gebhart/patrepeval huggingface dataset:
Characterization of glucose transporter isoforms in the adult and developing human eye (1993)

The expression of glucose transporter isoforms (Glut 1, Glut 3, Glut 4, and Glut 5) in the human eye was investigated at various ages ranging between 8 weeks gestation (first trimester) and adult using Western blot and immunohistochemical analyses. Glut 1 and Glut 3 expression and cellular localization patterns were similar to those of human brain. Glut 1 (50-kilodalton protein) was expressed by epithelial cells (retinal pigmented epithelium, choroidal, iridial, and pars planus), which form the blood-eye barrier, retinal Mueller cells, the lens fiber cells, iridial microvascular endothelial cells, and to a lesser extent by the outer segments of the photoreceptor cells in the adult eye. This pattern was conserved throughout development and was evident as early as 8 weeks gestation. In addition, the endothelial cells of vitreous hyaloid vessels expressed Glut 1 at 8 weeks gestation. Glut 3 (50 to 55-kilodalton protein) immunoreactivity was observed only in the adult inner synaptic layer of the retina. Neither Glut 4 nor Glut 5 was expressed in any occular tissue at any age examined. These results suggest that Glut 1 is the main glucose transporter of the human eye and that it is ontogenically conserved. In contrast, Glut 3 is associated with selective neuronal processes, and its expression is developmentally altered.
Nick sensing by vaccinia virus DNA ligase requires a 5' phosphate at the nick and occupancy of the adenylate binding site on the enzyme (1997)

Vaccinia virus DNA ligase has an intrinsic nick-sensing function. The enzyme discriminates at the substrate binding step between a DNA containing a 5' phosphate and a DNA containing a 5' hydroxyl at the nick. Further insights into nick recognition and catalysis emerge from studies of the active-site mutant K231A, which is unable to form the covalent ligase-adenylate intermediate and hence cannot activate a nicked DNA substrate via formation of the DNA-adenylate intermediate. Nonetheless, K231A does catalyze phosphodiester bond formation at a preadenylated nick. Hence, the active-site lysine of DNA ligase is not required for the strand closure step of the ligation reaction. The K231A mutant binds tightly to nicked DNA-adenylate but has low affinity for a standard DNA nick. The wild-type vaccinia virus ligase, which is predominantly ligase-adenylate, binds tightly to a DNA nick. This result suggests that occupancy of the AMP binding pocket of DNA ligase is essential for stable binding to DNA. Sequestration of an extrahelical nucleotide by DNA-bound ligase is reminiscent of the base-flipping mechanism of target-site recognition and catalysis used by other DNA modification and repair enzymes.
Anti-HIV-1 activity of leflunomide (2003)

Background: Leflunomide inhibits de novo pyrimidine synthesis by inhibiting the activity of dihydroorotic acid dehydrogenase and has other immunomodulatory properties that make it a promising candidate for an anti-HIV drug. Objectives: To compare the anti-HIV activity of leflunomide with that of the immunomodulatory drugs hydroxyurea and mycophenolic acid; to assess whether there is an additive or synergistic effect when leflunomide is used in conjunction with mycophenolic acid; and to characterize the molecular mechanism of the anti-HIV activity of leflunomide. Methods: Anti-HIV activity was examined in peripheral blood mononuclear cells. CD4 cell survival was examined in tonsillar lymphocytes by fluorescence-activating cell sorting. Results: Leflunomide decreased HIV replication by approximately 75% at concentrations that can be obtained with conventional dosing. This activity was similar to that of hydroxyurea but superior to mycophenolic acid. Leflunomide and mycophenolic acid together have modest additive anti-HIV effects. Restoration of HIV replication by uridine indicates that leflunomide's primary mechanism at lower concentrations is inhibition of dihydroorotic acid dehydrogenase while at higher concentrations additional mechanisms may be involved. Conclusions: Leflunomide's anti-HIV activity and clinical profile make it an attractive candidate for further study of its effects. Since HIV RNA levels are an effective predictor of AIDS-free survival, leflunomide's partial suppression of HIV RNA may be valuable in certain patients.
Interleukin 1 is processed and released during apoptosis. (1991)

Interleukin (IL-) 1 alpha and 1 beta are synthesized as 31- to 34-kDa pro molecules. They are released from monocytes and macrophages as proteolytically processed 17-kDa mature molecules that bind with high affinity to specific receptors on target cells. IL-1 is not released via the classic secretory pathway. The pro molecules are synthesized as cytosolic proteins without signal peptides. Although the proteases that convert the pro molecules to the mature forms are cytosolic enzymes, processed IL-1 is not detected associated with the cell but is found only in culture supernatants. We demonstrate here that release of IL-1 is efficiently induced by cell injury. When the injury causes cellular necrosis, IL-1 alpha is released as a mixture of unprocessed and processed molecules but IL-1 beta is released exclusively as the biologically inactive pro form. In contrast, when cells undergo apoptosis, maturation of both IL-1 alpha and IL-1 beta is efficient. When apoptosis is rapid, as in macrophages that are targets for allospecific cytotoxic T lymphocytes, processing is observed to occur intracellularly. These findings suggest that cell injury is an important physiologic stimulus for release of IL-1. The nature of the injury profoundly affects the forms of IL-1 that are released.
Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma. (1981)

We have prospectively examined in 51 patients the relationship between the level of airway responsiveness to histamine and methacholine and the minimum medications required to control asthma. First we determined the least medication that was required to control symptoms so that they did not disturb sleep, were not present on waking, and did not require use of inhaled salbutamol (200 microgram) more than four times daily. When baseline FEV1 was greater than 70% of predicted and when there had been no respiratory infection or allergen exposure for six weeks, histamine and methacholine inhalation tests were carried out on separate days to determine the provocation concentration causing a fall in FEV1 of 20% (PC20). There was a close correlation between the PC20 to the two agents. The patients were grouped into 1, those who required no medication; 2, those who required salbutamol (200 microgram) occasionally but not daily; 3, those who required daily salbutamol; and 4, those who required additional beclomethasone dipropionate. The mean PC20 was highest in group 1 and lowest in group 4; there was a significant difference between each group. The results indicate that airway responsiveness to vasoactive amines is either an important determinant of the severity of asthma and the medication requirements or a consequence of the severity of asthma. They raise the possibility that measurement of responsiveness may be useful in some patients with established asthma to substantiate or question medication needs.
Vascular nitric oxide: effects of physical activity, -importance for health (2006)

NO (nitric oxide), formed in the vascular endothelium and derived from a biochemical reaction catalysed by eNOS (endothelial NO synthase), appears to play a role in exercise-induced dilation of blood vessels supplying cardiac and skeletal muscle. Endothelium-dependent, NO-mediated vasodilation is augmented by exercise training. Increases in eNOS gene transcription, eNOS mRNA stability and eNOS protein translation appear to contribute to increased NO formation and, consequently, enhanced NO-mediated vasodilation after training. Enhanced endothelial NO formation may also have a role(s) in the prevention and management of atherosclerosis because several steps in the atherosclerotic disease process are inhibited by NO. A growing body of work suggests that exercise training, perhaps via increased capacity for NO formation, retards atherosclerosis. This has significant implications for human health, given that atherosclerosis is the leading killer in Western society.
SVM-based texture classification in Optical Coherence Tomography (2013)

This paper describes a new method for automated texture classification for glaucoma detection using high resolution retinal Optical Coherence Tomography (OCT). OCT is a non-invasive technique that produces cross-sectional imagery of ocular tissue. Here, we exploit information from OCT images, specifically the inner retinal layer thickness and speckle patterns, to detect glaucoma. The proposed method relies on support vector machines (SVM), while principal component analysis (PCA) is also employed to improve classification performance. Results show that texture features can improve classification accuracy over what is achieved using only layer thickness as existing methods currently do.
Stability of Dicalcium Phosphate Dihydrate in Aqueous Solutions and Solubility of Octocalcium Phosphate (1960)

Abstract The hydrolysis of dicalcium phosphate dihydrate, CaHPO 4 ·2H 2 O, in dilute phosphoric acid solutions and in water was investigated at 25° C. in the absence of CO 2 . Octocalcium phosphate, Ca 4 H(PO 4 ) 3 ·3H 2 O, was found to precipitate when the pH of the solution was higher than 6.38. The extent of the hydrolysis was larger the higher the initial pH of the solution. The solution composition followed the metastable solubility isotherm for dicalcium phosphate dihydrate until a singular point between octocalcium phosphate and dicalcium phosphate dihydrate was reached. At this point the solution had a pH of 6.38 and Ca and P concentrations of 1.36 × 10 ‐3 M and 2.21 × 10 ‐3 M , respectively. The solubility product of octocalcium phosphate was calculated to be (Ca) 4 (H)(PO 4 ) 3 = 1.25 × 10 ‐47 . Relative rates of solution and precipitation of both dicalcium and octocalcium phosphates are discussed. No formation of anhydrous dicalcium phosphate or hydroxyapative was detected in equilibrations for as long as 90 days, even though both of these compounds are more stable than dicalcium phosphate dihydrate under the experimental conditions.
IL15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands in the Single-Chain Format for Cancer Immunotherapy (2019)

IL15 and costimulatory receptors of the tumor necrosis superfamily (TNFRSF) have shown great potential to support and drive an antitumor immune response. However, their efficacy as monotherapy is limited. Here, we present the development of a novel format for a trifunctional antibody-fusion protein that combines and focuses the activity of IL15/TNFSF-ligand in a targeting-mediated manner to the tumor site. The previously reported format consisted of a tumor-directed antibody (scFv), IL15 linked to an IL15Rα-fragment (RD), and the extracellular domain of 4-1BBL, where noncovalent trimerization of 4-1BBL into its functional unit led to a homotrimeric molecule with 3 antibody and 3 IL15-RD units. To reduce the size and complexity of the molecule, we have now designed a second format, where 4-1BBL is introduced as single-chain (sc), that is 3 consecutively linked 4-1BBL ectodomains. Thus, a monomeric trifunctional fusion protein presenting only 1 functional unit of each component was generated. Interestingly, the <i>in vitro</i> activity on T-cell stimulation was conserved or even enhanced for the soluble and target-bound molecule, respectively. Also, in a lung tumor mouse model, comparable antitumor effects were observed. Furthermore, corroborating the concept, OX40L and GITRL were also successfully incorporated into the novel single-chain format and the advantage of target-bound trifunctional versus corresponding combined bifunctional fusion proteins demonstrated by measuring T-cell proliferation and cytotoxic potential <i>in vitro</i> and antitumor effects of RD_IL15_scFv_scGITRL in a lung tumor mouse model <i>in vivo</i> Thus, the trifunctional antibody-fusion protein single-chain format constitutes a promising innovative platform for further therapeutic developments.
Prevention of chain cleavage in the chemical synthesis of 2′-silylated oligoribonucleotides (1989)

Strong aqueous ammonium hydroxide used to remove N-acyl protecting groups from synthetic oligoribonucleotides causes removal of some alkylsilyl protecting groups from 2'-hydroxyls and leads to chain cleavage. This problem is most severe when 30% ammonium hydroxide is used and substantially reduced but still detectable when 3:1 ammonium hydroxide-ethanol is used. We have virtually eliminated this unwanted cleavage by incorporating the labile phenoxyacetyl amino protecting group on adenosine and guanosine. The N-benzoyl protecting group remains adequate for cytidine nucleosides. Synthetic oligoribonucleotides containing these N-acylated nucleosides and 2'-t-butyldimethylsilyl or 2'-triisopropylsilyl protecting groups can be deacylated by room temperature treatment in saturated anhydrous methanolic ammonia (8-12 h) without causing any detectable chain cleavage.
Chapter 1. Elemental Sustainability for Catalysis (2015)

The current use of chemical elements in any application including catalysis should not restrict their use for future generations. By promoting holistic strategies for extraction, manufacture, utilisation and recovery of elements it will be possible to develop a sustainable global circular economy, whereby all elements are continually recirculated for use. More specifically, the importance of catalysis for the production of chemicals and materials is widely accepted, but current rates of recovery and reuse of elements for catalysis are typically low. It is hoped that the Earth-abundant elements would fulfil all the catalysis needs of the chemical industry but in practice this is not possible, many transformations are only economically feasible when a critical or scarce element is utilised as a catalyst. There is therefore a pressing need to consider more sustainable strategies for the improved recovery of catalytically relevant elements, with a view towards reuse. The sustainability of catalysts must consider aspects such as energy consumption for preparation and recovery, whilst also minimising the detrimental impact on the environment. In this chapter we highlight catalytic elements of concern and suggest strategies for their sustainable use.
Histone Demethylase LSD1 Regulates Neural Stem Cell Proliferation (2010)

Lysine-specific demethylase 1 (LSD1) functions as a transcriptional coregulator by modulating histone methylation. Its role in neural stem cells has not been studied. We show here for the first time that LSD1 serves as a key regulator of neural stem cell proliferation. Inhibition of LSD1 activity or knockdown of LSD1 expression led to dramatically reduced neural stem cell proliferation. LSD1 is recruited by nuclear receptor TLX, an essential neural stem cell regulator, to the promoters of TLX target genes to repress the expression of these genes, which are known regulators of cell proliferation. The importance of LSD1 function in neural stem cells was further supported by the observation that intracranial viral transduction of the LSD1 small interfering RNA (siRNA) or intraperitoneal injection of the LSD1 inhibitors pargyline and tranylcypromine led to dramatically reduced neural progenitor proliferation in the hippocampal dentate gyri of wild-type adult mouse brains. However, knockout of TLX expression abolished the inhibitory effect of pargyline and tranylcypromine on neural progenitor proliferation, suggesting that TLX is critical for the LSD1 inhibitor effect. These findings revealed a novel role for LSD1 in neural stem cell proliferation and uncovered a mechanism for neural stem cell proliferation through recruitment of LSD1 to modulate TLX activity.
Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis (2008)

Development of obesity-associated insulin resistance and diabetes mellitus type 2 has been linked to activation of proinflammatory pathways in the liver, leading to impaired insulin signal transduction. To further define the role of hepatic NF-kappaB activation in this process, we have analyzed glucose metabolism in mice with liver-specific inactivation of the NF-kappaB essential modulator gene (NEMO(L-KO) mice) exposed to a high-fat diet (HFD). These animals are protected from the development of obesity-associated insulin resistance, highlighting the importance of hepatic NF-kappaB activation in this context. However, hepatic NEMO deficiency synergizes with HFD in the development of liver steatosis as a consequence of decreased peroxisome proliferator-activated receptor (PPAR-alpha) and increased PPAR-gamma expression. Steatosis interacts with increased inflammation, causing elevated apoptosis in the livers of these mice under HFD. These changes result in liver tumorigenesis of NEMO(L-KO) mice under normal diet, a process that is largely aggravated when these mice are exposed to HFD. These data directly demonstrate the interaction of hepatic inflammation, dietary composition, and metabolism in the development of liver tumorigenesis.
Ca2+ waves in astrocytes (1991)

The glial cell is the most numerous cell type in the central nervous system and is believed to play an important role in guiding brain development and in supporting adult brain function. One type of glial cell, the astrocyte also may be an integral computational element in the brain since it undergoes neurotransmitter-triggered signalling. Here we review the role of the astrocyte in the central nervous system, emphasizing receptor-mediated Ca2+ physiology. One focus is the recent discovery that the neurotransmitter glutamate induces a variety of intracellular Ca2+ changes in astrocytes. Simple Ca2+ spikes or intracellular Ca2+ oscillations often appear spatially uniform. However, in many instances, the Ca2+ rise has a significant spatial dimension, beginning in one part of the cell it spreads through the rest of the cell in the form of a wave. With high enough agonist concentration an astrocyte syncitium supports intercellular waves which propagate from cell to cell over relatively long distances. We present results of experiments using more specific pharmacological glutamate receptor agonists. In addition to describing the intercellular Ca2+ wave we present evidence for another form of intercellular signalling. Some possible functions of a long-range glial signalling system are also discussed.
Integrins and signal transduction (1999)

Integrins are dynamic cell-surface receptors that provide a physical link between the extracellular matrix and the cell cytoskeleton. The interaction of integrins with extracellular matrix ligands also results in the generation of intracellular signals that regulate cell survival and growth, cell differentiation, and cell motility. The signaling pathways regulated by integrins are both diverse and complex, and involve cross-talk among multiple pathways. An added level of complexity resides in the findings that intracellular signals generated by a variety of agonists can modulate cell adhesion by regulating integrin-matrix interactions. The identification and functional characterization of integrin receptor-proximal components involved in this fascinating "inside-out" and "outside-in" signal transduction remains an area of intense investigation. This review focuses on recent advances in this area.
Distributed robust economic dispatch in power systems: A consensus &#x002B; innovations approach (2012)

The paper presents a fully distributed approach for economic dispatch in power systems. The approach is based on the consensus + innovations framework, in which each network agent participates in a collaborative process of neighborhood message exchange and local computation. The distributed approach is shown to converge to the optimal dispatch under rather weak assumptions on the agent communication network connectivity. Intuitively, the proposed approach includes a consensus term which achieves convergence to a common incremental cost value and an innovation term which ensures that the total generation is equal to the load to be supplied. Further, in the proposed approach each network bus only needs to be aware of its local cost parameters and the local predicted load and the neighborhood communication involves exchanging only the locally determined marginal energy price with a few neighbors. Robustness of the proposed approach and techniques for convergence rate improvement are discussed. Finally, simulation studies on the benchmark IEEE 14 bus system demonstrate the effectiveness of the approach.
Differential pharmacology and clinical utility of empagliflozin in type 2 diabetes (2016)

With rates of obesity and diabetes rising across the world, effective therapies to treat hyperglycemia and its associated comorbidities continue to be in demand. Empagliflozin is a highly selective sodium glucose transporter-2 inhibitor that improves serum glucose levels by inducing glucosuria. Taken orally, it is rapidly absorbed with linear pharmacokinetics consistent in Asian and Caucasian populations. Empagliflozin treatment demonstrates consistent reductions in hemoglobin A1c, fasting plasma glucose, body weight, and blood pressure in individuals with type 2 diabetes. Improvements in glycemic control and metabolic end points are evident with empagliflozin monotherapy, as add-on to oral hypoglycemics or add-on to insulin. The nonglycemic effects of empagliflozin with consistent improvements in blood pressure, body weight, and waist circumference provide additional rationale for use in patients with type 2 diabetes. Moreover, treatment with empagliflozin has recently shown significant reductions in both microvascular and macrovascular complications of diabetes.
Generation, representation and flow of phase information in structure determination: recent developments in and around SHARP 2.0 (2003)

The methods for treating experimental data in the isomorphous replacement and anomalous scattering methods of macromolecular phase determination have undergone considerable evolution since their inception 50 years ago. The successive formulations used are reviewed, from the most simplistic viewpoint to the most advanced, including the exploration of some blind alleys. A new treatment is proposed and demonstrated for the improved encoding and subsequent exploitation of phase information in the complex plane. It is concluded that there is still considerable scope for further improvements in the statistical analysis of phase information, which touch upon numerous fundamental issues related to data processing and experimental design.