gebhart/patrepeval huggingface dataset:
Signal Processing, Glycosylation, and Secretion of Mutant Hemagglutinins of a Human Influenza Virus by Saccharomyces cerevisiae (1987)

We investigated the nature of signal recognition, transport, and secretion of mutant hemagglutinins (HAs) of a human influenza virus by the yeast Saccharomyces cerevisiae. The cDNA sequences encoding variant forms of influenza HA were expressed in S. cerevisiae. The HA polypeptides (HA500 and HA325) that were synthesized with their N-terminal signal peptides were correctly targeted to the membrane compartment where they were glycosylated. In contrast, the HA polypeptides (HA484 and HA308) lacking the signal peptide were expressed in the cytoplasm and did not undergo any glycosidic modification, demonstrating the importance of the heterologous signal sequence in the early steps of translocation in S. cerevisiae. The analysis of the N-terminal amino acid sequence of HA500 and HA325 polypeptides demonstrated the correct cleavage of the signal peptide, indicating the structural compatibility of a heterologous signal peptide for efficient recognition and processing by the yeast translocation machinery. The membrane-sequestered and glycosylated HA polypeptides were relatively stable in S. cerevisiae compared with the signal-minus, nonglycosylated HA molecules. Although both the anchor-minus HA (HA500) and HA1 (HA325) polypeptides were targeted efficiently to the membrane, their glycosylation and transport patterns were shown to be different. During pulse-chase, the HA500 remained cell-associated with no detectable secretion into the extracellular medium, whereas the HA325 secreted into the medium. Furthermore, only the cell-associated and secreted forms of HA325 and not HA500 appeared to have undergone hyperglycosylation with the extensive addition of high-molecular-weight outer-chain mannans. Possible reasons for the observed phenotypic behavior of these two mutant HAs are discussed.
Role of apical and basolateral membranes in replication of human cytomegalovirus in polarized retinal pigment epithelial cells (1996)

Human retinal pigment epithelial (RPE) cells, which are permissive for human cytomegalovirus (HCMV) replication, were used to evaluate virus infection from apical and basolateral membranes of polarized cells. Tests of HCMV infectivity showed that the apical membrane was 20-30-fold more susceptible to infection than the basolateral membrane; in contrast, both membranes were equally susceptible to infection by herpes simplex virus type 1 (HSV-1). Neutralizing monoclonal antibodies (MAbs) to HCMV glycoprotein B (gB) blocked penetration of virions into polarized RPE cells. This indicated that gB has a function in fusion of the virion envelope with the apical membrane of these cells, as it has with the cell membrane of unpolarized human fibroblasts. In contrast to HSV-1-infected RPE cells, the paracellular permeability of polarized RPE cells changed slowly following infection with HCMV. Confocal microscopy examination of HCMV-infected RPE cells revealed that the pattern of ZO-1 staining was altered at late times. Addition of gB-specific neutralizing MAbs to the apical and basolateral membranes of HCMV-infected RPE cells failed to inhibit plaque development; this indicated that progeny virions infect adjacent cells before disassembly of tight junctions and are sequestered from neutralization during spread across lateral cell membranes. The finding that progeny HCMV virions cross lateral cell membranes, which differ substantially in protein composition from apical membranes, suggests that polarized RPE cells contain multiple receptors for HCMV.
The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer (2008)

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.
How protein thermodynamics and folding mechanisms are altered by the chaperonin cage: Molecular simulations (2003)

How the Escherichia coli GroEL/ES chaperonin assists folding of a substrate protein remains to be uncovered. Recently, it was suggested that confinement into the chaperonin cage itself can significantly accelerate folding of a substrate. Performing comprehensive molecular simulations of eight proteins confined into various sizes L of chaperonin-like cage, we explore how and to what extent protein thermodynamics and folding mechanisms are altered by the cage. We show that a substrate protein is remarkably stabilized by confinement; the estimated increase in denaturation temperature DeltaTf is as large as approximately 60 degrees C. For a protein of size R0, the stabilization DeltaTf scales as (R0/L)nu, where nu approximately 3, which is consistent with a mean field theory of polymer. We also found significant free energy cost of confining a protein, which increases with R0/L, indicating that the confinement requires external work provided by the chaperonin system. In kinetic study, we show the folding is accelerated in a modestly well confined case, which is consistent with a recent experimental result on ribulose-1,5-bisphosphate carboxylase-oxygenase folding and simulation results of a beta hairpin. Interestingly, the acceleration of folding is likely to be larger for a protein with more complex topology, as quantified by the contact order. We also show how ensemble of folding pathways are altered by the chaperonin-like cage calculating a variant of value used in the study of spontaneous folding.
CT guided interstitial high dose rate brachytherapy for recurrent malignant gliomas. (1999)

This paper describes the technique and preliminary results of high dose rate (HDR) interstitial brachytherapy for recurrent grade III and grade IV gliomas. Although in the initial treatment of malignant gliomas brachytherapy has been shown to give better results than external beam therapy, this has previously always been with low dose rate (LDR) brachytherapy. Stereotactic frames are used for interstitial LDR brachytherapy but a CT image-guided technique does not require such a frame. The survival rates for our initial 53 patients do not significantly differ from LDR results. However, using HDR there are several advantages, including a much shorter treatment time with HDR than LDR and better patient comfort. HDR also allows better individualized optimization of the treatment than LDR.
The iron–siderophore transporter FhuA is the receptor for the antimicrobial peptide microcin J25: role of the microcin Val11–Pro16 β-hairpin region in the recognition mechanism (2005)

The role of the outer-membrane iron transporter FhuA as a potential receptor for the antimicrobial peptide MccJ25 (microcin J25) was studied through a series of in vivo and in vitro experiments. The requirement for both FhuA and the inner-membrane TonB-ExbB-ExbD complex was demonstrated by antibacterial assays using complementation of an fhuA(-) strain and by using isogenic strains mutated in genes encoding the protein complex respectively. In addition, MccJ25 was shown to block phage T5 infection of Escherichia coli, in vivo, by inhibiting phage adhesion, which suggested that MccJ25 prevents the interaction between the phage and its receptor FhuA. This in vivo activity was confirmed in vitro, as MccJ25 inhibited phage T5 DNA ejection triggered by purified FhuA. Direct interaction of MccJ25 with FhuA was demonstrated for the first time by size-exclusion chromatography and isothermal titration calorimetry. MccJ25 bound to FhuA with a 2:1 stoichiometry and a K(d) of 1.2 microM. Taken together, our results demonstrate that FhuA is the receptor for MccJ25 and that the ligand-receptor interaction may occur in the absence of other components of the bacterial membrane. Finally, both differential scanning calorimetry and antimicrobial assays showed that MccJ25 binding involves external loops of FhuA. Unlike native MccJ25, a thermolysin-cleaved MccJ25 variant was unable to bind to FhuA and failed to prevent phage T5 infection of E. coli. Therefore the Val11-Pro16 beta-hairpin region of MccJ25, which is disrupted upon cleavage by thermolysin, is required for microcin recognition.
Prodigiosin1a (1963)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProdigiosin1aA. J. Castro, J. F. Deck, M. T. Hugo, E. J. Lowe, J. P. Marsh Jr., and R. J. PfeifferCite this: J. Org. Chem. 1963, 28, 3, 857–860Publication Date (Print):March 1, 1963Publication History Published online1 May 2002Published inissue 1 March 1963https://pubs.acs.org/doi/10.1021/jo01038a508https://doi.org/10.1021/jo01038a508research-articleACS PublicationsRequest reuse permissionsArticle Views179Altmetric-Citations19LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
The 3.8 Å resolution cryo-EM structure of Zika virus (2016)

The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune neurological syndrome have generated worldwide concern. Zika virus is a flavivirus like the dengue, yellow fever, and West Nile viruses. We present the 3.8 angstrom resolution structure of mature Zika virus, determined by cryo-electron microscopy (cryo-EM). The structure of Zika virus is similar to other known flavivirus structures, except for the ~10 amino acids that surround the Asn(154) glycosylation site in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, which is recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses, which suggests that differences in this region may influence virus transmission and disease.
Intraspinal extradural sensory rhizotomy in patients with failure of lumbar disc surgery (1981)

Questionnaires were sent to 60 patients who had undergone an intraspinal extradural sensory rhizotomy after failure of back surgery to assess the efficacy of the procedure. Questionnaires were returned from 47 patients. The operative results were uniformly poor in improving the level of activity of the patient. However, nearly 60% of the patients obtained relief of their pain. Section of only one root, either L-5 or S-1, relieved pain in 50% of the cases. Section of both roots, L-5 and S-1, appeared more effective, since 66% of these patients were relieved of their pain. The technique of performing an intraspinal extradural sensory rhizotomy is discussed in detail.
JCV-DNA and BKV-DNA in the CNS Tissue and CSF of AIDS Patients and Normal Subjects. Study of 41 Cases and Review of the Literature (1996)

We studied the distribution and localization of the human papova-viruses JCV and BKV in the central nervous system (CNS) and cerebrospinal fluid (CSF) of HIV-positive patients with and without progressive multifocal leukoencephalopathy (PML) as compared with HIV-seronegative patients. The presence of JCV-DNA and BKV-DNA was evaluated by nested polymerase chain reaction (PCR) and in situ hybridization (ISH) on CNS autopsy tissues of AIDS patients with (group A, n = 13) and without (group B, n = 16) PML and of HIV-negative patients (group C, n = 12). PCR for JCV-DNA and BKV-DNA was also performed on CSF samples collected 7-420 days before death in all the 29 AIDS patients. Tissue PCR for JCV-DNA was positive in all the cases in group A, in 44 percent of the patients in group B, and in 33 percent of the patients in group C. ISH was positive in all the cases with PML and in three AIDS cases without PML (12 percent), but negative in all the HIV-negative cases. BKV-DNA was detected in two cases from group A and in one case from group B. CSF was PCR-positive for JCV-DNA in 8 of 13 (62 percent) AIDS patients with PML, but in none of the HIV patients without PML, irrespective of the presence of JCV-DNA in CNS tissues. No CSF sample was positive for BKV-DNA. Our data demonstrates that JCV-DNA and, rarely, BKV-DNA can be detected in the CNS of immunocompromised patients with and without PML and also in the CNS of HIV-negative subjects. However, only HIV-positive patients with clinically evident PML and JCV-DNA in the brain have PCR-detectable JCV-DNA in their CSF.
Capsule Polysaccharide Conjugate Vaccine against Diarrheal Disease Caused by Campylobacter jejuni (2008)

The capsule polysaccharide (CPS) of Campylobacter jejuni is one of the few identified virulence determinants of this important human pathogen. Since CPS conjugate vaccines have been so effective against other mucosal pathogens, we evaluated this approach using CPSs from two strains of C. jejuni, 81-176 (HS23 and HS36 serotype complex) and CG8486 (HS4 serotype complex). The CPSs of 81-176 and CG8486 were independently linked to the carrier protein CRM(197) by reductive amination between an aldehyde(s), strategically created at the nonreducing end of each CPS, and accessible amines of CRM(197). In both cases, the CPS:CRM(197) ratio used was 2:1 by weight. Mass spectrometry and gel electrophoresis showed that on average, each glycoconjugate preparation contained, at least in part, two to five CPSs attached to one CRM(197). When administered subcutaneously to mice, these vaccines elicited robust immune responses and significantly reduced the disease following intranasal challenge with the homologous strains of C. jejuni. The CPS(81-176)-CRM(197) vaccine also provided 100% protection against diarrhea in the New World monkey Aotus nancymaae following orogastric challenge with C. jejuni 81-176.
Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer (2010)

This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations.
X-ray Crystal Structures of Monomeric and Dimeric Peptide Inhibitors in Complex with the Human Neonatal Fc Receptor, FcRn (2010)

The neonatal Fc receptor, FcRn, is responsible for the long half-life of IgG molecules in vivo and is a potential therapeutic target for the treatment of autoimmune diseases. A family of peptides comprising the consensus motif GHFGGXY, where X is preferably a hydrophobic amino acid, was shown previously to inhibit the human IgG:human FcRn protein-protein interaction (Mezo, A. R., McDonnell, K. A., Tan Hehir, C. A., Low, S. C., Palombella, V. J., Stattel, J. M., Kamphaus, G. D., Fraley, C., Zhang, Y., Dumont, J. A., and Bitonti, A. J. (2008) Proc. Natl. Acad. Sci. U.S.A., 105, 2337-2342). Herein, the x-ray crystal structure of a representative monomeric peptide in complex with human FcRn was solved to 2.6 A resolution. The structure shows that the peptide binds to human FcRn at the same general binding site as does the Fc domain of IgG. The data correlate well with structure-activity relationship data relating to how the peptide family binds to human FcRn. In addition, the x-ray crystal structure of a representative dimeric peptide in complex with human FcRn shows how the bivalent ligand can bridge two FcRn molecules, which may be relevant to the mechanism by which the dimeric peptides inhibit FcRn and increase IgG catabolism in vivo. Modeling of the peptide:FcRn structure as compared with available structural data on Fc and FcRn suggest that the His-6 and Phe-7 (peptide) partially mimic the interaction of His-310 and Ile-253 (Fc) in binding to FcRn, but using a different backbone topology.
Radiolabeled Humanized Anti-CD3 Monoclonal Antibody Visilizumab for Imaging Human T-Lymphocytes (2009)

Visilizumab can be efficiently labeled with (99m)Tc with high efficiency and SA and could be a valuable tool for the study of human T-lymphocyte trafficking and lymphocytic infiltration of tissues and organs.
Targeting of cholera toxin and Escherichia coli heat labile toxin in polarized epithelia: role of COOH-terminal KDEL. (1995)

Vibrio cholerae and Escherichia coli heat labile toxins (CT and LT) elicit a secretory response from intestinal epithelia by binding apical receptors (ganglioside GM1) and subsequently activating basolateral effectors (adenylate cyclase). We have recently proposed that signal transduction in polarized cells may require transcytosis of toxin-containing membranes (Lencer, W. I., G. Strohmeier, S. Moe, S. L. Carlson, C. T. Constable, and J. L. Madara. 1995. Proc. Natl. Acad. Sci. USA. 92:10094-10098). Targeting of CT into this pathway depends initially on binding of toxin B subunits to GM1 at the cell surface. The anatomical compartments in which subsequent steps of CT processing occur are less clearly defined. However, the enzymatically active A subunit of CT contains the ER retention signal KDEL (RDEL in LT). Thus if the KDEL motif were required for normal CT trafficking, movement of CT from the Golgi to ER would be implied. To test this idea, recombinant wild-type (wt) and mutant CT and LT were prepared. The COOH-terminal KDEL sequence in CT was replaced by seven unrelated amino acids: LEDERAS. In LT, a single point mutation replacing leucine with valine in RDEL was made. Wt and mutant toxins displayed similar enzymatic activities and binding affinities to GM1 immobilized on plastic. Biologic activity of recombinant toxins was assessed as a Cl- secretory response elicited from the polarized human epithelial cell line T84 using standard electrophysiologic techniques. Mutations in K(R)DEL of both CT and LT delayed the time course of toxin-induced Cl- secretion. At T1/2, dose dependencies for K(R)DEL-mutant toxins were increased > or = 10-fold. KDEL-mutants displayed differentially greater temperature sensitivity. In direct concordance with a slower rate of signal transduction. KDEL-mutants were trafficked to the basolateral membrane more slowly than wt CT (assessed by selective cell surface biotinylation as transcytosis of B subunit). Mutation in K(R)DEL had no effect on the rate of toxin endocytosis. These data provide evidence that CT and LT interact directly with endogenous KDEL-receptors and imply that both toxins may require retrograde movement through Golgi cisternae and ER for efficient and maximal biologic activity.
An immunodominant cytotoxic T cell epitope on the VP7 rotavirus protein overlaps the H2 signal peptide (1993)

C57BL/6 (H-2b) mice were primed with the bovine RF strain of rotavirus to study the induction of CD8+ cytotoxic T lymphocytes (CTLs). These rotavirus-specific CTLs were detected only after in vitro restimulation with the virus. Using a recombinant vaccinia virus we identified the RF VP7 protein as a major target of these CTLs. The response against this protein was obtained also after in vitro restimulation with simian SA11 and human WA strains of rotavirus. Using published Db and Kb allele-specific motifs to predict possible CTL epitopes in the RF VP7 protein, we synthesized and tested 18 predicted peptides of VP7. Only one peptide was able to sensitize target cells at a concentration below 5 x 10(-7) M. This CTL epitope was also induced by immunization with the RF VP7 expressed with a baculovirus vector, and was shown to be immunodominant by its capacity to inhibit, in an unlabelled target assay, the bulk response against cells infected with recombinant vaccinia virus expressing VP7. This CTL epitope overlaps the H2 signal peptide of the protein.
Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies (2006)

Increased fetal DNA levels in maternal plasma may be a sign of placental or fetal pathology even in the presence of normal uterine Doppler velocimetry, allowing a more precise diagnostic evaluation. The finding that elevated fetal DNA in IUGR pregnancies correlates with abnormal umbilical Doppler velocimetry suggests that fetal DNA release is associated more with fetal chronic hypoxia than with fetal size.
Androgen‐supported estrogen‐enhanced epithelial proliferation in the prostates of intact noble rats (1989)

Using a stathmokinetic in vivo metaphase-arrest technique, we studied cell proliferation and histological changes in the ventral (VP) and dorsolateral (DLP) prostate lobes of intact Noble (Nb) rats following a 16 week treatment with testosterone (T) or 5 alpha-dihydrotestosterone (DHT) administered separately or in combination with various estrogens. The combined treatment of rats with T and either estradiol-17 beta, estradiol-17 alpha, or moxestrol induced florid dysplasia and markedly elevated the mitotic index (MI) in affected regions of the DLP. In contrast, joint DHT and estrogen treatment caused only mild proliferative lesions in this lobe. The separate administration of either androgens or estrogens suppressed epithelial proliferation in both the VP and DLP, but they differed in their histological effects on these tissues. Thus DHT or T alone maintained the morphological integrity of VP and DLP, whereas E2-17 beta or moxestrol caused massive atrophy of both lobes. Although dysplastic foci were randomly scattered throughout the DLP, the most dramatic lesions occurred in periurethral ducts. With the exception of joint T and E2-17 alpha treatment, which induced proliferative alterations in the VP, dysplasia was always restricted to the DLP of all animals receiving both androgens and estrogens. Concomitant comparative stathmokinetic studies of the prostates of T-treated castrates suggest that protracted androgen-supported estrogen stimulation of the DLP is necessary to overcome factors that normally limit cell proliferation.
Negative effects of melatonin on depression (1976)

In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in these patients, as well as causing a loss of sleep and weight and a drop in oral temperature. Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and calcium in three of four patients studied. The authors discuss the implications of this finding.