gebhart/patrepeval huggingface dataset:
Selection of a single amino acid substitution in the hemagglutinin molecule by chicken eggs can render influenza A virus (H3) candidate vaccine ineffective (1995)

This study investigated whether a single amino acid change in the hemagglutinin (HA) molecule influenced the efficacy of formalin-inactivated influenza A (H3N1) vaccine candidates derived from high-growth reassortants between the standard donor of high-yield genes (A/PR/8/34 [H1N1]) and host cell variants generated from the same clinical isolate (A/Memphis/7/90 [H3N2]) by passage in embryonated chicken eggs. Two clones of the isolate generated by growth in eggs differed from the parent virus (represented by an MDCK cell-grown counterpart) solely by the presence of Lys (instead of Glu) at position 156 or Ile (instead of Ser) at position 186 in the HA1 subunit. The protective efficacy of egg-grown HA Lys-156 and HA Ile-186 reassortant variants was compared with that of the MDCK cell-grown reassortant vaccine. Classically, antibody titers in serum have been used to demonstrate vaccine efficacy. Here, parameters of B-cell responsiveness were monitored, including the kinetics, character, and localization of the primary antibody-forming cell (AFC) response and the development of B-cell memory in lymphoid tissues associated with the priming site (spleen) and responsive to pulmonary challenge with infectious virus (upper and lower respiratory tract lymph nodes). We show that the egg-grown HA Lys-156 variant induced an AFC profile vastly different from that elicited by the other two reassortant vaccines. The vaccine was poorly immunogenic; it induced antibodies that were cross-reactive prior to challenge but which, postchallenge with a lethal dose of the MDCK cell-grown reassortant virus, were targeted primarily to the HA Lys-156 variant, were of the immunoglobulin M isotype, were nonprotective, and were derived from the spleen. In contrast, the egg-grown HA Ile-186 variant was remarkably like the MDCK cell-grown virus in that protective immunoglobulin G antibodies were unaffected by the Ile-186 substitution but poorly recognized HA with Lys-156. Furthermore, memory AFC responsiveness was localized to regional lymphoid tissue in the upper respiratory tract, where challenge HA was found. Thus, it is recommended that in the selection of vaccine candidates, virus populations with the egg-adapted HA Lys-156 substitution be eliminated and that, instead, egg-grown isolates which minimally contain Ile-186 be used as logical alternatives to MDCK cell-grown viruses.
mRNA for surface immunoglobulin gamma chains encodes a highly conserved transmembrane sequence and a 28-residue intracellular domain. (1982)

To probe the structure of the gamma heavy chain of membrane IgG and the mRNA and gene segments that encode it, we have analyzed cDNA clones derived from a gamma 1 membrane RNA of B lymphoma 2PK-3. The nucleotide sequence of the clones indicated that membrane gamma 1 chains bear a COOH-terminal 71-residue segment that is absent from secretory gamma 1 chains. This terminus includes a 26-residue hydrophobic transmembrane region homologous to that of membrane mu chains and, significantly, a 28-residue intracellular domain found only on gamma chains. The extra domain suggests that receptor IgG, on memory B cells, may generate a different signal on binding antigen than does receptor IgM, on virgin B cells. The gamma 1 membrane terminus is encoded by two gene segments 1.5 and 2.4 kilobase pairs downstream from the C gamma 1 gene, and homologous segments occur 3' to the C gamma 2a and C gamma 3 genes. Small amounts of membrane gamma mRNAs persist in plasmacytomas secreting IgG1, IgG2a, or IgG2b, suggesting that competition between alternative RNA processing pathways governs the synthesis of membrane and secretory gamma chain mRNAs.
High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level (2016)

The precise annotation and accurate identification of neural structures are prerequisites for studying mammalian brain function. The orientation of neurons and neural circuits is usually determined by mapping brain images to coarse axial-sampling planar reference atlases. However, individual differences at the cellular level likely lead to position errors and an inability to orient neural projections at single-cell resolution. Here, we present a high-throughput precision imaging method that can acquire a co-localized brain-wide data set of both fluorescent-labelled neurons and counterstained cell bodies at a voxel size of 0.32 × 0.32 × 2.0 μm in 3 days for a single mouse brain. We acquire mouse whole-brain imaging data sets of multiple types of neurons and projections with anatomical annotation at single-neuron resolution. The results show that the simultaneous acquisition of labelled neural structures and cytoarchitecture reference in the same brain greatly facilitates precise tracing of long-range projections and accurate locating of nuclei.
Simultaneous induction of apoptosis, collagen type I expression and mineralization in the developing coronal suture following FGF4 and FGF2 application. (2001)

This study aimed to evaluate the disturbances in normal coronal suture development resulting in craniosynostosis, a congenital disorder in which the calvarial sutures close prematurely. Craniosynostosis syndromes can be caused by mutations in the genes encoding for the fibroblast growth factor receptors (FGFRs) 1, 2, and 3. These gain-of-function mutations cause the transcribed receptor to be constitutively activated. To mimic this genetic defect, fibroblast growth factor (FGF) 2 or 4 was administered near the developing coronal suture in normal mouse embryos through ex utero surgery. The effect on apoptosis and bone differentiation, as collagen type I expression and mineralization, within the FGF-exposed coronal suture was investigated through (immuno)histochemical staining. An increase in the number of apoptotic cells together with ectopic collagen type I expression within the suture and accelerated mineralization followed FGF application. Macroscopically, this presented as a synostotic coronal suture. These results suggest that both apoptosis and differentiation are two processes that are simultaneously implicated in synostosis of the coronal suture in case of a FGFR-related craniosynostosis.
Estrogenic Regulation of Growth and Polypeptide Growth Factor Secretion in Human Breast Carcinoma (1987)

HORMONAL influences on cancer cell proliferation have recently received much attention with the proposal of autocrine or self-stimulating polypeptide growth factors (1). The growth of several types of cancer has long been known to be under endocrine control by steroid hormones: leukemia, prostate carcinoma, endometrial carcinoma, and breast carcinoma. The present article will summarize what is known at present concerning the possible interaction of steroidal endocrine and polypeptide autocrine and paracrine regulators in control of human breast cancer growth. Breast cancer is notable among the above mentioned cancers in that its growth is dependent upon estrogenic hormones in about one-third of clinical cases and can be inhibited by antiestrogenic antagonists (2). The frequency of breast cancer in women who never had functional ovaries is only 1% that in women with intact ovaries. Thus estrogens are involved, at least initially, in nearly all breast cancers.
Discovery of the First Highly M5-Preferring Muscarinic Acetylcholine Receptor Ligand, an M5 Positive Allosteric Modulator Derived from a Series of 5-Trifluoromethoxy N -Benzyl Isatins (2009)

This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca(2+) mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
The role of androgen in the maintenance of sexual functioning in oophorectomized women. (1987)

Five aspects of sexual behavior were monitored daily in three groups of women who had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy approximately 4 years ago for benign disease. One group had been receiving an estrogen-androgen preparation intramuscularly once a month since their surgery (E-A). The second group had been receiving estrogen alone (E) and the third group of women had remained untreated. Plasma estradiol and testosterone were measured at an established baseline and again on days 2, 4, 8, 15, 21, and 28 postinjection. Women who received both sex steroids reported higher rates of sexual desire (p less than 0.01), sexual arousal (p less than 0.01), and numbers of fantasies (p less than 0.01) than those who were either given E or who were untreated. Moreover, changes in these behaviors covaried with plasma testosterone but not with plasma estradiol levels during the treatment month as the drug was being metabolized. Rates of coitus and orgasm were also higher in the E-A group during the first two postinjection weeks (p less than 0.01) coincident with their higher testosterone levels. These findings imply that androgen may be critical for the maintenance of optimal levels of sexual functioning in postmenopausal women.
Novel Cambinol Analogs as Sirtuin Inhibitors: Synthesis, Biological Evaluation, and Rationalization of Activity (2009)

The tenovins and cambinol are two classes of sirtuin inhibitor that exhibit antitumor activity in preclinical models. This report describes modifications to the core structure of cambinol, in particular by incorporation of substituents at the N1-position, which lead to increased potency and modified selectivity. These improvements have been rationalized using molecular modeling techniques. The expected functional selectivity in cells was also observed for both a SIRT1 and a SIRT2 selective analog.
Establishment of an interleukin 6 (IL 6)/B cell stimulatory factor 2‐dependent cell line and preparation of anti‐IL 6 monoclonal antibodies (1988)

Abstract Murine hybridomas producing monoclonal antibodies (mAb) specific to human interleukin 6 (IL6/BSF‐2) were established. One of these hybridomas (MH60.BSF2) was found to be dependent on IL6 for its in vitro growth. None of the known biological factors tested, such as recombinant (r) human (Hu) Illα, rHuILlα, rHuIL2, rHuIL3, rHuIL4, rHu interferon (1FN)‐γ, HuIFN‐β, rHuG‐CSF, or recombinant murine (Mu) IL3, MuIL4, rMuIL5, could induce the in vitro growth of MH60.BSF2 cells. The half‐maximum tritiated thymidine uptake by MH60.BSF2 cells could be achieved by picogram amounts of rIL 6, making this hybridoma clone an indicator cell for specific and sensitive detection of the IL6 activity in test samples. The MH166.BSF2 clone was found to produce IgG l ,χ type mAb (αBSF2‐166) capable of neutralizing IL6 activity. The other clone, MH60.BSF2, produced IgM,x type mAb (aBSF2‐60) unable to neutralize IL6 activity. Both mAb specifically reacted with IL6 as demonstrated by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and Western blotting analysis. An enzyme‐linked immunosorbent assay (ELISA) utilizing αBSF2‐166 and rabbit anti‐IL 6 antibodies was established which could detect as low as 50 pg/ml of IL6. Since both the ELISA and MH60.BSF2 hybridoma could detect small amounts of IL6 in biological fluids, they constitute powerful tools in exploring the presence or the role of IL6 in various immunological disorders.
Olefin inversion. Protection of the sulfide function in the stereospecific synthesis of trans-thiacyclooct-4-ene (1980)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOlefin inversion. Protection of the sulfide function in the stereospecific synthesis of trans-thiacyclooct-4-eneVanda Cere, Alberto Guenzi, Salvatore Pollicino, Edda Sandri, and Antonino FavaCite this: J. Org. Chem. 1980, 45, 2, 261–264Publication Date (Print):January 1, 1980Publication History Published online1 May 2002Published inissue 1 January 1980https://pubs.acs.org/doi/10.1021/jo01290a011https://doi.org/10.1021/jo01290a011research-articleACS PublicationsRequest reuse permissionsArticle Views271Altmetric-Citations14LEARN 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
Exocyclic Amine of the Conserved G·U Pair at the Cleavage Site of the Tetrahymena Ribozyme Contributes to 5‘-Splice Site Selection and Transition State Stabilization (1996)

A phylogenetically conserved guanine.uracil (G.U) pair defines the 5'-exon/intron boundary of precursor RNAs containing group I introns. In this wobble base pair, the G forms two hydrogen bonds with U in a base pairing geometry shifted from that of a canonical Watson-Crick pair. On the basis of thermodynamic measurements of synthetic base pair analogs (inosine, diaminopurine riboside, guanosine, or adenosine paired with U, C, or isocytidine) in place of the G.U pair, we have previously reported that the N2 exocyclic amine of the G is important for docking the 5'-exon into the active site of the Tetrahymena ribozyme [Strobel, S. A., & Cech, T. R. (1995) Science 267, 675-679]. Here we describe kinetic characterization of ribozyme-substrate combinations containing the same series of analogs. By measuring the rate constants of 5'-exon miscleavage (cleavage at incorrect phosphates), we demonstrate that the 5'-exon/intron boundary is primarily defined by the exocyclic amine of the G. The amine makes its contribution (2.5 kcal.mol-1) in the context of all three wobble pairs tested but fails to make a significant contribution (< 0.8 kcal.mol-1) when presented in a Watson-Crick base pairing geometry. We also demonstrate that the exocyclic amine makes a modest contribution to chemical transition state stabilization (1.0 kcal.mol-1 relative to an inosine-U pair). The majority of this transition state contribution (0.7 kcal.mol-1) is independent of that contributed by the 2'-hydroxyl of the neighboring U. This argues against the model in which substantial transition state stabilization is derived from a water molecule bridging between the exocyclic amine of G and the 2'-hydroxyl of U. Instead it suggests that the tertiary interaction between the exocyclic amine and its hydrogen bonding partner in the active site is slightly improved during the chemical transition. We conclude that the exocyclic amine of G is the primary contributor to many characteristics of reactivity that have been ascribed to the conserved G.U pair, including stabilization of the chemical transition state and definition of the 5'-exon/intron boundary.
Increase in Activated T Cells and Reduction in Suppressor/Cytotoxic T Cells in Acute Rheumatic Fever and Active Rheumatic Heart Disease: A Longitudinal Study (1993)

In a prospective study, patients with acute rheumatic fever (ARF) and active rheumatic heart disease (ARHD) showed a significant increase in CD4+ T cells, CD22+ B cells, and CD4:CD8 cell ratio but a significant decrease in the percentages of CD8+ and CD3+ T lymphocytes compared with patients with quiescent RHD (CRHD) or streptococcal pharyngitis (SP) and normal controls. The proportion of interleukin-2 receptor (IL-2R)+ (CD25+) cells was higher in peripheral blood mononuclear cell cultures (both before and after phytohemagglutinin stimulation) of ARF and ARHD patients than in those of CRHD or SP patients or controls; this finding persisted up to 48 weeks. In ARF patients, the percentage of CD8+ cells returned to within normal range at 48 weeks. Furthermore, the percentage of IL-2R+ cells correlated positively with the percentage of CD4+ but not of CD8+ lymphocytes, suggesting that helper/inducer T cells are in an immunologically activated state and may account for aberrations in the distribution of lymphocyte populations in peripheral blood of ARF and ARHD patients.
Integrin α9β1 is a receptor for nerve growth factor and other neurotrophins (2008)

The integrin alpha9beta1 is a multifunctional receptor that interacts with a variety of ligands including vascular cell adhesion molecule 1, tenascin C and osteopontin. We found that this integrin is a receptor for nerve growth factor (NGF) and two other neurotrophins, brain-derived neurotrophic factor and NT3, using a cell adhesion assay with the alpha9SW480 cell line. Interaction of alpha9beta1 with NGF was confirmed in an ELISA assay by direct binding to purified integrin. alpha9beta1 integrin binds to neurotrophins in a manner similar to another common neurotrophin receptor, p75(NTR) (NGFR), although alpha9beta1 activity is correlated with induction of pro-survival and pro-proliferative signaling cascades. This property of alpha9beta1 resembles the interaction of NGF with a high affinity receptor, TrkA, however, this integrin shows a low affinity for NGF. NGF induces chemotaxis of cells expressing alpha9beta1 and their proliferation. Moreover, alpha9beta1 integrin is a signaling receptor for NGF, which activates the MAPK (Erk1/2) pathway. The alpha9beta1-dependent chemotactic ability of NGF appears to result from the activation of paxillin.
Clinical application of fuzzy‐controlled blood pressure stabilization in patients prone to hypotension during hemodialysis (2009)

Abstract BACKGROUND The prevalence of intradialytic hypotensive events is still high in patients undergoing hemodialysis (HD). A biofeedback control system to prevent hypotensive destabilization of the patient during hemodialysis was developed. METHODS A blood pressure (BP)–guided closed‐loop system consists of a non‐invasive blood pressure measurement device connected to a fuzzy controller (FC). It regulates ultrafiltration rate (UFR) and dialysate conductivity (DC) depending on the actual BP and its short‐ and long‐term trends as well. Twenty‐eight HD patients prone to hypotension were selected for the study. In 102 HD sessions it was proven whether an increase in DC from 14.3 mS/cm to a maximum of 17.0 mS/cm infl uenced the serum sodium concentration of the patients and interdialytic weight gain (IDGW), when DC was reset to 14.3 mS/cm for the remaining 60 minutes of treatment. In the next step, 69 conventional HD sessions without the fuzzy controller and 144 sessions with fuzzy‐controlled ultrafiltration were compared with 32 sessions with simultaneous fuzzy‐controlled ultrafiltration and modification of dialysate conductivity. RESULTS No significant differences in serum sodium concentration and weight gain were observed when DC was reset for the remaining 60 minutes of treatment. In conventional HD the frequency of low blood pressure situations, &lt;90 mmHg, increased progressively toward the end of the treatment. The HD treatments with fuzzy‐controlled UFR resulted in no increases in the number of hypotensive episodes. Moreover, there was a significant decrease in the third and fourth treatment hours. The simultaneous fuzzy control of UFR + DC resulted in the lowest occurrence of BP drops. CONCLUSIONS Fuzzy control of HD treatments provides reliable blood pressure stabilization in patients prone to hypotension. This kind of treatment is safe because significant changes in body weight and serum sodium concentration do not occur. The cost of this treatment is limited because no special disposables are necessary.
Human Apolipoprotein C-I Accounts for the Ability of Plasma High Density Lipoproteins to Inhibit the Cholesteryl Ester Transfer Protein Activity (2000)

The aim of the present study was to identify the protein that accounts for the cholesteryl ester transfer protein (CETP)-inhibitory activity that is specifically associated with human plasma high density lipoproteins (HDL). To this end, human HDL apolipoproteins were fractionated by preparative polyacrylamide gradient gel electrophoresis, and 30 distinct protein fractions with molecular masses ranging from 80 down to 2 kDa were tested for their ability to inhibit CETP activity. One single apolipoprotein fraction was able to completely inhibit CETP activity. The N-terminal sequence of the 6-kDa protein inhibitor matched the N-terminal sequence of human apoC-I, the inhibition was completely blocked by specific anti-apolipoprotein C-I antibodies, and mass spectrometry analysis confirmed the identity of the isolated inhibitor with full-length human apoC-I. Pure apoC-I was able to abolish CETP activity in a concentration-dependent manner and with a high efficiency (IC(50) = 100 nmol/liter). The inhibitory potency of total delipidated HDL apolipoproteins completely disappeared after a treatment with anti-apolipoprotein C-I antibodies, and the apoC-I deprivation of native plasma HDL by immunoaffinity chromatography produced a mean 43% rise in cholesteryl ester transfer rates. The main localization of apoC-I in HDL and not in low density lipoprotein in normolipidemic plasma provides further support for the specific property of HDL in inhibiting CETP activity.
Nifedipine‐ and omega‐conotoxin‐sensitive Ca2+ conductances in guinea‐pig substantia nigra pars compacta neurones. (1993)

1. The membrane properties of substantia nigra pars compacta (SNc) neurones were recorded in guinea-pig in vitro brain slices. 2. In the presence of tetrodotoxin (TTX) a Ca(2+)-dependent slow oscillatory potential (SOP) was generated. Application of 0.5-20 microM nifedipine abolished both spontaneous and evoked SOPs. A tetraethylammonium chloride (TEA)-promoted high-threshold Ca2+ spike (HTS) was little affected by nifedipine. On the other hand, omega-conotoxin applied either locally or via the perfusion medium (1-10 microM) blocked a part of the HTS, but it did not alter the SOP. 3. In normal medium nifedipine blocked the spontaneous discharge, decreased the interspike interval (ISI) recorded during depolarizing current injections and selectively reduced the slow component of the spike after-hyperpolarization (AHP). omega-Conotoxin decreased both the rising and falling slopes of the normal action potential, reduced the peak amplitude of the spike AHP, and, in some of the neurones, reduced the ISI during depolarization. The Na+ spikes recorded in Ca(2+)-free medium were not altered by omega-conotoxin. 4. The SOP was not blocked by octanol (100-200 microM), amiloride (100-250 microM), or Ni2+ (100-300 microM). However, at 500 microM Ni2+ attenuated the SOP. 5. Application of apamin (0.5-2.0 microM) induced irregular firing or bursting, abolished the slow component of the spike AHP and reduced its peak amplitude. In the presence of TTX and apamin long-duration plateau potentials occurred, which were subsequently blocked by nifedipine. 6. In Ca(2+)-free, Co(2+)-containing medium TTX-sensitive spikes and voltage plateaux were generated by depolarizing current pulses. It is suggested that a persistent Na+ conductance underlies the plateaux, which may be co-activated during the SOP. 7. The results suggest that the Ca2+ currents underlying the SOP and the HTS are different and that they activate at least two Ca(2+)-dependent K+ conductances. These conductances play major roles in the maintenance of spontaneous discharge and in control of membrane excitability.