gebhart/patrepeval huggingface dataset:
Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: a play in 3 Akts (2010)

The protein serine/threonine kinase Akt, also known as protein kinase B (PKB), is arguably the most important signalling nexus in the cell. Akt integrates a plethora of extracellular signals to generate diverse outcomes, including proliferation, motility, growth, glucose homeostasis, survival, and cell death. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is the second most frequently mutated pathway in cancer, after p53, and mutations in components of this pathway are found in around 70% of breast cancers. Thus, understanding how Akt relays input signals to downstream effectors is critically important for the design of therapeutic strategies to combat breast cancer. In this review, we will discuss the various signals upstream of Akt that impact on its activity, how Akt integrates these signals and modulates the activity of downstream targets to control mammary gland development, and how mutations in components of the pathway result in breast cancer.
Prediction of immunodominant helper T cell antigenic sites from the primary sequence. (1987)

We have used a data base of 23 known immunodominant helper T cell antigenic sites located on 12 proteins to systematically develop an optimized algorithm for predicting T cell antigenic sites. The algorithm is based on the amphipathic helix model in which antigenic sites are postulated to be helices with one face predominantly polar and the opposite face predominantly apolar. Such amphipathic structures can form when the polarity of residues along the sequence varies with a more or less regular period. Hence they can be identified by methods (so called power spectrum procedures) that detect periodic variations in properties of a sequence. The choice of power spectrum procedure, hydrophobicity scale, and model parameters are examined. An algorithm is tested by comparing the predicted amphipathic segments with the locations of the known T cell sites, counting the number of matches, and calculating the probability of getting this number by chance alone. The optimum algorithm, which predicts the largest number of sites with the lowest chance probability, uses the Fauchere-Pliska hydrophobicity scale and a least squares fit of a sinusoid as its power spectrum procedure. By applying this algorithm, 18 of the 23 known sites are identified (75% sensitivity) with a high degree of significance (p less than 0.001). The success of the algorithm supports the hypothesis that stable amphipathic helices are fundamentally important in determining immunodominance. This approach may be of practical value in designing synthetic vaccines aimed at T cell immunity.
Temperature-stable spun elliptical-core optical-fiber current transducer (1993)

A temperature-stable electrical current transducer, with a spun birefringent elliptical-core optical fiber, has been designed, theoretically analyzed, constructed, and tested. The transducer uses a novel form of Sagnac interferometer to cancel the temperature dependence of the spun fiber.
Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions with cyclooctynes (2009)

Strain-promoted cycloadditions of nitrones with cyclooctynes (k(2) = 1.5 M(-1) s(-1) at 25 degrees C) are up to 25 times more rapid than comparable reactions of azides.
Self-Monitoring of Blood Glucose in Noninsulin-Using Type 2 Diabetic Patients (2012)

Given the importance of glycemic control in the development of diabetes complications, the plethora of tools now available to monitor the day-to-day trends in glycemia is remarkable. In this regard, self-monitoring of blood glucose (SMBG) has been considered a key component of patient management. Arguably, there remains almost universal agreement that SMBG should be available to all diabetic patients regardless of current treatment strategy. However, recently there have been reports that have challenged the current paradigm that all patients should use SMBG and concluded that SMBG for type 2 diabetic patients not on insulin may not be beneficial on glycemic control and must be weighed against the expense and inconvenience. In this two-part point-counterpoint narrative, Malanda et al. and Polonsky and Fisher take opposing views on the utility of SMBG to be valuable for individuals with type 2 diabetes not using insulin. In the narrative below, Malanda et al. suggest that the evidence for potentially beneficial SMBG-induced effects on glycemic control, hypoglycemic periods, and potential harms in type 2 diabetic patients who are not treated with insulin does not justify the use of SMBG. Moreover, the use of SMBG is associated with huge costs, which should be better redirected to effective strategies to improve health for this category of patients. -William T. Cefalu, MD Editor in Chief, Diabetes Care.
The Proinflammatory Cytokine High-Mobility Group Box-1 Mediates Retinal Neuropathy Induced by Diabetes (2014)

To test the hypothesis that increased expression of proinflammatory cytokine high-mobility group box-1 (HMGB1) in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy and in retinas of diabetic rats plays a pathogenetic role in mediating diabetes-induced retinal neuropathy. Retinas of 1-month diabetic rats and HMGB1 intravitreally injected normal rats were studied using Western blot analysis, RT-PCR and glutamate assay. In addition, we studied the effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced biochemical changes in the retina. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of HMGB1 protein and mRNA, activated extracellular signal-regulated kinase 1 and 2 (ERK1/2), cleaved caspase-3 and glutamate; and significant downregulation of synaptophysin, tyrosine hydroxylase, glutamine synthetase, and glyoxalase 1. Constant glycyrrhizin intake from the onset of diabetes did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of HMGB1 protein and mRNA, activated ERK1/2, cleaved caspase-3, and glutamate. In the glycyrrhizin-fed diabetic rats, the decrease in synaptophysin, tyrosine hydroxylase, and glyoxalase 1 caused by diabetes was significantly attenuated. These findings suggest that early retinal neuropathy of diabetes involves upregulated expression of HMGB1 and can be ameliorated by inhibition of HMGB1.
Mitosis-specific Negative Regulation of Epidermal Growth Factor Receptor, Triggered by a Decrease in Ligand Binding and Dimerization, Can Be Overcome by Overexpression of Receptor (1997)

The function of epidermal growth factor receptor (EGFR) was found to be negatively regulated in M phase in which it showed less phosphotyrosine content and reduced intrinsic kinase activity accompanied by retarded electrophoretic mobility owing to total hyperphosphorylation. Ligand-induced autophosphorylation and downstream signaling of EGFR were tightly suppressed in M phase due to a decrease in ligand binding affinity and the inability of epidermal growth factor (EGF) to induce receptor dimerization. There was no change in the number of surface-exposed EGF receptors between G0/G1 and M phases of the cell cycle. Hyperphosphorylation (due to serine and/or threonine phosphorylation) correlates with the unresponsiveness of cells to EGF-mediated stimulation of tyrosine phosphorylation in cells that express the normal or basal level of EGFR. This M phase-specific negative regulation was overcome by overexpression of EGFR, which was responsive to ligand throughout the cell cycle and revealed ligand-induced signaling in the M phase. These findings indicate that EGFR does not respond to ligand stimulation in M phase and suggest that a negative regulation of ligand-receptor interactions in M phase may control the normal function of receptor tyrosine kinase and that receptor overexpression will disrupt this cell cycle-dependent regulation of receptor tyrosine kinases.
New Approach to Noninvasive Manometry Based on Pressure Dependent Resonant Shift of Elastic Microcapsules in Ultrasonic Frequency Characteristics (1988)

To measure physiological pressure in situ , we have developed a new technique based on the principle that an elastic microcapsule in liquid changes its resonant frequency depending on the surrounding pressure. The following results were ohtained: 1) The frequency characteristics of transmission wave through microcapsules showed marked attenuation with a specific spectral peak, indicating the resonance of the microcapsules. 2) Pressure dependent change in amplitude of the attenuation peak increased linearly with the increment of pressure. 3) Pressure dependent resonant shifts were also observed in proportion to the pressure increment.
Frameless stereotaxy for surgery of the epilepsies: preliminary experience (1994)

✓ Frameless stereotactic techniques used in conjunction with three-dimensional images allow accurate planning and performance of a variety of neurosurgical procedures. The authors have used the frameless stereotactic Allegro Viewing Wand system to provide real-time correlation of the operating field and computerized images in 42 neurosurgical operations, including 31 epilepsy procedures. The system consists of an image-processing computer that creates three-dimensional and triplanar images; a mobile computer to display reformatted magnetic resonance images; and a hand-guided, articulated, position-sensing arm with a probe. At the start of the operation, the probe identifies the patient's facial and scalp features and correlates these with the computerized images. The position-sensing arm can then guide the operation and locate anatomical structures and lesions of interest. This system can be used to advantage in performing smaller craniotomies and intraoperatively locating anatomical structures and lesions to be removed. Postoperative magnetic resonance images demonstrate that this technique was accurate to within 3 mm in measuring the anteroposterior resection of fixed structures, such as hippocampus and corpus callosum. Disadvantages include longer preoperative preparation for data analysis and lack of both real-time computer analysis of tissue removal and angiographic data display. Preliminary experience suggests that the viewing wand system's advantages outweigh the disadvantages, and it is most helpful as an adjunctive navigational device in the microsurgical treatment of epilepsy.
Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae (2008)

Several members of the Rubiaceae and Violaceae plant families produce a series of cyclotides or macrocyclic peptides of 28-37 aa with an embedded cystine knot. The cyclic peptide backbone together with the knotted and strongly braced structure confers exceptional chemical and biological stability that has attracted attention for potential pharmaceutical applications. Cyclotides display a diverse range of biological activities, such as uterotonic action, anti-HIV activity, and neurotensin antagonism. In plants, their primary role is probably protection from insect attack. Ingestion of the cyclotide kalata B1 severely retards the growth of larvae from the Lepidopteran species Helicoverpa armigera. We examined the gut of these larvae after consumption of kalata B1 by light, scanning, and transmission electron microscopy. We established that kalata B1 induces disruption of the microvilli, blebbing, swelling, and ultimately rupture of the cells of the gut epithelium. The histology of this response is similar to the response of H. armigera larvae to the Bacillus thuringiensis delta-endotoxin, which is widely used to control these insect pests of crops such as cotton.
Effects of tamoxifen, an antiestrogen, on rat prostate carcinogenesis by 3,2′-dimethyl-4-aminobiphenyl and testosterone do not support an estrogen role in testosterone promotion (1997)

These findings suggest that estrogen, which is derived from testosterone by the action of aromatase, is not involved in the strong promotion by TP of DMAB prostate carcinogenesis.
IL-11 Signaling as a Therapeutic Target for Cancer (2015)

IL-11 is a member of the IL-6 family of cytokines. While it was discovered over 20 years ago, we have very little understanding of the role of IL-11 during normal homeostasis and disease. Recently, IL-11 has gained interest for its newly recognized role in the pathogenesis of diseases that are attributed to deregulated mucosal homeostasis, including gastrointestinal cancers. IL-11 can increase the tumorigenic capacity of cells, including survival of the cell or origin, proliferation of cancerous cells and survival of metastatic cells at distant organs. Here we outline our current understanding of IL-11 biology and recent advances in our understanding of its role in cancer. We advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers.
Transcriptional and Translational Regulation of α-Acetolactate Decarboxylase of Lactococcus lactis subsp. lactis (2000)

The alpha-acetolactate decarboxylase (ALDC) gene, aldB, is the penultimate gene of the leu-ilv-ald operon, which encodes the three branched-chain amino acid (BCAA) biosynthesis genes in Lactococcus lactis. Its product plays a dual role in the cell: (i) it catalyzes the second step of the acetoin pathway, and (ii) it controls the pool of alpha-acetolactate during leucine and valine synthesis. It can be transcribed from the two promoters present upstream of the leu and ilv genes (P1 and P2) or independently under the control of its own promoter (P3). In this paper we show that the production of ALDC is limited by two mechanisms. First, the strength of P3 decreases greatly during starvation for BCAAs and under other conditions that generally provoke the stringent response. Second, although aldB is actively transcribed from P1 and P2 during BCAA starvation, ALDC is not significantly produced from these transcripts. The aldB ribosome binding site (RBS) appears to be entrapped in a stem-loop, which is itself part of a more complex RNA folding structure. The function of the structure was studied by mutagenesis, using translational fusions with luciferase genes to assess its activity. The presence of the single stem-loop entrapping the aldB RBS was responsible for a 100-fold decrease in the level of aldB translation. The presence of a supplementary secondary structure upstream of the stem-loop led to an additional fivefold decrease of aldB translation. Finally, the translation of the ilvA gene terminating in the latter structure decreased the level of translation of aldB fivefold more, leading to the complete extinction of the reporter gene activity. Since three leucines and one valine are present among the last six amino acids of the ilvA product, we propose that pausing of the ribosomes during translation could modulate the folding of the messenger, as a function of BCAA availability. The purpose of the structure-dependent regulation could be to ensure the minimal production of ALDC required for the control of the acetolactate pool during BCAA synthesis but to avoid its overproduction, which would dissipate acetolactate. Large amounts of ALDC, necessary for operation of the acetoin pathway, could be produced under favorable conditions from the P3 transcripts, which do not contain the secondary structures.
GSM/TDMA adaptive antenna field-trial results (2003)

Adaptive antennas have generated great interest and several manufacturers and operators are separately or jointly performing field-tests to gain more detailed knowledge of the potential of the technology. This article summarizes many of the experiences that since 1996 have been collected during field trials carried out for both GSM and TDMA (IS-136) by Ericsson in co-operation with two major network operators, Mannesmann Mobilfunk and AT and T Wireless Services.
Presence of epidermal growth factor receptor as an indicator of poor prognosis in patients with breast cancer. (1985)

Epidermal growth factor receptors are present in some breast cancers in man, and there is an inverse relation to oestrogen receptor state. We assessed the presence of epidermal growth factor receptors as a single prognostic indicator in a series of breast tumours by comparing this with the Bloom and Richardson scores for these tumours. One hundred and eight ductal tumours were examined for epidermal growth factor receptors by radioligand binding. There was a significant (p less than 0.01) correlation between the presence of the growth factor receptor and poor prognosis as assessed by the Bloom and Richardson score, suggesting that epidermal growth factor receptor state could be a useful prognostic marker. Epidermal growth factor receptor state was not significantly correlated with the lymph node state but showed a tendency to be associated with large tumours.
Innentitelbild: Sauerstoff steuert molekulare Schalter (Angew. Chem. 40/2007) (2007)

Licht, Luft und Wärme genügen, um einen molekularen Schalter mit Sauerstoff zu steuern. T. Linker et al. zeigen in der Zuschrift auf S. 7833 ff., dass die Oxidation ortho-substituierter Bisarylanthracene mit Singulettsauerstoff eine Achsenrotation erzwingt und zu einem 180°-Schaltvorgang führt. Nach Abspaltung von Sauerstoff unter milden Bedingungen kann durch Thermolyse das trans-Isomer regeneriert werden. Somit wird in nur drei Stufen der Ausgangszustand des Schalters erreicht, wobei Sauerstoff als einziges weiteres Produkt anfällt.
4-Hydroxy-5,6-dihydropyrones as Inhibitors of HIV Protease:  The Effect of Heterocyclic Substituents at C-6 on Antiviral Potency and Pharmacokinetic Parameters (2001)

Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.
Integrated, Nontargeted Ultrahigh Performance Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry Platform for the Identification and Relative Quantification of the Small-Molecule Complement of Biological Systems (2009)

To address the challenges associated with metabolomics analyses, such as identification of chemical structures and elimination of experimental artifacts, we developed a platform that integrated the chemical analysis, including identification and relative quantification, data reduction, and quality assurance components of the process. The analytical platform incorporated two separate ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS(2)) injections; one injection was optimized for basic species, and the other was optimized for acidic species. This approach permitted the detection of 339 small molecules, a total instrument analysis time of 24 min (two injections at 12 min each), while maintaining a median process variability of 9%. The resulting MS/MS(2) data were searched against an in-house generated authentic standard library that included retention time, molecular weight (m/z), preferred adducts, and in-source fragments as well as their associated MS/MS spectra for all molecules in the library. The library allowed the rapid and high-confidence identification of the experimentally detected molecules based on a multiparameter match without need for additional analyses. This integrated platform enabled the high-throughput collection and relative quantitative analysis of analytical data and identified a large number and broad spectrum of molecules with a high degree of confidence.
Ghrelin Agonist (TZP‐101): Safety, Pharmacokinetics and Pharmacodynamic Evaluation in Healthy Volunteers: A Phase I, First‐in‐Human Study (2008)

The authors evaluate the human safety, tolerability, pharmacokinetics, and pharmacodynamics of TZP-101, an agonist of the hGHS-R1a (ghrelin) receptor. Healthy subjects were randomized to either single-dose TZP-101 (20-600 microg/kg) or placebo by 30-minute intravenous infusion. Subjects underwent continuous cardiac monitoring, 12-lead electrocardiograms, and assessment for orthostatic hypotension, injection site tolerability, vital signs, and adverse events during the 24-hour postdose period. Blood and urine samples were collected for pharmacokinetic/pharmacodynamic assessment for 24 hours. Forty-eight subjects randomly received 1 of 6 TZP-101 doses or placebo. TZP-101 was well tolerated, with single episodes each of headache, lower abdominal pain, diarrhea, and dizziness. At the highest dose, 2 subjects experienced bradycardia. All events were self-limited. Mean arterial blood pressure and heart rate decreased from baseline approximately 45 to 60 minutes after infusion start at higher doses. No other significant changes were observed. Pharmacokinetic analysis revealed less than dose-proportional behavior of drug with low clearance (approximately 7 mL/h/kg), small volume of distribution (approximately 114 mL/kg), and half-life values of approximately 13 hours, which were independent of dose. Pharmacodynamic analyses suggested TZP-101, at doses as low as 40 microg/kg, expressed activity at the receptor. TZP-101 displayed a promising pharmacokinetic, pharmacodynamic, and safety profile for use in gastrointestinal motility disorders.
The ARF1 GTPase-Activating Protein: Zinc Finger Motif and Golgi Complex Localization (1995)

Hydrolysis of guanosine triphosphate (GTP) by the small guanosine triphosphatase (GTPase) adenosine diphosphate ribosylation factor-1 (ARF1) depends on a GTPase-activating protein (GAP). A complementary DNA encoding the ARF1 GAP was cloned from rat liver and predicts a protein with a zinc finger motif near the amino terminus. The GAP function required an intact zinc finger and additional amino-terminal residues. The ARF1 GAP was localized to the Golgi complex and was redistributed into a cytosolic pattern when cells were treated with brefeldin A, a drug that prevents ARF1-dependent association of coat proteins with the Golgi. Thus, the GAP is likely to be recruited to the Golgi by an ARF1-dependent mechanism.
Non-proteinuric pre-eclampsia: a novel risk indicator in women with gestational hypertension (2008)

This study highlights differences between non-proteinuric pre-eclampsia and gestational hypertension. The subclassification of 'non-proteinuric pre-eclampsia' should be added to existing classification systems to alert clinicians to potential risks.
Experimental study of the effect of quantum-well structures on the thermoelectric figure of merit (1996)

Recently, it has been shown theoretically that it may be possible to increase the thermoelectric figure of merit ($Z$) of certain materials by preparing them in the form of two-dimensional quantum-well structures. Using $\mathrm{PbTe}/{\mathrm{Pb}}_{1\ensuremath{-}x}{\mathrm{Eu}}_{x}\mathrm{Te}$ multiple-quantum-well structures grown by molecular-beam epitaxy, we have performed thermoelectric and other transport measurements as a function of quantum-well thickness and doping. Our results are found to be consistent with theoretical predictions and indicate that an increase in $Z$ over bulk values may be possible through quantum confinement effects using quantum-well structures.