gebhart/patrepeval huggingface dataset:
Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity (1995)

The Vpr accessory gene product of human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus is believed to play a role in permitting entry of the viral core into the nucleus of nondividing cells. A second role for Vpr was recently suggested by Rogel et al. (M. E. Rogel, L. I. Wu, and M. Emerman, J. Virol. 69:882-888, 1995), who showed that Vpr prevents the establishment in vitro of chronically infected HIV producer cell lines, apparently by causing infected cells to arrest in the G2/M phase of the cell cycle. In cycling cells, progression from G2 to M phase is driven by activation of the p34cdc2/cyclin B complex, an event caused, in part, by dephosphorylation of two regulatory amino acids of p34cdc2 (Thr-14 and Tyr-15). We show here that Vpr arrests the cell cycle in G2 by preventing the activation of the p34cdc2/cyclin B complex. Vpr expression in cells caused p34cdc2 to remain in the phosphorylated, inactive state, p34cdc2/cyclin B complexes immunoprecipitated from cells expressing Vpr were almost completely inactive in a histone H1 kinase assay. Coexpression of a constitutively active mutant p34cdc2 molecule with Vpr relieved the G2 arrest. These findings strongly suggest that Vpr arrests cells in G2 by preventing the activation of the p34cdc2/cyclin B complex that is required for entry into M phase. In vivo, Vpr might, by preventing p34cdc2 activation, delay or prevent apoptosis of infected cells. This would increase the amount of virus each infected cell produced.
Vertical ridge augmentation: what is the limit? (1996)

The aim of this study is to show the possibility of achieving more than a 4-mm new vertical bone apposition on partially edentulous ridges. Six healthy, partially edentulous patients were treated from July 1993 to September 1993. After accurate radiographic investigation, all of the patients were treated using the Branemark System. After insertion, 14 fixtures were left circumferentially exposed for 37 mm. Autogenous bone graft harvested from a bone filter was placed around the exposed threads and completely covered with titanium-reinforced Gore-Tex augmentation membranes (TR-GTAM). Flaps were coronally displaced to passively cover the regenerative materials. Only one of the six membranes was exposed and it was removed immediately. After a 12-month healing period, the membranes were removed in conjunction with the second-stage surgical procedure. In the five cases where the membranes were kept covered, all of the available space underneath the TR-GTAM was filled with regenerative tissue. In all of the cases a histologic biopsy was performed. In one case all the space was filled with more than 7 mm of bone. In three cases all the space was filled with more than 5 mm of bone. In one case the most coronal part (approximately 1 mm) of the regenerative tissue was represented by connective tissue; the remaining tissue was represented by bone. The measurements demonstrated an average of vertical ridge augmentation of 4.95 mm. In the only case where the membrane underwent exposure and was then removed there was no regenerative tissue present.
The Effects of Clomiphene in Impotence a Clinical and Endocrine Study (1972)

Hormone treatment for impotence and impotentia ejaculandi (delayed or absent ejaculation in the presence of normal erections and desire) (Johnson, 1965) is based on two assumptions: namely—that (1) potency in the male is androgen dependent and (2) impotency is due to relative androgen deficiency (Miller, 1968; Margolis et al. , 1967; Sobotka, 1969). The synthetic preparations most frequently used are methyl testosterone, various esters, including the propionate, deconate, enanthate, etc. (Tuthill, 1955; Kupperman, 1967) and more recently a number of testosterone- ‘aphrodisiac’ combinations (Margolis et al. , 1967; Cooper et al. , 1971, etc.). Despite some claims of therapeutic success for the various regimes, the administration of exogenous hormones has several pharmacologic disadvantages. For instance methyl testosterone, which has to be taken sublingually or bucally, may be associated with severe toxic effects such as cholestatic jaundice, etc. (Goodman and Gilman, 1965). Parenterally administered testosterone esters, although less toxic and more certainly absorbed than methyl testosterone, have all the drawbacks of the intramuscular route; also their rate(s) of tissue release may not be optimal for metabolism. Additionally, all these synthetic compounds may inhibit endogenous testosterone formation and spermatogenesis by suppressing pituitary gonadotrophins. Long term administration may result in Leydig cell inactivity and even disuse atrophy. Recently Harkness et al. (1964, 1968) have observed that clomiphene (Fig. 1), a non-steroid triethylene derivative which in females stimulates the anovulatory ovary to secrete oestrogens (Bishop, 1970), significantly raised the levels of urinary steroid metabolites, including testosterone, in a proportion of ‘normal’ and corticosteroid deficient males. This unexpected testosterone elevating effect suggested its possible ‘experimental’ use as an alternative drug treatment in impotence. Accordingly a limited pilot study on five ‘primary’ (non-organic) impotent males was conducted: its main aims were (a) to assess the potential clinical utility of the drug and (b) to study its effects on the ‘pituitary-testes-axis' as reflected by plasma testosterone levels.
Requirements for Specific Binding of Low Affinity Inhibitor Fragments to the SH2 Domain ofpp60Src Are Identical to Those for High Affinity Binding of Full Length Inhibitors (2003)

Results from a novel approach which uses protein crystallography for the screening of a low affinity inhibitor fragment library are analyzed by comparing the X-ray structures with bound fragments to the structures with the corresponding full length inhibitors. The screen for new phospho-tyrosine mimics binding to the SH2 domain of (pp60)src was initiated because of the limited cell penetration of phosphates. Fragments in our library typically had between 6 and 30 atoms and included compounds which had either millimolar activity in a Biacore assay or were suggested by the ab initio design program LUDI but had no measurable affinity. All identified fragments were located in the phospho-tyrosine pocket. The most promising fragments were successfully used to replace the phospho-tyrosine and resulted in novel nonpeptidic high affinity inhibitors. The significant diversity of successful fragments is reflected in the high flexibility of the phospho-tyrosine pocket. Comparison of the X-ray structures shows that the presence of the H-bond acceptors and not their relative position within the pharmacophore are essential for fragment binding and/or high affinity binding of full length inhibitors. The X-ray data show that the fragments are recognized by forming a complex H-bond network within the phospho-tyrosine pocket of SH2. No fragment structure was found in which this H-bond network was incomplete, and any uncompensated H-bond within the H-bond network leads to a significant decrease in the affinity of full length inhibitors. No correlation between affinity and fragment binding was found for these polar fragments and hence affinity-based screening would have overlooked some interesting starting points for inhibitor design. In contrast, we were unable to identify electron density for hydrophobic fragments, confirming that hydrophobic interactions are important for inhibitor affinity but of minor importance for ligand recognition. Our results suggest that a screening approach using protein crystallography is particularly useful to identify universal fragments for the conserved hydrophilic recognition sites found in target families such as SH2 domains, phosphatases, kinases, proteases, and esterases.
Backward-Wave Oscillator Efficiency (1955)

The theoretical and experimental results of a study of the factors which determine the efficiency of backward-wave oscillators are described. The dependence of power output upon space charge, circuit loss, beam thickness, velocity spread, and circuit mismatches is determined by a combination of theoretical and empirical means. In addition, the effect of circuit mismatches upon the starting current and frequency is discussed. The study shows that efficiency can be increased by increasing either the gain parameter C or the space-charge parameter wq/w. Circuit loss, beam thickness, and velocity spread are found to decrease the efficiency. The use of the results reported here permits the designer to control the factors affecting the power output and predict the efficiency of a tube with reasonable accuracy before it is built.
Recognition Accuracy and Response Bias to Happy and Sad Facial Expressions in Patients With Major Depression. (2004)

Impaired facial expression recognition has been associated with features of major depression, which could underlie some of the difficulties in social interactions in these patients. Patients with major depressive disorder and age- and gender-matched healthy volunteers judged the emotion of 100 facial stimuli displaying different intensities of sadness and happiness and neutral expressions presented for short (100 ms) and long (2,000 ms) durations. Compared with healthy volunteers, depressed patients demonstrated subtle impairments in discrimination accuracy and a predominant bias away from the identification as happy of mildly happy expressions. The authors suggest that, in depressed patients, the inability to accurately identify subtle changes in facial expression displayed by others in social situations may underlie the impaired interpersonal functioning.
Biochemical characterization of Bacillus subtilis type II isopentenyl diphosphate isomerase, and phylogenetic distribution of isoprenoid biosynthesis pathways (2004)

An open reading frame (Acc. no. P50740) on the Bacillus subtilis chromosome extending from bp 184,997-186,043 with similarity to the idi-2 gene of Streptomyces sp. CL190 specifying type II isopentenyl diphosphate isomerase was expressed in a recombinant Escherichia coli strain. The recombinant protein with a subunit mass of 39 kDa was purified to apparent homogeneity by column chromatography. The protein was shown to catalyse the conversion of dimethylallyl diphosphate into isopentenyl diphosphate and vice versa at rates of 0.23 and 0.63 micromol.mg(-1).min(-1), respectively, as diagnosed by 1H spectroscopy. FMN and divalent cations are required for catalytic activity; the highest rates were found with Ca2+. NADPH is required under aerobic but not under anaerobic assay conditions. The enzyme is related to a widespread family of (S)-alpha-hydroxyacid oxidizing enzymes including flavocytochrome b2 and L-lactate dehydrogenase and was shown to catalyse the formation of [2,3-13C2]lactate from [2,3-13C2]pyruvate, albeit at a low rate of 1 nmol.mg(-1).min(-1). Putative genes specifying type II isopentenyl diphosphate isomerases were found in the genomes of Archaea and of certain eubacteria but not in the genomes of fungi, animals and plants. The analysis of the occurrence of idi-1 and idi-2 genes in conjunction with the mevalonate and nonmevalonate pathway in 283 completed and unfinished prokaryotic genomes revealed 10 different classes. Type II isomerase is essential in some important human pathogens including Staphylococcus aureus and Enterococcus faecalis where it may represent a novel target for anti-infective therapy.
Neurite‐promoting activity from fetal skeletal muscle: Immunological comparison with laminin (1987)

Polycation-binding neurite-promoting factor (PNPF) from skeletal muscle of bovine fetuses has been compared to mouse tumor laminin by an immunological approach. Antiserum prepared against PNPF blocked the neurite-promoting activity in a dose-dependent manner. The anti-PNPF antiserum bound to Mr = 200,000-195,000 bands as well as several components of higher molecular weight, as detected in immunoblots of reduced PNPF. The anti-PNPF antiserum did not inhibit the neurite-promoting activity of mouse laminin, although it did bind to native laminin. Antilaminin antiserum bound to PNFP and identified the same Mr = 200,000-195,000 bands and two other higher-molecular-weight bands, as did the anti-PNPF antiserum. The activity of PNPF was confirmed to be sensitive to treatment with heparitinase. It is concluded that PNPF from bovine fetal muscle contains a complex of heparan sulfate and high-molecular-weight components, particularly of Mr = 200,000-195,000, which share antigenic determinants with mouse laminin. However antilaminin antiserum fails to inhibit the activity of PNPF, suggesting that the active site, and/or adjacent regions, of PNPF are antigenically different from the neurite-promoting site of purified mouse tumor laminin.
Phenotypic modification of primary sensory neurons: the role of nerve growth factor in the production of persistent pain (1996)

Inflammation results in an early and maintained elevation in nerve growth factor (NGF) levels in inflamed tissues. Neutralizing the action of the increased NGF with specific anti-NGF antibodies substantially diminishes inflammatory hypersensitivity, indicating that this neurotrophin is a key mediator in the production of inflammatory pain. The hyperalgesic actions of NGF may in part be the consequence of an increase in sensitivity of the peripheral terminals of high threshold nociceptors either as a result of a direct action of NGF on trkA expressing sensory fibres or indirectly via the release of sensitizing mediators from trkA expressing inflammatory cells and postganglionic sympathetic neurons. NGF is also, however, retrogradely transported in sensory neurons to the dorsal root ganglion where it alters transcription of a number of proteins and peptides. This chapter reviews evidence suggesting that an NGF-mediated modification of gene expression in the dorsal root ganglion during inflammation is central to the pathophysiology of persistent pain. The phenotype changes produced by NGF during inflammation include elevation of neuropeptides which may amplify sensory input signals in the spinal cord and augment neurogenic inflammation in the periphery and the upregulation of growth related molecules which may lead to a hyperinnervation of injured tissue by promoting terminal sprouting.
Akt Phosphorylates Sec24: New Clues into the Regulation of ER‐to‐Golgi Trafficking (2010)

Regulation of protein transport within the early secretory pathway is a relatively unexplored area. Here, we propose a new player in the control of protein transport from the endoplasmic reticulum (ER) to the Golgi. Akt is an important signaling kinase whose functioning is perturbed in diseases such as cancer and diabetes. We discovered that Akt phosphorylates Sec24, an essential coat protein II (COPII) component involved in mediating cargo selection for ER-to-Golgi trafficking. We discuss how this finding may provide new insights into the regulation of protein transport.
Brain-Penetrating Nanoparticles Improve Paclitaxel Efficacy in Malignant Glioma Following Local Administration (2014)

Poor drug distribution and short drug half-life within tumors strongly limit efficacy of chemotherapies in most cancers, including primary brain tumors. Local or targeted drug delivery via controlled-release polymers is a promising strategy to treat infiltrative brain tumors, which cannot be completely removed surgically. However, drug penetration is limited with conventional local therapies since small-molecule drugs often enter the first cell they encounter and travel only short distances from the site of administration. Nanoparticles that avoid adhesive interactions with the tumor extracellular matrix may improve drug distribution and sustain drug release when applied to the tumor area. We have previously shown model polystyrene nanoparticles up to 114 nm in diameter were able to rapidly diffuse in normal brain tissue, but only if coated with an exceptionally dense layer of poly(ethylene glycol) (PEG) to reduce adhesive interactions. Here, we demonstrate that paclitaxel (PTX)-loaded, poly(lactic-co-glycolic acid) (PLGA)-co-PEG block copolymer nanoparticles with an average diameter of 70 nm were able to diffuse 100-fold faster than similarly sized PTX-loaded PLGA particles (without PEG coatings). Densely PEGylated PTX-loaded nanoparticles significantly delayed tumor growth following local administration to established brain tumors, as compared to PTX-loaded PLGA nanoparticles or unencapsulated PTX. Delayed tumor growth combined with enhanced distribution of drug-loaded PLGA-PEG nanoparticles to the tumor infiltrative front demonstrates that particle penetration within the brain tumor parenchyma improves therapeutic efficacy. The use of drug-loaded brain-penetrating nanoparticles is a promising approach to achieve sustained and more uniform drug delivery to treat aggressive gliomas and potentially other brain disorders.
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation (2015)

During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
Brefeldin A-inhibited guanine nucleotide-exchange activity of Sec7 domain from yeast Sec7 with yeast and mammalian ADP ribosylation factors (1998)

The Saccharomyces cerevisiae Sec7 protein (ySec7p), which is an important component of the yeast secretory pathway, contains a sequence of approximately 200 amino acids referred to as a Sec7 domain. Similar Sec7 domain sequences have been recognized in several guanine nucleotide-exchange proteins (GEPs) for ADP ribosylation factors (ARFs). ARFs are approximately 20-kDa GTPases that regulate intracellular vesicular membrane trafficking and activate phospholipase D. GEPs activate ARFs by catalyzing the replacement of bound GDP with GTP. We, therefore, undertook to determine whether a Sec7 domain itself could catalyze nucleotide exchange on ARF and found that it exhibited brefeldin A (BFA)-inhibitable ARF GEP activity. BFA is known to inhibit ARF GEP activity in Golgi membranes, thereby causing reversible apparent dissolution of the Golgi complex in many cells. The His6-tagged Sec7 domain from ySec7p (rySec7d) synthesized in Escherichia coli enhanced binding of guanosine 5'-[gamma-[35S]thio]triphosphate by recombinant yeast ARF1 (ryARF1) and ryARF2 but not by ryARF3. The effects of rySec7d on ryARF2 were inhibited by BFA in a concentration-dependent manner but not by inactive analogues of BFA (B-17, B-27, and B-36). rySec7d also promoted BFA-sensitive guanosine 5'-[gamma-thio]triphosphate binding by nonmyristoylated recombinant human ARF1 (rhARF1), rhARF5, and rhARF6, although the effect on rhARF6 was very small. These results are consistent with the conclusion that the yeast Sec7 domain itself contains the elements necessary for ARF GEP activity and its inhibition by BFA.
Evidence for an Important Interaction Between a Complement-Derived CD21 Ligand on Follicular Dendritic Cells and CD21 on B Cells in the Initiation of IgG Responses (1998)

The addition of Ags to mononuclear leukocyte cultures typically elicits modest Ab responses, implying that cosignals beyond those provided by T cells and macrophages may be needed. Recently, we reported that Ab responses could be dramatically enhanced (10-1000-fold) by the addition of follicular dendritic cells (FDC), suggesting that FDC may provide an important costimulatory signal. This result prompted a study of molecules involved in FDC-mediated enhancement of Ab responses stimulated by specific Ag with memory T and B cells or nonspecifically by the addition of LPS. In this study, we report evidence supporting the concept that FDC bear a ligand that engages complement receptor II (CR2 or CD21) on B cells and provides a critical cosignal for both Ag-specific and polyclonal responses. A blockade of the CR2 ligand on FDC by the use of soluble CR2 or a blockade of CR2 on B cells by use of CR2 knockout mice (or B cells with CR2 blocked) reduced Ab responses from the microg/ml to the ng/ml range (10-1000-fold reductions). FDC from C3 knockout mice, which cannot generate the CR2-binding fragments (iC3b, C3d, and C3dg), were unable to provide costimulatory activity, suggesting the CR2 ligand on FDC consists of C3 fragments. FDC trap complement-activating Ag-Ab complexes, and it appears that FDC present B cells with both specific Ag to engage B cell receptors and a CR2 ligand to engage B cell-CR2. In short, optimal induction of specific Ab responses appears to require the combination of specific Ag and costimulatory molecules from both T cells and FDC.
Cln3 Deltaex7/8 knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth (2002)

Juvenile-onset neuronal ceroid lipofuscinosis (JNCL; Batten disease) features hallmark membrane deposits and loss of central nervous system (CNS) neurons. Most cases of the disease are due to recessive inheritance of an approximately 1 kb deletion in the CLN3 gene, encoding battenin. To investigate the common JNCL mutation, we have introduced an identical genomic DNA deletion into the murine CLN3 homologue (Cln3) to create Cln3( Deltaex7/8) knock-in mice. The Cln3( Deltaex7/8) allele produced alternatively spliced mRNAs, including a variant predicting non-truncated protein, as well as mutant battenin that was detected in the cytoplasm of cells in the periphery and CNS. Moreover, Cln3( Deltaex7/8) homozygotes exhibited accrual of JNCL-like membrane deposits from before birth, in proportion to battenin levels, which were high in liver and select neuronal populations. However, liver enzymes and CNS development were normal. Instead, Cln3( Deltaex7/8) mice displayed recessively inherited degenerative changes in retina, cerebral cortex and cerebellum, as well as neurological deficits and premature death. Thus, the harmful impact of the common JNCL mutation on the CNS was not well correlated with membrane deposition per se, suggesting instead a specific battenin activity that is essential for the survival of CNS neurons.