gebhart/patrepeval huggingface dataset:
A Novel Peptide Containing a Nine Amino Acid Sequence from Nur77 Induces Bcl-2-Dependent Apoptosis in AML. (2006)

Abstract Nur77 (also known as TR3 and NGFI-B) is a nuclear orphan receptor that in response to various stimuli can translocate from the nucleus to the mitochondria, bind Bcl-2, and induce a conformational change in Bcl-2 that exposes its BH3 domain. This conformational change of Bcl-2 transforms this protein into a pro-apoptotic molecule that can induce cytochrome c release and apoptosis (Cell 116:527, 2004). Interestingly, in acute myeloid leukemia (AML) cell lines and blasts, Nur77 is absent. We have recently generated a nine amino acid peptide from the Nur77 protein (TR3) that is capable of inducing the same pro-apoptotic conformational change in Bcl-2 that Nur77 elicits (manuscript submitted). We tested the hypothesis that a cell-permeable version of this peptide can induce Bcl-2-dependent apoptosis in AML cells and AML stem cells. Primary AML samples (n=6) were incubated with 20 μM control or TR3 peptide for 24 hrs. Induction of apoptosis was measured as CD34+38−123+ PS/Annexin V+ by multiparametric flow cytometry. Our results demonstrate that the L-enantiomer form of TR3 indeed induces apoptosis in total AML cells (60%, p=0.001) and CD34+38−123+ stem cells (67%, p=0.001), as compared to control peptide. Bax expression did not affect the peptide’s ability to induce apoptosis, as wild-type HCT116 cells and HCT116 cells deficient in Bax showed similar levels of apoptosis after treatment with the TR3 peptide. However, Bcl-2 expression was shown to be critical since lentiviral shRNA ablation of Bcl-2 in KG1 cells completely prevented induction of apoptosis by TR3 peptides. We conclude that the TR3 peptide is a potent inducer of apoptosis that mimics the action of Nur77 on Bcl-2 at the mitochondrial level. These results suggest that the Nur77 peptide or compounds that mimic this peptide may have utility as a novel therapeutic agent against Bcl-2 expressing cancers and leukemias.
Exploring the Synthetic Versatility of the Lewis Acid Induced Decomposition Reaction of α-Diazo-β-hydroxy Esters. The Case of Ethyl Diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (2011)

Ethyl diazo(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate was prepared by aldol-type condensation of ethyl diazoacetate with isatin. A systematic and mechanistic study on the Lewis acid induced decomposition reaction of this valuable diazo precursor was carried out with the aim to gain new insights into the mechanistic aspects of the reaction as well as to further understand the factors and experimental conditions which affect the relative product distribution. The reaction, which may proceed via cationic and noncationic mechanisms, was found to be significantly influenced by the reaction environment determined by the characteristics of the Lewis acid employed, by the ability of the Lewis acid to form a complex with the alcohol functionality of the α-diazo-β-hydroxy ester, and by the polarity and nucleophilicity of the solvent used.
Baroreflex Sensitivity in Patients With Vasovagal Syncope (1997)

In patients with vasovagal syncope, during the application of subhypotensive LBNP, there is impaired forearm vasoconstriction or paradoxical forearm vasodilation. This suggests impaired cardiopulmonary baroreceptor inactivation or paradoxical activation of these receptors and is consistent with reduced cardiopulmonary baroreceptor sensitivity.
SNPServer: a real-time SNP discovery tool (2005)

SNPServer is a real-time flexible tool for the discovery of SNPs (single nucleotide polymorphisms) within DNA sequence data. The program uses BLAST, to identify related sequences, and CAP3, to cluster and align these sequences. The alignments are parsed to the SNP discovery software autoSNP, a program that detects SNPs and insertion/deletion polymorphisms (indels). Alternatively, lists of related sequences or pre-assembled sequences may be entered for SNP discovery. SNPServer and autoSNP use redundancy to differentiate between candidate SNPs and sequence errors. For each candidate SNP, two measures of confidence are calculated, the redundancy of the polymorphism at a SNP locus and the co-segregation of the candidate SNP with other SNPs in the alignment. SNPServer is available at http://hornbill.cspp.latrobe.edu.au/snpdiscovery.html.
Search for supersymmetry in events with one lepton and multiple jets exploiting the angular correlation between the lepton and the missing transverse momentum in proton–proton collisions at s=13TeV (2018)

Results are presented from a search for supersymmetry in events with a single electron or muon and hadronic jets. The data correspond to a sample of proton-proton collisions at s = 13 TeV with an integrated luminosity of 35.9 fb -1 , recorded in 2016 by the CMS experiment. A number of exclusive search regions are defined according to the number of jets, the number of b-tagged jets, the scalar sum of the transverse momenta of the jets, and the scalar sum of the missing transverse momentum and the transverse momentum of the lepton. Standard model background events are reduced significantly by requiring a large azimuthal angle between the direction of the lepton and of the reconstructed W boson, computed under the hypothesis that all of the missing transverse momentum in the event arises from a neutrino produced in the leptonic decay of the W boson. The numbers of observed events are consistent with the expectations from standard model processes, and the results are used to set lower limits on supersymmetric particle masses in the context of two simplified models of gluino pair production. In the first model, where each gluino decays to a top quark-antiquark pair and a neutralino, gluino masses up to 1.8 TeV are excluded at the 95% CL. The second model considers a three-body decay to a light quarkantiquark pair and a chargino, which subsequently decays to a W boson and a neutralino. In this model, gluinos are excluded up to 1.9 TeV.
Comparative Pharmacokinetics of the Complement Inhibitor CDX‐1135 (2013)

CDX‐1135 (sCR1) is a soluble, recombinant glycoprotein derived from the human complement regulatory protein Complement Receptor Type 1 (CR1, CD35, C3b/C4b receptor). CDX‐1135 inhibits the classical, alternative and lectin pathways of the complement cascade. CDX‐1135 is a single‐chain polypeptide of 1931 amino acids with approximately 35 kDa of N‐linked glycosylation. A pharmacokinetic study in rats was performed to compare four lots of CDX‐1135. Briefly, Sprague Dawley rats with jugular vein cannulas were administered a single intravenous injection of CDX‐1135 (10 mg/kg) in a lateral tail vein. Periodic blood samples were taken from the cannula, up to 96 hours after test article administration. Plasma was assayed for circulating levels of CDX‐1135 using an ELISA method. Lot A exhibited a mean AUC last of 1.32 × 10 6 hr*ng/ml compared to 1.85 × 10 6 hr*ng/ml for lot B, 2.22 × 10 6 hr*ng/ml for lot C, and 2.67 × 10 6 hr*ng/ml for lot D. Lot A exhibited a mean terminal half‐life of 22.6 hours compared to 24.9 hours for lot B, 21.8 hours for lot C, and 26.7 hours for lot D. These results can be explained by the rapid removal of CDX‐1135 molecules bearing asialo glycans, with the remaining molecules exhibiting very similar pharmacokinetics, as represented by the terminal half‐life. The pharmacokinetics of CDX‐1135, with slight variability between lots, is typical of many glycosylated recombinant proteins.
Amino acid and peptide hemin derivatives as new promising virucidal agents (2012)

We synthesized a series of hemin derivatives (HDs) substituted by residues of amino acids and peptides at either one or two propionic-acid residues, and studied the virucidal activity of the compounds obtained against herpes simplex virus. Compounds 6,7-bis-(methyl ester N 0 L-seryl)-protohemin (IX) (2) and 6,7-bis-[methyl ester N 0 -L-arginyl)-protohemin (IX) (6) shown the highest virucidal activity. We also investigated the interaction between HDs and lipid-membrane components as a possible mechanism of virucidal action. A model system including Clark's electrode and a micellar solution of methyl linoleate was used to quantitatively assess the capability of HDs to catalyze the oxidation of polyunsaturated fatty acids as components of lipid membranes. Another model system including liposomes that consisted of dioleoylphosphatydylcholine and was loaded with the fluorescent dye carboxyfluorescein was employed to examine the effect of HDs on lipid-membrane permeability. The kinetics and efficacy of increasing liposome-membrane permeability on exposure to HDs appeared to depend on the nature of the substituents in the HDs. The findings are strongly suggestive of the presence of two different modes of interaction between an HD and the lipid membrane, i.e. oxidative and non-oxidative mechanisms possibly underlie the virucidal action of HDs.
Benzo[a]pyrene Induces Apoptosis in RL95-2 Human Endometrial Cancer Cells by Cytochrome P450 1A1 Activation (2007)

Benzo[a]pyrene (B[a]P) has been shown to be an inducer of apoptosis in some cell types. To date, due to the lack of an appropriate model system, studies of the cellular and biochemical mechanism(s) by which B[a]P induces apoptosis have been focused on Hepa1c1c7 cells. Moreover, the precise relationship between the bioactivation of B[a]P by CYP1A1 or CYP1B1 and the occurrence of cytotoxicity-mediated apoptosis requires further elucidation. In the present study, we showed that B[a]P-induced apoptosis in RL95-2 cells is accompanied by the activation of caspases. In addition, the mitochondrial changes, including the decrease of mitochondrial potential and the release of mitochondrial cytochrome c and second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein binding protein with low PI (Smac/DIABLO) into the cytosol, support the suggestion that the mitochondrial pathway is robustly associated with B[a]P-evoked apoptosis. This study showed the involvement of the nuclear translocation of mitochondrial apoptosis-inducing factor in B[a]P-induced apoptosis of RL95-2 cells. Exposure to B[a]P up-regulates aryl hydrocarbon receptor, heat-shock protein 90, cytochrome P450 1A1 (CYP1A1), cytochrome P450 1B1 (CYP1B1), and epoxide hydrolase significantly, which might be prerequisites for the conversion of B[a]P to B[a]P-7,8-dihydroxy-9,10-epoxide. Although both CYP1A1 and CYP1B1 proteins were up-regulated significantly by B[a]P, only CYP1A1 exhibited activity. Thus, CYP1A1 is believed to be a central oxidative enzyme that is ultimately required for formation of B[a]P-7,8-dihydroxy-9,10-epoxide from B[a]P in RL95-2 cells. Altogether, our data showed that RL95-2 cells are susceptible to apoptosis by exposure to B[a]P and that B[a]P-evoked apoptosis is mediated predominantly by the activation of CYP1A1. Here we suggest that RL95-2 cells are an excellent model for the investigation of xenobiotic mechanisms associated with CYP1A1 as well as CYP1B1.
Design and Implementation of Multiplierless Adjustable Fractional-Delay All-Pass Filters (2005)

This paper describes an algorithm for finding the multiplierless coefficient representations for adjustable fractional-delay (AFD) all-pass filters. The optimization is performed in three basic steps. First, an initial filter is generated using a simple design scheme. Second, this filter is used as a start-up solution for the nonlinear optimization algorithm which is employed for determining a parameter space of the infinite-precision coefficients. This space includes the feasible space where the filter meets the given criteria. The third step involves finding the discrete coefficient values in this space so that the resulting filter meets the criteria with the simplest coefficient representation forms. Examples are included for illustrating the efficiency of the proposed synthesis scheme. In addition, the performance and the complexity of the multiplierless AFD all-pass filters are compared with those of the multiplierless AFD finite-impulse response filters implemented using the modified Farrow structure proposed by Vesma and Saramaki (1997). This comparison shows that the number of adders for the resulting filters are in the best case less than 50 percent compared with those implemented using the modified Farrow structure.
Loss of contractile function in hyperthermia: roles of oxidant production and arachidonic acid metabolism (2008)

The mechanisms for the loss of muscle contractile function in hyperthermia are poorly understood. Previously we demonstrated that oxidant production is elevated in skeletal muscle during hyperthermia, in part through pathways of arachidonic acid (AA) metabolism. Here, we hypothesized that scavenging of oxidants or blocking AA metabolism preserves function in hyperthermia. Rat diaphragm bundles were exposed to 30 min of 40, 41, 42 or 43ºC. Function was unaffected below 42 ºC but at 43ºC a significant loss of peak force (52.8±7.5% of baseline) and an increase in contracture were observed. Treatment with Tiron or Trolox during and after 43ºC exposure or treatment with DTT after exposure had no effect on loss of function. Lipoxygenase (LOX) and cyclooxygenase (COX) inhibitors (baicalein or ETYA; and indomethacin or ibuprofen, respectively) greatly decreased function and increased contracture at 42°C in a dose dependent manner, and even further at 43°C. The inhibitors decreased function to a greater extent when combined at 42°C (−67.9 &amp;#916;%max Force ±2.5). Treatment with the PLA2 inhibitor BEL (20&amp;#956;M) also decreased function at 43°C (−84.3 &amp;#916;%max Force ±3.8). Overall, results demonstrate that oxidant stress does not appear to contribute significantly to the loss of function in intact muscle, but AA metabolism through LOX and COX pathways are essential in protecting skeletal muscle during hyperthermia. NHLBI 53333
ChemInform Abstract: Unnatural Enantiomers of 5‐Azacytidine Analogues: Synthesis and Enzymatic Properties (2001)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Why direction-giving is hard: the complexity of using landmarks in one-dimensional navigation (1989)

The authors outline a formal model of topological navigation in one-dimensional spaces such as single roads. They formally define the concepts of direction giving and of custom map, as well as some specifications for feature detector models, including the idea of sensor synchronicity. The representations necessary to model and make use of differences between the world itself, the world as perceived by the map maker, and the world as experienced by the navigator are discussed. The difficulty of giving precise meaning to what is meant by a 'good' map is shown, and an operational definition of what is meant by a 'landmark' is given: regardless of starting position, any custom map can attain a landmark with but a single direction. It is shown that even in the simplest case, NP-complete problems arise in the efficient selection and sequencing of sensor modalities, even while attempting to navigate from one single object to another. A heuristic is provided that appears reasonable for map creation, and examples are given of several very different maps, each of which is optimal under eight reasonable criteria.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Influence of vinyl ester/styrene network structure on thermal and mechanical behavior (2001)

Abstract The influence of vinyl ester/styrene network structure on thermal and mechanical properties was investigated. The crosslink density of the resins was altered by changing the molecular weight of the vinyl ester oligomer and by varying the amount of styrene used during the crosslinking reaction leading to variations in both the physical network structure and the chemical composition of the polymeric networks. The glass transition temperatures of the network polymers were found to increase systematically with increasing crosslink density without the additional influence of the chemical composition as determined from both differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The breadth of the glass transition regions increased with crosslink density for the DSC data, but the breadth assessed from the DMA data did not vary significantly for the network materials. A secondary relaxation was observed for the materials using DMA, and this relaxation did not appear to be significantly affected by changes in either the crosslink density or the composition of the network. Cooperativity studies involving time–temperature scaling of dynamic mechanical data in the glass formation temperature region were also conducted. The degree of segmental cooperativity at T g appeared to be primarily influenced by the chemical composition of the networks. These issues dealing with the structure of the networks provided insight into the associated fracture properties in the glassy state (ambient temperature). Specifically, an empirically based linear correlation was found between the fracture toughness of the networks and the cooperative domain size at the glass transition temperature normalized by the crosslink density. © 2001 John Wiley &amp; Sons, Inc. J Appl Polym Sci 80: 917–927, 2001
Lateral substitution in the peripheral moieties of triphenylen-2,3,6,7,10,11-hexayl hexakis(4-alkoxybenzoate)s: dimethyl-substituted systems (1993)

Lateral substitution in the peripheral phenyl groups of the triphenylen-2,3,6,7,10,11-hexayl hexakis(4-alkoxybenzoate)s has been investigated via dimethyl substitution ortho to the terminal alkoxy chain or the ester linking group. Similarly, lateral methyl substitution in the terminal alkoxy chain was also investigated. The discotic mesogenic compounds were prepared by the esterification of 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP) with the respective 4-alkoxy-3,5- or 4-alkoxy-2,6-dimethylbenzoyl chlorides in the presence of pyridine. Thermal polarized light microscopy and differential scanning calorimetry were used to investigate the liquid-crystalline behaviour of the materials prepared. The compounds with dimethyl substitution in the 3 and 5 positions in the peripheral phenyl rings were found to exhibit the hexagonal disordered (Dhd) columnar mesophase and the discotic nematic mesophase (ND), whereas the analogous compounds with substitution at the 2 and 6 positions only exhibited discotic nematic (ND) mesophases. Thus, methyl substitution was found to suppress totally columnar phase formation in the second series of compounds, where the methyl groups were positioned pointing in towards the triphenylene core.
Retardation of CO2 Caused by Capillary Pressure Hysteresis: A New CO2 Trapping Mechanism (2011)

Summary Containment security of geologically stored CO2 is improved substantially through trapping mechanisms. Therefore, to simulate the potential viability of a storage site, it is necessary to account for immobilization processes. In this paper, we focus on a quantitative measure for the contribution of hysteresis in reducing plume transport, with particular emphasis on capillary-pressure-induced migration retardation. Rocks with large pore-body-to-throat-size ratio, or a low permeability, are the best candidates for this mechanism to be operative. In the present work, a self-consistent relative permeability and capillary pressure hysteresis model is incorporated within a simulator. With this model, it is possible to compare and contrast hysteresis-induced retardation to other mechanisms of trapping. The self-consistent parameterization of all of the transport properties is used to quantify sensitivity compactly. The sensitivity of the CO2-plume shape and the amount of CO2 trapped to the strength of the capillary pressure hysteresis is also described. Simulated results show that the CO2-plume shapes with and without capillary pressure hysteresis are significantly different. As expected, capillary pressure hysteresis retards the buoyant transport of the CO2 plume. Although a portion of the CO2 is connected, and therefore not residual, the plume remains immobile for all practical purposes. Also, because of the decreased driving potential, gravity tonguing below the caprock is reduced in comparison to the case without capillary pressure hysteresis, thus suggesting enhanced storage efficiency. However, the total dissolution of CO2 in saline water is reduced because of the reduced contact area with the brine. Thus, one mechanism of containment is offset by the other. Inclusion of accurate hysteresis models is important for qualifying storage sites constrained by spatial-domain limits. It is anticipated that site-acceptability criteria would change as a result of this study, thereby impacting risk evaluation.
The concept of risk and the value of novel markers of acute kidney injury (2013)

Kashani and colleagues studied two novel markers, insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinases-2, in the urine of patients at high risk of acute kidney injury (AKI). They validated these markers in a separate large multicenter study and compared them with known markers of AKI such as neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinases-2 performed better than other known markers and their combination provided additional information. These markers could be useful in clinical practice to uncover silent episodes of AKI or to make an early identification of patients at risk. Ultimately they could help to detect and possibly prevent episodes of acute injury to the kidney, sometimes referred to as kidney attack.
Nanoparticles restore lysosomal acidification defects: Implication for Parkinson and other lysosomal-related diseases (2016)

Lysosomal impairment causes lysosomal storage disorders (LSD) and is involved in pathogenesis of neurodegenerative diseases, notably Parkinson disease (PD). Strategies enhancing or restoring lysosomal-mediated degradation thus appear as tantalising disease-modifying therapeutics. Here we demonstrate that poly(DL-lactide-<i>co</i>-glycolide) (PLGA) acidic nanoparticles (aNP) restore impaired lysosomal function in a series of toxin and genetic cellular models of PD, i.e. ATP13A2-mutant or depleted cells or glucocerebrosidase (GBA)-mutant cells, as well as in a genetic model of lysosomal-related myopathy. We show that PLGA-aNP are transported to the lysosome within 24 h, lower lysosomal pH and rescue chloroquine (CQ)-induced toxicity. Re-acidification of defective lysosomes following PLGA-aNP treatment restores lysosomal function in different pathological contexts. Finally, our results show that PLGA-aNP may be detected after intracerebral injection in neurons and attenuate PD-related neurodegeneration <i>in vivo</i> by mechanisms involving a rescue of compromised lysosomes.