gebhart/patrepeval huggingface dataset:
Single-channel SCAM Identifies Pore-lining Residues in the First Extracellular Loop and First Transmembrane Domains of Cx46 Hemichannels (2003)

Gap junction (GJ) channels provide an important pathway for direct intercellular transmission of signaling molecules. Previously we showed that fixed negative charges in the first extracellular loop domain (E1) strongly influence charge selectivity, conductance, and rectification of channels and hemichannels formed of Cx46. Here, using excised patches containing Cx46 hemichannels, we applied the substituted cysteine accessibility method (SCAM) at the single channel level to residues in E1 to determine if they are pore-lining. We demonstrate residues D51, G46, and E43 at the amino end of E1 are accessible to modification in open hemichannels to positively and negatively charged methanethiosulfonate (MTS) reagents added to cytoplasmic or extracellular sides. Positional effects of modification along the length of the pore and opposing effects of oppositely charged modifying reagents on hemichannel conductance and rectification are consistent with placement in the channel pore and indicate a dominant electrostatic influence of the side chains of accessible residues on ion fluxes. Hemichannels modified by MTS-EA+, MTS-ET+, or MTS-ES- were refractory to further modification and effects of substitutions with positively charged residues that electrostatically mimicked those caused by modification with the positively charged MTS reagents were similar, indicating all six subunits were likely modified. The large reductions in conductance caused by MTS-ET+ were visible as stepwise reductions in single-channel current, indicative of reactions occurring at individual subunits. Extension of single-channel SCAM using MTS-ET+ into the first transmembrane domain, TM1, revealed continued accessibility at the extracellular end at A39 and L35. The topologically complementary region in TM3 showed no evidence of reactivity. Structural models show GJ channels in the extracellular gap to have continuous inner and outer walls of protein. If representative of open channels and hemichannels, these data indicate E1 as constituting a significant portion of this inner, pore-forming wall, and TM1 contributing as pore-lining in the extracellular portion of transmembrane span.
Are you my mother? Bayesian phylogenetic inference of recombination among putative parental strains. (2003)

Reconstructing evolutionary relationships using Bayesian inference has become increasingly popular due to the ability of Bayesian inference to handle complex models of evolution. In this review we concentrate on inference of recombination events between strains of viruses when these events are sporadic, ie rare relative to point mutations. Bayesian inference is especially attractive in the detection of recombination events because it allows for simultaneous inferences about the presence, number and location of crossover points and the identification of parental sequences. Current frequentist recombination identification falls into a sequential testing trap. The most likely parental sequences and crossover points are identified using the data and then the certainty of recombination is assessed conditional on this identification. After briefly outlining basic phylogenetic models, Bayesian inference and Markov chain Monte Carlo (MCMC) computation, we summarise three different approaches to recombination detection and discuss current challenges in applying Bayesian phylogenetic inference of recombination.
Changes in myocardial iron content following administration of intravenous iron (Myocardial‐IRON): Study design (2018)

Treatment with intravenous ferric carboxymaltose (FCM) has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency. However, the underlying mechanisms for these beneficial effects remain undetermined. The aim of this study is to quantify cardiac magnetic resonance changes in myocardial iron content after administration of intravenous FCM in patients with heart failure and iron deficiency and contrast them with parameters of heart failure severity. This is a multicenter, double-blind, randomized study. Fifty patients with stable symptomatic heart failure, left ventricular ejection fraction <50%, and iron deficiency will be randomly assigned 1:1 to receive intravenous FCM or placebo. Intramyocardial iron will be evaluated by T2* and T1 mapping cardiac magnetic resonance sequences before and at 7 and 30 days after FCM. After 30 days, patients assigned to placebo will receive intravenous FCM in case of persistent iron deficiency. The main endpoint will be changes from baseline in myocardial iron content at 7 and 30 days. Secondary endpoints will include the correlation of these changes with left ventricular ejection fraction, functional capacity, quality of life, and cardiac biomarkers. The results of this study will add important knowledge about the effects of intravenous FCM on myocardial tissue and cardiac function. We hypothesize that short-term (7 and 30 days) myocardial iron content changes after intravenous FCM, evaluated by cardiac magnetic resonance, will correlate with simultaneous changes in parameters of heart failure severity. The study is registered at http://www.clinicaltrials.gov (NCT03398681).
Keyword spotting for video soundtrack indexing (2002)

The amount of available video information is dramatically increasing due to the development of multimedia applications. As a consequence, content based retrieval tools are urgently needed for fast and easy access to multimedia database but also to movies and recorded video news. In particular, queries may rely on off-line indexing. Keyword spotting on video soundtracks could be of great help in this indexation process and in the future associated with pattern or event recognition out of the strictly visual information. Specific constraints for this application are identified and a solution based on phonemic lattices is proposed. The word spotter achieves indexing on open vocabularies uttered by any speaker. It is fast enough for practical applications and does not require much additional stored information.
Modification of Peanut Allergen Ara h 3: Effects on IgE Binding and T Cell Stimulation (2002)

The engineered hypoallergenic Ara h 3 variant displays two characteristics essential for recombinant allergen immunotherapy; it has a reduced binding capacity for serum IgE from peanut-hypersensitive patients and it can stimulate T-cell proliferation and activation.
Transient acoustic holography for reconstructing the particle velocity of the surface of an acoustic transducer (2006)

A transient acoustic holography method based on the Rayleigh integral and the time-reversal mirror principle is described. The method reconstructs the particle velocity of the surface of an acoustic source from the waveform of the signal measured over a surface lying in front of the source. The possibility of applying the transient holography to studying pulsed sources used in ultrasonic diagnostics is investigated. A rectangular source that produces a short acoustic pulse and has a nonradiating defect on its surface is considered. A numerical simulation is used to demonstrate the possibility of a holographic reconstruction of the source vibrations. The effects of the spatial sampling step and the size of the measurement region on the reconstruction quality are demonstrated.
Strategies for Preparation of Oriented Cellulose Nanowhiskers Composites (2012)

Due to hierarchical structure of cellulose, its building blocks known as “cellulose nanowhiskers” (CNW) have raised a great deal of research interest over the last decades. Natural affinity of CNW for self-assembly and structural anisotropy allow them to orient under external forces. This book chapter provides a review on the major developments in fabrication techniques of CNW alignment in polymers. First, we will present self-assembly phenomenon of CNW in aqueous medium. Following this, the book chapter will focus on discussion of major strategies reported in the literature on aligning CNW in polymer by external forces: mechanical and by applying electric and magnetic fields. Further, the chapter highlights recent developments in cellulose composite fibers and aligning CNWs by electrospinning and wet-spinning techniques. As insights are gained into CNW reinforcement mechanisms and processing options, future research directions and potential applications are anticipated. These potential application areas will be briefly introduced as well.
Tetrahydrouridine: Physiologic disposition and effect upon deamination of cytosine arabinoside in man. (1977)

[14C]-tetrahydrouridine (THU), a strong inhibitor of cytidine (CR) deaminase, was, after iv administration, rapidly and quantitatively cleared from the blood with a plasma half-life of about 1 hour. The main pathway of excretion was through the kidneys: most of a dose of 50 mg/kg was excreted within 12 hours and excretion was essentially complete within 48 hours. Oral administration of the same dose revealed absorption of about 10% from the gastrointestinal tract. THU at 10, 25, and 50 mg/kg given 15 minutes before [3H]-cytosine arabinoside (ara-C) at a dose of 0.003 mg/kg produced about a two fold increase in ara-C blood levels at all times measured from 5 minutes to 4 hours, with only slight increases in the half-life of ara-C. A dose-related effect of THU upon the deamination of ara-C was obvious only during the time from 15 minutes to 1 hour after the injection of 3H-ara-C. The inhibitory effect of THU upon CR deaminase was also reflected in a considerably increased ratio of ara-C/uracil arabinoside in the urine.
Activating anti-idiotypic human anti-mouse antibodies for immunotherapy of ovarian carcinoma (1994)

Human anti-mouse antibodies (HAMA) are observed frequently after immunoscintigraphy with monoclonal antibodies (MoAb) directed against CA-125. As the authors have shown previously, HAMA can cause false-positive CA-125 values in routine CA-125 immunoradiometric assay (IRMA) tumor-marker assays (in one case, up to 900 days after immunoscintigraphy). In 32 patients, the authors found a HAMA frequency of 34% (11/32: 3/7 after the first administration, 6/13 after the second, and 2/2 after the third). Ten patients developed extremely high CA-125 levels after undergoing the CIS IRMA assay (up to 80,000 U/ml) in parallel to a significant HAMA increase. The use of different assays, or HAMA removal before in vitro testing, can solve this problem. After a new CA-125 assay containing antibodies that recognize different epitopes on the CA-125 antigen (Biomira Tru-Quant OV) was applied, only mildly increased assay results or normal levels were measured. Most of HAMA-positive patients demonstrated a predominantly anti-idiotypic response, determined with two different HAMA assays. Seven patients with anti-idiotypic HAMA responses after OC-125 immunoscintigraphy remained free of tumor or had stable disease (2-42 or more months), contrary to their poor prognoses that had been made based on the underlying stages of their tumors. All of these patients are currently doing well (Karnofsky Index > 70%) and show no significant tumor progression. In light of their extremely poor prognoses (5-year survival rates of 3-5% in recurrent International Federation of Gynecology and Obstetrics III/IV stages), without further chemotherapy, these courses are extremely unusual. Preliminary in vitro experiments lead to the postulation that anti-idiotypic HAMA may trigger an antitumor effect either by suppressing the growth of CA-125-expressing cancer cells directly, or by activating the patient's immune response via induction of Ab3. Similar results are observed after immunoscintigraphy with a technetium-99m-labeled anti-CA-125 monoclonal antibody (B43.13), which the authors now also use for immunotherapy of ovarian cancer patients by repeated injections, hoping that induction of anti-idiotypic HAMA will be beneficial for prolonged survival of patients with ovarian carcinoma.
Interferon-gamma enhances induction of lymphotoxin in recombinant interleukin 2-stimulated peripheral blood mononuclear cells. (1985)

Human peripheral blood mononuclear cells (PBMC) were induced by recombinant human interleukin 2 (rIL 2) to secrete lymphotoxin (LT) and interferon-gamma (IFN-gamma). Induction of both LT and IFN-gamma by rIL 2 is regulated at the transcriptional level. Treatment of PBMC with rIL 2 in combination with recombinant human IFN-gamma (rIFN-gamma) resulted in an earlier appearance of LT mRNA and an augmented production of LT than did rIL 2 treatment alone. IFN-gamma alone had no effect on production of either LT or its mRNA. PBMC cultured in the presence of rIL 2 plus anti-rIFN-gamma resulted in decreased LT production. Only a 15-min incubation of PBMC with rIL 2 is needed to stimulate LT production, whereas 3 hr is necessary for IFN-gamma production. These results suggest that rIL 2, in addition to being a T cell growth factor, may exhibit other activities through induction of LT and IFN-gamma.
Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma (2011)

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.
Toward a Science of Metabolic Engineering (1991)

Application of recombinant DNA methods to restructure metabolic networks can improve production of metabolite and protein products by altering pathway distributions and rates. Recruitment of heterologous proteins enables extension of existing pathways to obtain new chemical products, alter posttranslational protein processing, and degrade recalcitrant wastes. Although some of the experimental and mathematical tools required for rational metabolic engineering are available, complex cellular responses to genetic perturbations can complicate predictive design.
Deep transient electromagnetic soundings with a grounded source over near-surface conductors (1989)

Three-dimensional (3-D) transient electromagnetic (TEM) responses are assessed for near-surface conductors beneath and remote from a grounded-wire transmitter. When a conductor is located close to the transmitter the time derivative of the magnetic field (vertical component), after early times, is shifted in amplitude from that of the layered host. Depending on the location of the transmitter, the response that is observed can be shifted above or shifted below the layered-host response. The conductor's response does not vanish at late times and is important for large transmitter-receiver separations. When the conductor is near to a receiver that is remote from the transmitter, the conductor is detectable only at early times. During these times the conductor can produce responses with sign reversals and other behaviour not characteristic of a layered earth. At later times the responses are more or less that of the layered half-space. An exception to this is when the receiver is located over the edge or close to the edge of the conductor. In this case the conductor produces a response at later time which is like that of the transmitter close to the conductor. The response is shifted in amplitude compared to the layered-earth response. If the transmitter is located close to a near-surface conductor it distorts layered-earth interpretations of the deeper geoelectric section. However, the effect of the conductor can be removed to a large degree by scaling the amplitude of the layered-earth curves that are used to fit the data by an arbitrary constant. This scaling can be determined in the inversion process and allows for acceptable data fits. Alternatively, prior to inversion, the data can be rescaled so that the area beneath the decay curve equals the DC magnetic field of the transmitter. This type of scaling also allows for acceptable data fits. In either situation the layered-earth interpretation then provides an accurate estimate of the deeper geoelectric section. Nevertheless, the interpreted layering in the near surface is still biased by conductors in the near surface.
Cyclic Di-GMP Stimulates Protective Innate Immunity in Bacterial Pneumonia (2007)

Innate immunity is the primary mechanism by which extracellular bacterial pathogens are effectively cleared from the lung. We have previously shown that cyclic di-GMP (c-di-GMP [c-diguanylate]) is a novel small molecule immunomodulator and immunostimulatory agent that triggers protective host innate immune responses. Using a murine model of bacterial pneumonia, we show that local intranasal (i.n.) or systemic subcutaneous (s.c.) administration of c-di-GMP prior to intratracheal (i.t.) challenge with Klebsiella pneumoniae stimulates protective immunity against infection. Specifically, i.n. or s.c. administration of c-di-GMP 48 and 24 h prior to i.t. K. pneumoniae challenge resulted in significantly increased survival. Pretreatment with c-di-GMP resulted in a 5-fold reduction in bacterial CFU in the lung (P < 0.05) and an impressive >1,000-fold decrease in CFU in the blood (P < 0.01). c-di-GMP administration stimulated a robust innate response to bacterial challenge, characterized by enhanced accumulation of neutrophils and alphabeta T cells, as well as activated NK and alphabeta T lymphocytes, which was associated with earlier and more vigorous expression of chemokines and type I cytokines. Moreover, lung macrophages recovered from Klebsiella-infected mice pretreated with c-di-GMP expressed greater quantities of inducible nitric oxide synthase and nitric oxide ex vivo than did macrophages isolated from infected mice pretreated with the control, c-GMP. These findings demonstrate that c-di-GMP delivered in either a compartmentalized or systemic fashion stimulates protective innate immunity in the lung and protects mice against bacterial invasion. We propose that the cyclic dinucleotide c-di-GMP may be used clinically as an effective immunomodulator, immune enhancer, and vaccine adjuvant to protect against respiratory infection and pneumonia in humans and animals.
The transcription factor Schnurri plays a dual role in mediating Dpp signaling during embryogenesis (2001)

Decapentaplegic (Dpp), a homolog of vertebrate bone morphogenic protein 2/4, is crucial for embryonic patterning and cell fate specification in Drosophila. Dpp signaling triggers nuclear accumulation of the Smads Mad and Medea, which affect gene expression through two distinct mechanisms: direct activation of target genes and relief of repression by the nuclear protein Brinker (Brk). The zinc-finger transcription factor Schnurri (Shn) has been implicated as a co-factor for Mad, based on its DNA-binding ability and evidence of signaling dependent interactions between the two proteins. A key question is whether Shn contributes to both repression of brk as well as to activation of target genes. We find that during embryogenesis, brk expression is derepressed in shn mutants. However, while Mad is essential for Dpp-mediated repression of brk, the requirement for shn is stage specific. Analysis of brk; shn double mutants reveals that upregulation of brk does not account for all aspects of the shn mutant phenotype. Several Dpp target genes are expressed at intermediate levels in double mutant embryos, demonstrating that shn also provides a brk-independent positive input to gene activation. We find that Shn-mediated relief of brk repression establishes broad domains of gene activation, while the brk-independent input from Shn is crucial for defining the precise limits and levels of Dpp target gene expression in the embryo.
4-Deoxypyrido[1',2':1,2]imidazo[5,4-c]rifamycin SV derivatives. A new series of semisynthetic rifamycins with high antibacterial activity and low gastroenteric absorption (1985)

A series of 4-deoxypyrido[1',2':1,2]imidazo[5,4-c]rifamycin SV derivatives (6-11) were prepared that demonstrated high antibacterial activity suitable for an intestinal disinfectant. These compounds are zwitterionic in nature and are poorly absorbed through the gastroenteric tract but maintain the ability to cross the bacterial cell wall. X-ray crystallographic data are presented to demonstrate the zwitterionic nature of these compounds. The structure-activity relationship of this novel series of antibiotics is discussed and the derivative with the highest ratio between subcutaneous and oral activity (6) was selected for clinical development. At the outset of this work several 3-(quaternary ammonium bromides) (1-5) were prepared and tested for antibacterial activity. These compounds were demonstrated to be too polar to even cross the bacterial cell wall but led to the synthesis of 6-11.
Microbial Functionality in the Human Gastrointestinal Tract (2004)

The gastro-intestinal (GI) tract is the primary site of food intake, perception and conversion. It represents one of the most important metabolic organs of the body and is colonised by a myriad of microbes that contribute to nutrient processing, affect immune function, and stimulate a variety of other host activities. Genomes of GI-tract resident microbial species have been sequenced, e.g. the Lactobacillus plantarum WCFS1 genome sequence has been published and an ever improving annotation database is in facilitating ongoing research to provide a model for specific and mechanistically predictable interactions of host and microbe. Bifidobacteria are of particular interest as they are dominantly present in the human GI-tract. The genome of Bifidobacterium longum has been sequenced and its analysis has provided insights into the interactions of Bifidobacteria with their hosts. Research into novel species, such as the recently identified Akkermansia muciniphila, which grows solely on mucin, will help to unravel the species-specific functionality of microbes. This article provides an overview of current research initiatives undertaken to elucidate microbial functionality in the human GI-tract.