gebhart/patrepeval huggingface dataset:
In Vitroandin VivoStructure-Activity Relationships of Novel Androgen Receptor Ligands with Multiple Substituents in the B-Ring (2005)

We recently reported two nonsteroidal androgen receptor (AR) ligands that demonstrate tissue-selective pharmacological activity, identifying these S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide analogs as the first members of a new class of drugs known as selective androgen receptor modulators. The purpose of these studies was to explore additional structure-activity relationships of selective androgen receptor modulators to enhance their AR binding affinity, AR-mediated transcriptional activation, and in vivo pharmacological activity. The AR binding affinity (K(i)) of 29 novel synthetic AR ligands was determined by a radioligand competitive binding assay and ranged from 1.0-51 nM. Compounds with electron-withdrawing substituents at the para- and meta-positions of the B-ring demonstrated the highest AR binding affinity. The AR-mediated transcriptional activation was determined using a cotransfection assay in CV-1 cells. Most compounds with two substituents in the B-ring maintained or improved their functional activity in vitro. However, compounds with three halogen substituents exhibited significant regioselectivity. Fifteen compounds were selected to examine their pharmacological activity in castrated rats. In vivo pharmacological activity and selectivity were significantly changed by structural modification in the B-ring. Compounds with halogen groups at the para- and meta-positions of the B-ring displayed the highest pharmacological activity. Incorporating substituents at the ortho-position of the B-ring resulted in poor pharmacological activity. In vitro and in vivo agonist activities were partially correlated. In conclusion, novel selective androgen receptor modulators with improved in vivo pharmacological activity can be designed and synthesized based on the structure-activity relationship identified in these studies.
GENETIC BASIS OF STARVATION SURVIVAL IN NONDIFFERENTIATING BACTERIA (1989)

1) Macromolecular degradation; 2) Escape from starvation; 3) Development of a more resistant cell state
A homogeneous method for investigation of methylation-dependent protein-protein interactions in epigenetics (2009)

Methylation of lysine residues on the tails of histone proteins is a major determinant of the transcription state of associated DNA coding regions. The interplay among methylation states and other histone modifications to direct transcriptional outcome is referred to as the histone code. In addition to histone methyltransferases and demethylases which function to modify the methylation state of lysine sidechains, other proteins recognize specific histone methylation marks essentially serving as code readers. While these interactions are highly specific with respect to site and methylation state of particular lysine residues, they are generally weak and therefore difficult to monitor by traditional assay techniques. Herein, we present the design and implementation of a homogeneous, miniaturizable, and sensitive assay for histone methylation-dependent interactions. We use AlphaScreen, a chemiluminescence-based technique, to monitor the interactions of chromodomains (MPP8, HP1beta and CHD1), tudor domains (JMJD2A) and plant homeodomains (RAG2) with their cognate trimethyllysine histone partners. The utility of the method was demonstrated by profiling the binding specificities of chromo- and tudor domains toward several histone marks. The simplicity of design and the sensitive and robust nature of this assay should make it applicable to a range of epigenetic studies, including the search for novel inhibitors of methylation-dependent interactions.
Tooth chipping can reveal the diet and bite forces of fossil hominins (2010)

Mammalian tooth enamel is often chipped, providing clear evidence for localized contacts with large hard food objects. Here, we apply a simple fracture equation to estimate peak bite forces directly from chip size. Many fossil hominins exhibit antemortem chips on their posterior teeth, indicating their use of high bite forces. The inference that these species must have consumed large hard foods such as seeds is supported by the occurrence of similar chips among known modern-day seed predators such as orangutans and peccaries. The existence of tooth chip signatures also provides a way of identifying the consumption of rarely eaten foods that dental microwear and isotopic analysis are unlikely to detect.
A bimanual teleoperated system for endonasal skull base surgery (2011)

We describe transnasal skull base surgery, including the current clinical procedure and the ways in which a robotic system has the potential to enhance the current standard of care. The available workspace is characterized by segmenting medical images and reconstructing the available 3D geometry. We then describe thin, ¿tentacle-like¿ robotic tools with shafts constructed from concentric tube robots, and an actuation unit designed to robotically control them in a teleoperated setting. Lastly, we discuss the results of a proof-of-concept study in a cadaveric specimen, illustrating the ability of the robot to access clinically relevant skull base targets.
Association of Host Cell Surface Adhesion Receptors and Other Membrane Proteins with HIV and SIV (1993)

We have developed a MAb-based capture assay to study the association of host cell membrane proteins with HIV and SIV. Class I and II MHC proteins were found to be associated with HIV as previously described. In addition to these molecules a number of other host molecules were found to be acquired by HIV, including CD71, CD63, CD43, and CD8. We have demonstrated that the major leukocyte adhesion receptors LFA-1 (CD11A/CD18) and CD44 are also associated with HIV. The level of surface expression of host membrane proteins did not predict relative expression (capture efficiency) of the virus. The use of virus-susceptible indicator cells showed that the assay involved host membrane protein-mediated capture of infectious HIV and SIV particles. Our data indicate that HIV and SIV acquire a number of host membrane proteins including adhesion receptors and that this process may be nonrandom. The acquisition of host cell adhesion receptors by HIV and SIV could have profound effects on the biology of the viruses, including binding, infectivity, and tropism.
Cloning of a Human cDNA for CTP-Phosphoethanolamine Cytidylyltransferase by Complementation in Vivo of a Yeast Mutant (1997)

CTP-phosphoethanolamine cytidylyltransferase (ET) is the enzyme that catalyzes the formation of CDP-ethanolamine in the phosphatidylethanolamine biosynthetic pathway from ethanolamine. We constructed a Saccharomyces cerevisiae mutant of which the ECT1 gene, putatively encoding ET, was disrupted. This mutant showed a growth defect on ethanolamine-containing medium and a decrease of ET activity. A cDNA clone was isolated from a human glioblastoma cDNA expression library by complementation of the yeast mutant. Introduction of this cDNA into the yeast mutant clearly restored the formation of CDP-ethanolamine and phosphatidylethanolamine in cells. ET activity in transformants was higher than that in wild-type cells. The deduced protein sequence exhibited homology with the yeast, rat, and human CTP-phosphocholine cytidylyltransferases, as well as yeast ET. The cDNA gene product was expressed as a fusion with glutathione S-transferase in Escherichia coli and shown to have ET activity. These results clearly indicate that the cDNA obtained here encodes human ET.
ß-Arrestin 2 Mediates Endocytosis of Type III TGF-ß Receptor and Down-Regulation of Its Signaling (2003)

beta-Arrestins bind to activated seven transmembrane-spanning (7TMS) receptors (G protein-coupled receptors) after the receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), thereby regulating their signaling and internalization. Here, we demonstrate an unexpected and analogous role of beta-arrestin 2 (betaarr2) for the single transmembrane-spanning type III transforming growth factor-beta (TGF-beta) receptor (TbetaRIII, also referred to as betaglycan). Binding of betaarr2 to TbetaRIII was also triggered by phosphorylation of the receptor on its cytoplasmic domain (likely at threonine 841). However, such phosphorylation was mediated by the type II TGF-beta receptor (TbetaRII), which is itself a kinase, rather than by a GRK. Association with betaarr2 led to internalization of both receptors and down-regulation of TGF-beta signaling. Thus, the regulatory actions of beta-arrestins are broader than previously appreciated, extending to the TGF-beta receptor family as well.
Increasing parvovirus filter throughput of monoclonal antibodies using ion exchange membrane adsorptive pre‐filtration (2010)

Pre-filtration using ion exchange membrane adsorbers can improve parvovirus filter throughput of monoclonal antibodies (mAbs). The membranes work by binding trace foulants, and although some antibody product also binds, yields > or =99% are easily achieved by overloading. Results show that foulant adsorption is dependent on pH and conductivity, but independent of scale and adsorber brand. The ability to use ion exchange membranes as pre-filters is significant because it provides a clean, well defined, chemically stable option for enhancing throughput. Additionally, ion exchange membranes facilitate characterization of parvovirus filter foulants. Examination of adsorber elution samples using sedimentation velocity analysis and SEC-MALS/QELS revealed the presence of high molecular weight species ranging from 8 to 13 nm in hydrodynamic radius, which are similar in size to parvoviruses and thus would be expected to plug the pores of a parvovirus filter. A study of two identical membranes in-series supports the hypothesis that the foulants are soluble, trace level aggregates in the feed. This study's significance lies in a previously undiscovered application of membrane chromatography, leading to a more cost effective and robust approach to parvovirus filtration for the production of monoclonal antibodies.
Phylogenetic Affiliation of Soil Bacteria That Degrade Aliphatic Polyesters Available Commercially as Biodegradable Plastics (1998)

Thirty-nine morphologically different soil bacteria capable of degrading poly(beta-hydroxyalkanoate), poly(epsilon-caprolactone), poly(hexamethylene carbonate), or poly(tetramethylene succinate) were isolated. Their phylogenetic positions were determined by 16S ribosomal DNA sequencing, and all of them fell into the classes Firmicutes and Proteobacteria. Determinations of substrate utilization revealed characteristic patterns of substrate specificities.
Digital light processing and MEMS : timely convergence for a bright future (1995)

Projection displays and microelectromechanical systems (MEMS) have evolved independently, occasionally crossing paths as early as the 1960s. But the commercially viable use of MEMS for projection displays was elusive until the recent invention of Texas Instruments Digital Light ProcessingTM (DLPTM) technology. DLP technology is based on the Digital Micromirror DeviceTM (DMDTM) microchip, a MEMS array of semiconductor-based digital light switches that precisely control a light source for projection display and hardcopy applications. DLP technology enables digital, high-resolution, color projection displays that have high contrast, are bright, are seamless, and have the accuracy of color and gray scale that only digital control can achieve.
Pulse Radiolytic Studies of Metallotexaphyrins in the Presence of Oxygen:  Relevance of the Equilibrium with Superoxide Anion to the Mechanism of Action of the Radiation Sensitizer Motexafin Gadolinium (Gd−Tex2+, Xcytrin) (2001)

Pulse radiolytic studies of aqueous solutions of four representative metallotexaphyrin complexes M−Tex2+ (M = Gd(III), Lu(III), Dy(III), and Y(III)), carried out in the presence of either dioxygen, or trimethyl-p-benzoquinone (TMQ). It was found that all four of these M−Tex2+ species set up an equilibrium with superoxide and the singly reduced TMQ (TMQ•-) on the pulse radiolytic time scale. Rate constants for the forward (k1) and back (k-1) reactions of Gd−Tex2+ with superoxide anions, at pH 8.5, were determined to be (9.8 ± 1.5) × 106 M-1 s-1 and (3.4 ± 0.5) × 106 M-1 s-1, respectively. For reaction with TMQ•-, the analogous rate constants were found to be (1.5 ± 0.2) × 107 M-1 s-1 and (3.7 ± 0.6) × 106 M-1 s-1, respectively. Equilibrium constants (Kkin), calculated from these kinetic parameters, were found to be 2.9 and 4.1 for Gd−Tex2+ reacting with O2•- (to produce Gd−Tex•+ and O2) and TMQ•- (to produce Gd−Tex•+ and TMQ), respectively. Equilibrium constants for the M-Tex2+ species reacting with O2•- and TMQ•- were also determined from analysis of the absorption following establishment of the equilibrium. The resulting values for Gd−Tex2+ were found to be 6.8 and 10.7, respectively. From these equilibrium constants, the redox potential for the M−Tex2+/M−Tex•+ couples at pH 8.5 were estimated and found to be ca. −110 mV vs NHE in the case of Gd−Tex2+.
Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression (2006)

Defective regulation of the cardiac ryanodine receptor (RyR2)/calcium release channel, required for excitation-contraction coupling in the heart, has been linked to cardiac arrhythmias and heart failure. For example, diastolic calcium "leak" via RyR2 channels in the sarcoplasmic reticulum has been identified as an important factor contributing to impaired contractility in heart failure and ventricular arrhythmias that cause sudden cardiac death. In patients with heart failure, chronic activation of the "fight or flight" stress response leads to protein kinase A (PKA) hyperphosphorylation of RyR2 at Ser-2808. PKA phosphorylation of RyR2 Ser-2808 reduces the binding affinity of the channel-stabilizing subunit calstabin2, resulting in leaky RyR2 channels. We developed RyR2-S2808A mice to determine whether Ser-2808 is the functional PKA phosphorylation site on RyR2. Furthermore, mice in which the RyR2 channel cannot be PKA phosphorylated were relatively protected against the development of heart failure after myocardial infarction. Taken together, these data show that PKA phosphorylation of Ser-2808 on the RyR2 channel appears to be a critical mediator of progressive cardiac dysfunction after myocardial infarction.
Lares: An Architecture for Secure Active Monitoring Using Virtualization (2008)

Host-based security tools such as anti-virus and intrusion detection systems are not adequately protected on today's computers. Malware is often designed to immediately disable any security tools upon installation, rendering them useless. While current research has focused on moving these vulnerable security tools into an isolated virtual machine, this approach cripples security tools by preventing them from doing active monitoring. This paper describes an architecture that takes a hybrid approach, giving security tools the ability to do active monitoring while still benefiting from the increased security of an isolated virtual machine. We discuss the architecture and a prototype implementation that can process hooks from a virtual machine running Windows XP on Xen. We conclude with a security analysis and show the performance of a single hook to be 28 musecs in the best case.
Nitrogen-Polar (000 1 ¯ ) GaN Grown on c-Plane Sapphire with a High-Temperature AlN Buffer (2017)

We demonstrate growing nitrogen-polar (N-polar) GaN epilayer on c-plane sapphire using a thin AlN buffer layer by metalorganic chemical vapor deposition. We have studied the influence of the AlN buffer layer on the polarity, crystalline quality, and surface morphology of the GaN epilayer and found that the growth temperature of the AlN buffer layer played a critical role in the growth of the GaN epilayer. The low growth temperature of the AlN buffer results in gallium-polar GaN. Even a nitridation process has been conducted. High growth temperature for an AlN buffer layer is required to achieve pure N-polarity, high crystalline quality, and smooth surface morphology for a GaN epilayer.
A feasibility study for megavoltage cone beam CT using a commercial EPID (1998)

This study used a standard commercial electronic portal imaging device (EPID) area detector attached to an isocentric linear accelerator and the Feldkamp algorithm to produce cone beam tomographic reconstructions. The EPID has a active area of 32.5 x 32.5 cm2, and can record 12-bit images using two monitor units (MU), with a resolution of 2.1 x 2.0 mm2 FWHM. Since the EPID was not large enough to record the full patient projection at about 1.5 geometric magnification, it was necessary to offset the detector to collect half-cone projections. Corrections are required to convert pixel values into units of exit dose and to realign the projections to overcome the +/- 4 mm support arm sag. With a geometric magnification of 1.5 the sensitive volume is a cylinder of radius 21 cm and length 17 cm. Unfortunately, the patient couch contains metal bed support rails that lie just outside this cylinder, and produce streak artefacts in the reconstruction. Using 90 views the system delivers a central dose of 90 cGy, and has a density resolution of 4%.
Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization. (1994)

An animal model of local allergen (airways) sensitization was employed to study the effects of rIFN-gamma administered by ultrasonic nebulization through the airways on IgE production and airways responsiveness. BALB/c mice exposed to aerosolized OVA daily for 10 days developed a predominant anti-OVA IgE response, immediate cutaneous reactivity to OVA, and increased airways responsiveness (AR). Mice were treated with rIFN-gamma, either systemically or locally via the airways, following different protocols; i.p. rIFN-gamma failed to modulate the course of OVA sensitization, although total IgE levels in the serum were decreased by 50%. Anti-OVA IgE levels remained elevated, immediate skin test responses to OVA persisted, and AR was increased. However, local treatment of the airways with nebulized rIFN-gamma caused a 66% decrease in serum anti-OVA IgE and a twofold rise in IgG2a levels. Cutaneous reactivity to OVA was reduced and AR was also normalized after nebulized rIFN-gamma. In contrast to the i.p. route, treatment with nebulized rIFN-gamma resulted in a reduction in the in vitro IgE production by lymphocytes in response to OVA and IL-4. The timing of treatment with nebulized rIFN-gamma was important in determining the immunomodulatory response. Treatment after day 7 of OVA exposure failed to modulate sensitization. Treatment regimens with nebulized rIFN-gamma that began before day 7 of OVA exposure were able to decrease anti-OVA IgE. Only treatment regimens that included 3 days of nebulized IFN-gamma before OVA sensitization caused a decrease in cutaneous reactivity and normalization of AR. The data demonstrate that both the route and timing of rIFN-gamma administration are critical factors in the immunomodulation of the immediate allergic response to allergen sensitization via the airways.
Cyclosporine metabolism in human liver: Identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs (1988)

The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid-inducible rat cytochrome P-450 (P-450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P-450 of the P-450III gene family, homologues of rat P-450 PCN and rabbit P-4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P-450 is the major cyclosporine-metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P-450 explain several clinically observed drug interactions with cyclosporine.
Mesencephalic Astrocyte-Derived Neurotrophic Factor Is an Ischemia-Inducible Secreted Endoplasmic Reticulum Stress Response Protein in the Heart (2008)

The endoplasmic reticulum (ER) stress response (ERSR) is activated when folding of nascent proteins in the ER lumen is impeded. Myocardial ischemia was recently shown to activate the ERSR; however, the role of this complex signaling system in the heart is not well understood. ER stress activates the transcription factor ATF6, which induces expression of proteins targeted to the ER, where they restore protein folding, thus fostering cytoprotection. We previously developed a transgenic mouse line that expresses a conditionally activated form of ATF6 in the heart. In this mouse line, ATF6 activation decreased ischemic damage in an ex vivo model of myocardial ischemia/reperfusion and induced numerous genes, including mesencephalic astrocyte-derived neurotrophic factor (MANF). In the present study, MANF expression was shown to be induced in cardiac myocytes and in other cell types in the hearts of mice subjected to in vivo myocardial infarction. Additionally, simulated ischemia induced MANF in an ATF6-dependent manner in neonatal rat ventricular myocyte cultures. In contrast to many other ER-resident ERSR proteins, MANF lacks a canonical ER-retention sequence, consistent with our finding that MANF was readily secreted from cultured cardiac myocytes. Knockdown of endogenous MANF with micro-RNA increased cell death upon simulated ischemia/reperfusion, whereas addition of recombinant MANF to media protected cultured cardiac myocytes from simulated ischemia/reperfusion-mediated death. Thus, a possible function of the ERSR in the heart is the ischemia-mediated induction of secreted proteins, such as MANF, that can function in an autocrine/paracrine manner to modulate myocardial damage from ER stresses, including ischemia.
Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. (1985)

We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozygotes, and the Senegal haplotype in sickle cell anemia patients are all linked to high G gamma-globin expression. In addition, haplotypes IX and Senegal, but not haplotype III, have high Hb F levels. All of these haplotype have a common subhaplotype (+- ) in the gamma-globin gene region. In addition, haplotypes IX, III, and Senegalese sickle cell anemia patients exhibit hematological amelioration of their disease. Conversely, haplotypes I, V, and A in thalassemia patients, which also have a common subhaplotype (-----), and the Benin subhaplotype (--++-) in sickle cell anemia patients are all associated with low G gamma-globin and low Hb F levels. Low G gamma-globin expression in the adult is associated with two haplotypes that are not common between thalassemia and sickle cell anemia patients. We conclude that the determinant for high G gamma-globin expression is haplotype-linked to common and genetically dominant subhaplotypes in the two diseases. The total Hb F level, unlike the high G gamma-globin expression, however, is linked to haplotypes but not to subhaplotypes, thus dissociating the two genetic effects.