gebhart/patrepeval huggingface dataset:
Tritium NMR spectroscopy of ligand binding to maltose-binding protein (1991)

Tritium-labeled alpha- and beta-maltodextrins have been used to study their complexes with maltose-binding protein (MBP), a 40-kDa bacterial protein. Five substrates, from maltose to maltohexaose, were labeled at their reducing ends and their binding studied. Tritium NMR spectroscopy of the labeled sugars showed large upfield chemical shift changes upon binding and strong anomeric specificity. At 10 degrees C, MBP bound alpha-maltose with 2.7 +/- 0.5-fold higher affinity than beta-maltose, and, for longer maltodextrins, the ratio of affinities (KD beta/KD alpha) was even larger (between 10 and 30). The maximum chemical shift change was 2.2 ppm, suggesting that the reducing end of bound alpha-maltodextrin makes close contact with an aromatic residue in the MBP-binding site. Experiments with maltotriose (and longer maltodextrins) also revealed the presence of two bound beta-maltotriose resonances in rapid exchange. We interpret these two resonances as arising from two distinct sugar-protein complexes. In one complex, the beta-maltodextrin is bound by its reducing end, and, in the other complex, the beta-maltodextrin is bound by the middle glucose residue(s). This interpretation also suggests how MBP is able to bind both linear and circular maltodextrins.
Design and characteristics of a parallel link compliant wrist (2002)

A mechanical design of a parallel link compliant wrist is described based on the passive compliance analysis. The compliant wrist has a three degrees of freedom parallel link mechanism and provide the necessary flexibility for pick-and-place, grinding and polishing operations. It is shown that using the design method we can construct a compliant wrist which has a desired Cartesian stiffness and a suitable work space. We built a compliant wrist as an example and examined the characteristics.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays (2000)

The reverse transcription polymerase chain reaction (RT-PCR) is the most sensitive method for the detection of low-abundance mRNA, often obtained from limited tissue samples. However, it is a complex technique, there are substantial problems associated with its true sensitivity, reproducibility and specificity and, as a quantitative method, it suffers from the problems inherent in PCR. The recent introduction of fluorescence-based kinetic RT-PCR procedures significantly simplifies the process of producing reproducible quantification of mRNAs and promises to overcome these limitations. Nevertheless, their successful application depends on a clear understanding of the practical problems, and careful experimental design, application and validation remain essential for accurate quantitative measurements of transcription. This review discusses the technical aspects involved, contrasts conventional and kinetic RT-PCR methods for quantitating gene expression and compares the different kinetic RT-PCR systems. It illustrates the usefulness of these assays by demonstrating the significantly different levels of transcription between individuals of the housekeeping gene family, glyceraldehyde-3-phosphate-dehydrogenase (GAPDH).
Emerging drugs for asthma (2008)

This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy. Current therapies for asthma are aimed at controlling disease symptoms, and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires lifetime therapy; and a subset of patients remains symptomatic despite optimal treatment, creating a clear unmet medical need. It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Significant areas of drug development include humanised mAb for asthma therapy, including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma-relevant mediators, or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.
Calorimetric study of octylcyanobiphenyl liquid crystal confined to a controlled-pore glass (2003)

We present a calorimetric study of the phase behavior of octylcyanobiphenyl (8CB) liquid crystal confined to a controlled-pore glass (CPG). We used CPG matrices with characteristic void diameters ranging from 400 to 20 nm. In bulk we obtain weakly first-order isotropic to nematic (I-N) phase transition and nearly continuous character of the nematic to smectic-A (N-SmA) phase transition. In all CPG matrices the I-N transition remains weakly first order, while the N-SmA one becomes progressively suppressed with decreasing CPG pore radius. With decreased pore diameters both phase transition temperatures monotonously decrease following similar trends, but increasing the stability range of the N phase. The heat-capacity response at the weakly first order I-N and continuous N-SmA phase transitions gradually approaches the tricritical-like and three-dimensional XY behavior, respectively. The main observed features were explained using a bicomponent single pore type phenomenological model.
Improving on police radar (1992)

The use of lasers, cameras, and advanced signal processing to help isolate individual offenders on crowded highways is discussed. The limitations of the predominant radar in use today, namely down-the-road Doppler-radar in which the axis of the antenna is directed along the line of travel of the target vehicle, are described. The potential of video records, across-the-road radar, and both across and down-the-road laser systems is examined. Passive monitoring and the use of surveillance cameras at red lights are also considered.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation (1994)

Mutations in the adult human skeletal muscle Na+ channel alpha subunit cause the disease paramyotonia congenita. Two paramyotonia congenita mutations, R1448H and R1448C, substitute histidine and cysteine for arginine in the S4 segment of domain 4. These mutations, expressed in a cell line, have only small effects on the activation of Na+ currents, but mutant channels inactivate more slowly with less voltage dependence than wild-type channels and exhibit an enhanced rate of recovery from inactivation. Increase of extracellular pH made the rate of inactivation of R1448H similar to that of R1448C, suggesting that this residue has an extracellular location and that its charge is important for normal inactivation. Analysis of single-channel data reveals that mutant channels inactivate normally from closed states, but poorly from the open state. The data suggest a critical role for the S4 helix of domain 4 in coupling between activation and inactivation.
Medium for Use in Antibiotic Susceptibility Testing of Anaerobic Bacteria (1976)

A medium is described which was designed for use in testing the minimal inhibitory concentration of antibiotics for anaerobic bacteria by agar dilution. It contains: Trypticase (1%), Gelysate (1%), yeast extract (0.5%), glucose (0.1%), pyruvate (0.1%), arginine (0.1%), NaCl (0.5%), hemin (5 mug/ml), vitamin K(1) (0.5 mug/ml), agar (1.5%). The medium does not require the addition of blood to support growth of most clinical isolates of anaerobic bacteria.
Prostaglandin dehydrogenase is a target for successful induction of cervical ripening (2017)

The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E<sub>2</sub> or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE<sub>2</sub> uses cell-specific EP2 receptor-mediated increases in Ca<sup>2+</sup> to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE<sub>2</sub> or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE<sub>2</sub> or metabolism-resistant dimethyl-PGE<sub>2</sub> resulted in preterm cervical ripening and delivery in mice. The ability of PGE<sub>2</sub> to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of <i>15-PGDH</i> elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for (<i>i</i>) the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE<sub>2</sub>-mediated cervical ripening or (<i>ii</i>) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.
Optimization model for the delivery of interactive multimedia documents (2002)

The delivery of multimedia information over future public networks may require sophisticated control facilities. In order both to minimize segment delivery latencies and to maximize network utilization, the delivery control facility must preallocate and release network resources based on dynamic models of both the interactive multimedia document and the network topology. It is shown that, by expressing these models as labeled access graphs that incorporate the relevant statistics, the algorithm for optimized delivery can be specified by a small set of rules. An optimization mechanism that utilizes the algorithm is described, and how it should obtain its input parameters and how it should be executed are specified. The practical validity of the mechanism is discussed for a group of services which includes video-on-demand and interactive electronic magazines.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspases 3 and 7. (2000)

The inhibitor of apoptosis, cIAP2, contains a putative Ring finger motif at the C terminus. Using in vitro ubiquitination assays, we found that the Ring finger of cIAP2 alone possesses intrinsic ubiquitin ligase activity and promotes substrate-independent ubiquitination. It also promotes ubiquitination of caspases 3 and 7 but not caspase-1. The Ring fingers of c-Cbl and Apc11 failed to promote caspase-7 ubiquitination, suggesting that the Ring finger of cIAP2 itself is involved in substrate recognition.
Intravitreal versus Sub-Tenon Posterior Triamcinolone Injection in Bilateral Diffuse Diabetic Macular Edema (2011)

Both intravitreal and ST injections of triamcinolone appear to yield a significant visual recovery and prompt resolution of DDME. The beneficial outcome appears to be more longstanding with intravitreal injection.
Interactive Effects of pH and Temperature on N-Methyl-D-Aspartate Receptor Activity in Rat Cortical Brain Slices (1997)

Low extracellular pH decreases the activity of the N-methyl-D-aspartate (NMDA) glutamate receptor, and may thus limit neuronal calcium overload during cerebral ischemia. During induced hypothermia, alkaline pH ("alphastat regulation") is often used to preserve cardiac and enzymatic function. The purpose of this study is to measure the functional activity of cerebral cortex NMDA receptors over the range of temperatures used in profound hypothermic cardiopulmonary bypass (20-37 degrees C). Extracellular pH was varied over a broad range relevant to both alphastat and pH stat acid-base management (7.0-7.8). Change in cytosolic free calcium evoked by 50 microM NMDA in brain slices was used as an index of NMDA receptor activity. Cortical slices (300 microns thick) were loaded with fura-2 Aspartate Methyl for study in a fluorometer. At 37 degrees C, a change in extracellular pH from 7.1 to 7.8 increased the NMDA-evoked change in cytosolic calcium in brain slices by a factor of 4 (p < 0.05). In contrast, at 20 degrees C there was minimal effect of changing extracellular pH from 7.1 to 7.8 (27% increase). We conclude that hypothermia results in decreased pH sensitivity of the NMDA receptor. The results predict that different strategies of pH management during induced hypothermia may have limited impact on NMDA receptor-mediated processes, such as neuronal calcium overload.
Terahertz quantum-cascade laser at λ≈100 μm using metal waveguide for mode confinement (2003)

We report lasing at ∼3.0 THz (λ≈98–102 μm) in a quantum-cascade structure in which mode confinement is provided by a double-sided metal waveguide. The depopulation mechanism is based on resonant phonon scattering, as in our previous work. Lasing takes place in pulsed mode up to a heat-sink temperature of 77 K. The waveguide consists of metallic films placed above and below the 10-μm-thick multiple-quantum-well gain region, which gives low losses and a modal confinement factor of nearly unity. Fabrication takes place via low-temperature metallic wafer bonding and subsequent substrate removal using selective etching. This type of waveguide is expected to be increasingly advantageous at even longer wavelengths.
First-in-human study assessing safety and tolerability of REGN1979, a novel CD20xCD3 bispecific antibody, in patients with CD20+ B-cell malignancies previously treated with anti-CD20 therapy. (2015)

TPS3089 Background: REGN1979 is a human bispecific antibody based on an IgG4 isotype modified to reduce Fc binding, designed to bridge CD20-expressing cells to cytotoxic T-cells by binding to the CD3 subunit of the TCR complex. Bridging results in targeted killing of CD20+ cells by T-cells that is independent of typical requirements for specific TCR recognition of a target cell. T-cell activation requires CD20, a well-validated surface target for B-cell malignancies. This MOA is distinct from that of other available anti-CD20 antibodies, and may provide additional therapeutic benefit to patients with CD20+ malignancies, including those who have relapsed after anti-CD20 therapy. REGN1979 has been shown to specifically kill CD20+ tumor cells in vitro, and has shown potent in vivo anti-tumor activity in several mouse models (established Raji tumors and B16_hCD20)( Varghese B et al. ASH 2014. Abstract 4501). In cynomolgus monkeys, REGN1979 at doses ≥ 0.01 mg/kg depleted peripheral and tissue CD20+ B-cells to similar levels achieved with significantly higher doses of rituximab (30 mg/kg). At ≥ 0.1 mg/kg, REGN1979 depleted B-cells in spleen, mesenteric lymph nodes, and thymus to undetectable levels. Methods: This open label, multicenter, Phase 1, FIH study (NCT02290951) uses a 3+3 dose-escalation design with a 28-day DLT observation period to assess both acute and late toxicity. Each dose level (DL) has an initial dose followed by a second and subsequent higher dose, if the initial dose was tolerated. Patients receive REGN1979 IV weekly during a 4-week induction period at their assigned DL, then monthly for 5 additional doses. There will be parallel independent dose escalation cohorts for patients with NHL and CLL at each DL. After determining the recommended dose for further study, there will be an expansion phase with independent cohorts for patients with indolent NHL, aggressive NHL, and CLL. The primary objective is to assess the safety, tolerability, and DLTs of REGN1979. Secondary objectives include characterization of the PK profile, immunogenicity, and preliminary anti-tumor activity of REGN1979. Enrollment is ongoing. Clinical trial information: NCT02290951.
Role of the virion host shutoff (vhs) of herpes simplex virus type 1 in latency and pathogenesis (1995)

The herpes simplex virus type 1 (HSV-1) UL41 gene product, virion host shutoff (vhs), has homologs among five alphaherpesviruses (HSV-1, HSV-2, pseudorabies virus, varicella-zoster virus, and equine herpesvirus 1), suggesting a role for this protein in neurotropism. A mutant virus, termed UL41NHB, which carries a nonsense linker in the UL41 open reading frame at amino acid position 238 was generated. UL41NHB and a marker-rescued virus, UL41NHB-R, were characterized in vitro and tested for their ability to replicate in vitro and in vivo and to establish and reactivate from latency in a mouse eye model. As demonstrated by Western blotting (immunoblotting) and Northern (RNA) blotting procedures, UL41NHB encodes an appropriately truncated vhs protein and, as expected for a vhs null mutant, fails to induce the degradation of cellular glyceraldehyde-3-phosphate dehydrogenase mRNA. The growth of UL41NHB was not significantly altered in one-step growth curves in Vero or mouse C3H/10T1/2 cells but was impaired in corneas, in trigeminal ganglia, and in brains of mice compared with the growth of KOS and UL41NHB-R. As a measure of establishment of latency, quantitative DNA PCR showed that the amount of viral DNA within trigeminal ganglia latently infected with UL41NHB was reduced by approximately 30-fold compared with that in KOS-infected ganglia and by 50-fold compared with that in UL41NHB-R-infected ganglia. Explant cocultivation studies revealed a low reactivation frequency for UL41NHB (1 of 28 ganglia, or 4%) compared with that for KOS (56 of 76, or 74%) or UL41NHB-R (13 of 20 or 65%). Taken together, these results demonstrate that vhs represents a determinant of viral pathogenesis.
The solution structure of the N-terminal domain of α2-macroglobulin receptor-associated protein (1997)

The three-dimensional structure of the N-terminal domain (residues 18-112) of alpha2-macroglobulin receptor-associated protein (RAP) has been determined by NMR spectroscopy. The structure consists of three helices composed of residues 23-34, 39-65, and 73-88. The three helices are arranged in an up-down-up antiparallel topology. The C-terminal 20 residues were shown not to be in a well defined conformation. A structural model for the binding of RAP to the family of low-density lipoprotein receptors is proposed. It defines a role in binding for both the unordered C terminus and the structural scaffold of the core structure. Pathogenic epitopes for the rat disease Heymann nephritis, an experimental model of human membranous glomerulonephritis, have been identified in RAP and in the large endocytic receptor gp330/megalin. Here we provide the three-dimensional structure of the pathogenic epitope in RAP. The amino acid residues known to form the epitope are in a helix-loop-helix conformation, and from the structure it is possible to rationalize the published results obtained from studies of fragments of the N-terminal domain.
Gene Transfer by Retrovirus Vectors Occurs Only in Cells That Are Actively Replicating at the Time of Infection (1990)

Previous reports have shown that retrovirus infection is inhibited in nonreplicating (stationary-phase [hereafter called stationary]) cells. Infection of stationary cells was shown to occur when the cells were allowed to replicate at times up to a week after infection, suggesting that an unintegrated retrovirus could persist in a form that was competent to integrate after release of the block to replication. However, those studies were complicated by the use of replication-competent virus, which can spread in the infected cells. We have used a replication-defective retrovirus vector to compare the efficiency of gene transfer in stationary and replicating rat embryo fibroblasts. In agreement with previous results, gene transfer was inhibited 100-fold in stationary versus replicating cells. In contrast to previously reported results, the block to infection could not be relieved by stimulating stationary cells to divide at times from 6 h to 10 days after infection. Thus, for successful retroviral infection, the infected cells must be replicating at the time of infection. These results have important implications for the use of retroviral vectors for gene transfer.
Potential Contribution of Exosomes to the Prion-Like Propagation of Lesions in Alzheimer’s Disease (2012)

Since the discovery of prion diseases, the concept has emerged that a protein could be a transmissible pathogen. As such, this transmissible pathogen agent can transfer its pathological mis-folded shape to the same but normally folded protein thus leading to the propagation of a disease. This idea is now extrapolated to several neurological diseases associated with protein mis-folding and aggregation, such as Alzheimer's disease (AD). AD is a slowly developing dementing disease characterized by the coexistence of two types of lesions: the parenchymal amyloid deposits and the intraneuronal neurofibrillary tangles (NFT). Amyloid deposits are composed of amyloid-beta peptides that derive from sequential cleavages of its precursor named amyloid protein precursor. NFT are characterized by intraneuronal aggregation of abnormally modified microtubule-associated Tau proteins. A synergistic relationship between the two lesions may trigger the progression of the disease. Thus, starting in the medial temporal lobe and slowly progressing through temporal, frontal, parietal, and occipital cortex, the spreading of NFT is well correlated with clinical expression of the disease and likely follows cortico-cortical neuronal circuitry. However, little is known about the mechanism driving the spatiotemporal propagation of these lesions ultimately leading to the disease. A growing number of studies suggest that amyloid deposits and NFT are resulting from a prion-like spreading. In the present chapter, we will develop the current hypotheses regarding the molecular and cellular mechanisms driving the development and spreading of AD lesions from the window of multivesicular endosomes/bodies and exosomes.