activity of Daptomycin against 297 Staphylococcal Isolates (1990)

The in vitro activity of daptomycin against 297 clinical isolates of Staphylococcus aureus and S. epidermidis sensu strictu was compared with the activities of cephalothin, dicloxacillin, tobramycin, and vancomycin. Minimal inhibitory concentrations (MICs) were determined by an agar dilution method. Cephalothin and dicloxacillin showed the highest activity against S. aureus on a weight-for-weight basis, all isolates being inhibited by 0.5 mg/l or less of either agent. Cephalothin was somewhat more active against S. epidermidis than was dicloxacillin. Daptomycin and vancomycin exhibited high and similar activity against both S. aureus and S. epidermidis (MIC90% = 1 and 2 mg/l, respectively). Tobramycin was highly active against S. aureus, but the activity against S. epidermidis was greatly variable (MIC range less than or equal to 0.03 - greater than or equal to 16 mg/l). The activity of daptomycin was markedly influenced by the test medium; the MICs were generally 32 times higher when the isolates were tested on Iso-Sensitest agar than on Mueller-Hinton agar. Supplementation of Iso-Sensitest agar with increasing concentrations of calcium potentiated the activity of daptomycin substantially, the results obtained on Iso-Sensitest agar supplemented with 20 mg Ca2+/l being similar to those obtained on Mueller-Hinton agar.
A Subunit Cytomegalovirus Vaccine Based on Recombinant Envelope Glycoprotein B and a New Adjuvant (1999)

A phase I randomized, double-blind, placebo-controlled trial was done with a cytomegalovirus (CMV) vaccine based on the envelope glycoprotein, gB, combined with a novel adjuvant, MF59. Participants received CMV gB vaccine with MF59 or CMV gB with alum or placebo at 0, 1, and 6 months. A fourth vaccine was given at 12 months to a subgroup. Levels of neutralizing antibody and antibody to gB 2 weeks after the third dose of vaccine exceeded those in seropositive control subjects. the formulation with MF59 was more immunogenic than that with alum. The optimal dose of gB appeared to be between 5 and 30 microg. The fourth dose produced a prompt rise in antibody level. There were no serious adverse events associated with vaccine. Local and systemic reactions were generally mild and, except for pain at the injection site, occurred with similar frequency in recipients of placebo and CMV vaccine.
Acute Myeloid Leukemia Associated with Nephrotic Syndrome: Case Report and Literature Review (2002)

The hematological malignancies associated with nephrotic syndrome are mainly Hodgkin's and non-Hodgkin's lymphomas and chronic lymphocytic leukemia. Acute myelogenous leukemia (AML) has rarely been described in association with the nephrotic syndrome. The clinical course of a 44-year-old patient with AML who presented with nephrotic syndrome is described and the clinicopathologic features of the other cases reported in the world literature are reviewed. We could not find a consistent pattern regarding the subtype of leukemia, renal pathology, and temporal relationship between the nephrotic syndrome and the leukemia or the response to treatment. The present case was unique in that the clinical course of the renal disorder correlated with the course of the leukemia responding to treatment with anti-leukemic agents. We conclude that nephrotic syndrome can also be associated with AML. In some cases there is a direct causal effect of the leukemic process on the renal pathology while in others it is exerted indirectly via other complications of the malignancy or the treatment.
Perceived Level of Noise by Mark VII and Decibels (E) (1972)

The calculation procedure Mark VII gives the perceived level of loudness or noisiness in PLdB. It utilizes a set of frequency-weighting contours based on an average of 25 experimental contours. The standard reference sound is defined as a 13-oct band centered at 3150 Hz. The perceived magnitude (loudness or noisiness) grows as the 23 power of the sound pressure, so that perceived magnitude doubles with each increase of 9 dB. The summation formula for the total subjective magnitude remains St = Sm + F (∑S − Sm), but the value of F is made to vary as a function of level in order to reflect the nonlinear growth (in log-log coordinates) of broad-band noise. As a result of the new reference sound at 3150 Hz, perceived level in decibels (PLdB) is approximately 8 dB lower than the older loudness level in phons. Except for the nearly constant difference of 8 dB, Mark VI and Mark VII give closely similar results for typical broad-band noises. The 8-dB downward shift makes it possible for a sound level meter with an “ear weighting” to give readings (E) in decibels within a decibel or two of perceived level in PLdB. With the frequency-weighting contours extended down to 1.0 Hz, Mark VII also provides a procedure for calculating the perceived levels of sonic booms and other impulse noises.
DNA and nucleotide-induced conformational changes in the Escherichia coli Rep and helicase II (UvrD) proteins. (1990)

The domain structures of the Escherichia coli Rep and Helicase II proteins and their ligand-dependent conformational changes have been examined by monitoring the sensitivity of these helicases to proteolysis by trypsin and chymotrypsin. Limited treatment of unliganded Rep protein (73 kDa) with trypsin results in cleavage at a single site in its carboxyl-terminal region, producing a 68-kDa polypeptide which is stabilized in the presence of ATP, ADP, or adenosine 5'-O-thiotriphosphate) (ATP gamma S). The purified 68-kDa Rep tryptic polypeptide retains single-stranded (ss) DNA binding, DNA unwinding (helicase), and full ATPase activities. When bound to ssDNA, the Rep protein can be cleaved by trypsin at an additional site in its carboxyl-terminal region, producing a 58-kDa polypeptide that also retains ssDNA binding and ATPase activities. This 58-kDa Rep tryptic polypeptide can also be produced by further tryptic treatment of the 68-kDa Rep tryptic polypeptide when the latter is bound to ssDNA. This 58-kDa polypeptide displays a lower affinity for ssDNA indicating that the 10-kDa carboxyl-terminal peptide facilitates Rep protein binding to ssDNA. The 58-kDa Rep tryptic polypeptide is also stabilized in the presence of nucleotides. Based on these and previous studies that showed that the 68-kDa Rep tryptic polypeptide cannot support DNA replication in a system that is dependent upon the phi X174 cis-A protein (Arai, N. & Kornberg, A. (1981) J. Biol. Chem. 256, 5294-5298), we conclude that the carboxyl-terminal end (approximately 5 kDa) of the Rep protein is not required for its helicase or ATPase activities. However, we suggest that this region of the Rep protein is important for its interactions with the phi X174 cis-A protein. Limited treatment of unliganded Helicase II protein (82 kDa) with chymotrypsin results in cleavage after Tyr254, producing a 29-kDa amino-terminal polypeptide and a 53-kDa carboxyl-terminal polypeptide, which remain associated under nondenaturing conditions. This chymotrypsin cleavage reduces the ssDNA binding activity and eliminates the ssDNA-dependent ATPase and helicase activities of the Helicase II protein. The binding of ATP, ADP, ATP gamma S, and/or DNA to Helicase II protein results in protection of this site (Tyr254) from cleavage by chymotrypsin. Limited treatment of Helicase II protein with trypsin results in cleavage near its carboxyl-terminal end producing two polypeptides with apparent Mr = 72,000, in a manner similar to that observed with the Rep protein; these polypeptides are also stabilized by binding ATP or single-stranded DNA.(ABSTRACT TRUNCATED AT 400 WORDS)