gebhart/patrepeval huggingface dataset:
α-Isopropylmalate, a Leucine Biosynthesis Intermediate in Yeast, Is Transported by the Mitochondrial Oxalacetate Carrier (2008)

In Saccharomyces cerevisiae, alpha-isopropylmalate (alpha-IPM), which is produced in mitochondria, must be exported to the cytosol where it is required for leucine biosynthesis. Recombinant and reconstituted mitochondrial oxalacetate carrier (Oac1p) efficiently transported alpha-IPM in addition to its known substrates oxalacetate, sulfate, and malonate and in contrast to other di- and tricarboxylate transporters as well as the previously proposed alpha-IPM transporter. Transport was saturable with a half-saturation constant of 75 +/- 4 microm for alpha-IPM and 0.31 +/- 0.04 mm for beta-IPM and was inhibited by the substrates of Oac1p. Though not transported, alpha-ketoisocaproate, the immediate precursor of leucine in the biosynthetic pathway, inhibited Oac1p activity competitively. In contrast, leucine, alpha-ketoisovalerate, valine, and isoleucine neither inhibited nor were transported by Oac1p. Consistent with the function of Oac1p as an alpha-IPM transporter, cells lacking the gene for this carrier required leucine for optimal growth on fermentable carbon sources. Single deletions of other mitochondrial carrier genes or of LEU4, which is the only other enzyme that can provide the cytosol with alpha-IPM (in addition to Oac1p) exhibited no growth defect, whereas the double mutant DeltaOAC1DeltaLEU4 did not grow at all on fermentable substrates in the absence of leucine. The lack of growth of DeltaOAC1DeltaLEU4 cells was partially restored by adding the leucine biosynthetic cytosolic intermediates alpha-ketoisocaproate and alpha-IPM to these cells as well as by complementing them with one of the two unknown human mitochondrial carriers SLC25A34 and SLC25A35. Oac1p is important for leucine biosynthesis on fermentable carbon sources catalyzing the export of alpha-IPM, probably in exchange for oxalacetate.
Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes (2012)

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.
Effects of metopimazine on gastro-intestinal and biliary tract smooth muscle in vitro. (1980)

The effects of the phenothiazine derivative metopimazine on the spontaneous or induced activities of guinea-pig isolated stomach and of the rabbit biliary and intestinal tracts were studied. A predominant inhibitory effect was observed except for the circular muscle layers of the duodenum and colon where activation appeared. Evidence from in vitro experiments suggest that metopimazine exerts an inhibitory action partly through a direct effect on smooth muscle cells and partly by reducing stimulated acetylcholine release (at least in the stomach). Finally the involvement of a non-adrenergic, non-cholinergic inhibitory system is postulated.
Targeted therapy of experimental renal cell carcinoma with a novel conjugate of monoclonal antibody 138H11 and calicheamicin thetaI1. (2000)

In search for a new therapeutic approach for metastasized renal cell carcinoma (RCC), we evaluated the cytotoxicity of a novel prodrug chemoimmunoconjugate with monoclonal antibody (mAb) 138H11 and the DNA-cleaving enediyne calicheamicin thetaI1 (Camtheta) in vitro and in vivo. Previously, mAb 138H11, produced against human renal gamma-glutamyltransferase, stained over 99% clear cell and papillary RCC on frozen sections, showing a membranous expression of the target antigen. In contrast, in normal kidneys gammaGT was restricted to the brush-border in the lumen of proximal tubules and not accessible to the circulation. Thus, human tumor-bearing kidneys perfused in an extra-corporeal system with 99mTc-138H11 revealed a high, specific uptake into the tumor. In this study, fluorescence-activated cell sorting analysis showed binding of mAb 138H11 to RCC cell lines, whereas squamous cell carcinoma lines, fibroblasts, and the murine RENCA were negative. XTT cell proliferation assays revealed efficient killing of the Caki-1 cell line by the 138H11-Camtheta conjugate using SPDP (EC50 = 5 x 10(-11) M) as a covalent linker. For in vivo testing, five groups of eight nude mice each were injected with 2.5 x 10(6) Caki-1 cells s.c. and treated with the following: (a) PBS; (b) 138H11; (c) Camtheta; (d) a mixture of 138H11 and Camtheta; and (e) 138H11-Camtheta conjugate. Treatment started on day 1 after tumor induction and was repeated three times. The data show a highly significant inhibition of tumor growth with the 138H11-Camtheta conjugate versus PBS (P = 0.004). Only mice treated with 138H11-Camtheta showed a tumor shrinkage to minimal residues. In a second experiment, lower doses of the 138H11-Camtheta conjugate were compared with an antineuroblastoma mAb (ch14.18), confirming targeted killing of RCC by the 138H11-Camtheta conjugate at tolerable toxicity in vivo. In conclusion, these combined results encourage further studies for targeted therapy of metastatic RCC with mAb 138H11 conjugates.
A new combination-erase technique for erasing nitride based (SONOS) nonvolatile memories (2003)

A new technique of erasing nonvolatile memory (NVM) devices based on nitride storage (SONOS) with bottom oxide thickness in the range of 30 /spl Aring/ has been developed. Oxide thickness in this range is necessary to minimize the undesirable effects of gate disturb while still enabling a low-voltage operation to maximize the cost benefit of SONOS memories. To erase such bitcells, Fowler-Nordheim tunneling (FNT) is preferred over hot-hole injection (HHI) due to the less damaging nature of FNT. However, FNT alone cannot be used to erase the device completely due to erase saturation limitations. Hence, the new "combination-erase" technique combines both FNT and HHI erase to achieve a fast and controlled erase. Furthermore, by using FNT erase at higher field conditions, and HHI erase at lower field conditions, the reliability of the bitcell is also improved.
Endbulb synapses in the anteroventral cochlear nucleus express a specific subset of AMPA-type glutamate receptor subunits. (1998)

The anteroventral cochlear nucleus (AVCN) acts as the first relay center in the conduction of auditory information from the ear to the brain, and it probably performs a crucial role in sound localization. Auditory nerve input to the principal neurons of the AVCN, the spherical bushy cells, appears to be mediated by an excitatory amino acid such as glutamate, which acts at a specialized, large synaptic ending called an endbulb of Held. Presumably, endbulb synapses contain some specific combination of glutamate receptors to facilitate rapid neurotransmission of auditory signals. AMPA glutamate receptor composition at the endbulb synapses was examined with both light and electron microscope immunocytochemistry. Electron microscope localization of AMPA receptors was examined with two techniques, preembedding immunoperoxidase and postembedding immunogold, which provide maximum sensitivity and greatest accuracy, respectively. Dense and frequent labeling was seen with the AMPA receptor subunit antibodies GluR2/3 and GluR4, which were colocalized at the endbulb synapses. In contrast, immunolabeling with antibody to GluR2 was low. These data indicate that the major glutamate receptor at this synapse is an AMPA receptor made up mainly of GluR3 and GluR4 subunits. Receptors composed of these subunits display properties, such as calcium permeability and rapid desensitization, that facilitate their specialized functions in auditory information processing.
Cutting Edge: Depletion of Foxp3+ Cells Leads to Induction of Autoimmunity by Specific Ablation of Regulatory T Cells in Genetically Targeted Mice (2009)

We have recently described two independent mouse models in which the administration of diphtheria toxin (DT) leads to specific depletion of regulatory T cells (Tregs) due to expression of DT receptor-enhanced GFP under the control of the Foxp3 promoter. Both mouse models develop severe autoimmune disorders when Foxp3(+) Tregs are depleted. Those findings were challenged in a recent study published in this journal suggesting the expression of Foxp3 in epithelial cells as the cause for disease development. By using genetic, cellular, and immunohistochemical approaches, we do not find evidence for Foxp3-expression in nonhematopoietic cells. DT injection does not lead to a loss of epithelial integrity in our Foxp3-DTR models. Instead, Foxp3 expression is Treg-specific and ablation of Foxp3(+) Tregs leads to the induction of fatal autoimmune disorders. Autoimmunity can be reversed by the adoptive transfer of Tregs into depleted hosts, and the transfer of Foxp3-deficient bone marrow into T cell-deficient irradiated recipients leads to full-blown disease development.
A Spatial Filtering Specification for the Autologistic Model (2004)

The autologistic model describes binary correlated data; its spatial version describes georeferenced binary data exhibiting spatial dependence. The conventional specification of a spatial autologistic model involves difficult-to-nearly-impossible computations to ensure that appropriate sets of probabilities sum to 1. Work summarized here accounts for spatial autocorrelation by including latent map pattern components as covariates in a model specification. These components derive from the surface zonation scheme used to aggregate attribute data, to construct a geographic weights matrix, and to evaluate geographic variability. The illustrative data analysis is based upon field plot observations for the pathogen Phytophthora capsici that causes disease in pepper plants. Results are compared with pseudolikelihood and Markov chain Monte Carlo estimation techniques, both for the empirical example and for two simulation experiments associated with it. The principal finding is that synthetic map pattern variables, which are eigenvectors computed for a geographic weights matrix, furnish an alternative, successful way of capturing spatial dependency effects in the mean response term of a logistic regression model, avoiding altogether the need to use other than traditional standard techniques to estimate model parameters.
Non-local polymerization driven diffusion based model: general dependence of the polymerization rate to the exposure intensity (2003)

The nonlocal diffusion model proposed by Sheridan and coworkers has provided a useful interpretation of the nature of grating formation inside photopolymer materials. This model accounts for some important experimental facts, such as the cut-off of diffraction efficiency for high spatial frequencies. In this article we examine the predictions of the model in the case of a general dependence of the polymerisation rate with respect to the intensity pattern. The effects of this dependence on the different harmonic components of the polymerisation concentration will be investigated. The influence of the visibility on the different harmonic components will also be studied. These effects are compared to the effects of varying RD and sigmaD.
Scope of the Suzuki−Miyaura Cross-Coupling Reactions of Potassium Heteroaryltrifluoroborates (2008)

A wide variety of bench-stable potassium heteroaryltrifluoroborates were prepared, and general reaction conditions were developed for their cross-coupling to aryl and heteroaryl halides. The cross-coupled products were obtained in good to excellent yields. This method represents an efficient and facile installation of heterocyclic building blocks onto preexisting organic substructures.
Wnt Signaling as a Therapeutic Target for Cancer (2006)

The Wnt/beta-catenin signaling pathway is tightly regulated and has important functions in development, tissue homeostasis, and regeneration. Deregulation of Wnt/beta-catenin signaling is frequently found in various human cancers. Eighty percent of colorectal cancers alone reveal activation of this pathway by either inactivation of the tumor-suppressor gene adenomatous polyposis coli or mutation of the proto-oncogene beta-catenin. Activation of Wnt/beta-catenin signaling has been found to be important for both initiation and progression of cancers of different tissues. Therefore, targeted inhibition of Wnt/beta-catenin signaling is a rational and promising new approach for the therapy of cancers of various origins.
A prion protein variant in a family with the telencephalic form of Gerstmann‐Straussler‐Scheinker syndrome (1991)

We present a patient with a mutation in the open reading frame of the prion protein gene (PRNP), which results in substitution of valine for alanine at codon 117. The patient is a member of a large American kindred of German descent with the telencephalic form of Gerstmann-Sträussler-Scheinker syndrome (GSS). Two other affected members of this kindred carried this mutation, as inferred from haplotypes of their offspring and spouses. The mutation was absent in one member with a protracted neurologic illness that differed from the other affected members' illnesses. The identification of a distinct PRNP mutation in the telencephalic form of GSS supports the hypothesis that allelic forms of PRNP may correspond to distinct clinical disease entities.
Timing of RFID Adoption in a Supply Chain (2009)

This paper studies the incentives behind the adoption of radio-frequency identification (RFID) in a supply chain. One prominent feature of RFID technology is that once RFID tags are attached on the items at an upstream site, the same tags can be reused at its downstream sites at lower or zero variable cost. This creates an interesting, one-sided “free-rider” problem, where the downstream would wait to free-ride on the upstream's first move, but not vice versa. Using a stylized game-theoretic model, we characterize the equilibrium strategies of the two firms. Compared to the first-best solution, firms in equilibrium tend to adopt too late. We then study the dual benefits of technology coordination between the two firms and find that it would not only save redundant costs of putting tags, but also speed up the downstream's RFID adoption. We also show that the equal-cost-split arrangement shifts the benefit of free-riding to the upstream, thereby mitigating the negative impacts in many cases. But it may distort the market when it operates in the optimal manner. The general message of the model is that technology coordination and cost-split each contribute to the mitigation of the free-rider problem in RFID adoption.
A 96-channel neural stimulation system for driving AIROF microelectrodes (2005)

We present the design and testing of a 96-channel stimulation system to drive activated iridium oxide (AIROF) microelectrodes within safe charge-injection limits. Our system improves upon the traditional capacitively coupled, symmetric charge-balanced biphasic stimulation waveform so as to maximize charge-injection capacity without endangering the microelectrodes. It can deliver computer-controlled cathodic current pulse for to up to 96 AIROF microelectrodes and positively bias them during the inter-pulse interval. The stimulation system is comprised of (1) 12 custom-designed PCB boards each hosting an 8-channel ASIC chip, (2) a motherboard to communicate between these 12 boards and the PC, (3) the PC interface equipped with a DIO card and the corresponding software. We plan to use this system in animal experiments for intracortical neural stimulation of implanted electrodes within our visual prosthesis project.
Resolving LAL Test interferences. (1990)

A greater understanding of the nature of LAL-Test interferences and the use of permissible dilution have minimized inhibition problems. Common interference mechanisms include suboptimal pH, endotoxin aggregation or adsorption, container effects, unbalanced cation concentration, enzyme or protein modification, and non-specific LAL activation. Dilution is the best approach to resolving interferences because over 90% are concentration dependent and are solved by the 1:40 dilution with LAL Reagent Water. Other problems are approached by using dilution plus a specific pretreatment procedure designed to neutralize the offending mechanism.
Age and the Prevalence of Bleeding Disorders in Women With Menorrhagia (2005)

These results demonstrate that underlying bleeding disorders are frequently found in adolescent, postadolescent reproductive age, and perimenopausal-age women presenting with menorrhagia and suggest that women with menorrhagia should be considered for further hemostatic evaluation.
Neurexins: Synaptic Cell Surface Proteins Related to the α-Latrotoxin Receptor and Laminin (1992)

A family of highly polymorphic neuronal cell surface proteins, the neurexins, has been identified. At least two genes for neurexins exist. Each gene uses alternative promoters and multiple variably spliced exons to potentially generate more than a 100 different neurexin transcripts. The neurexins were discovered by the identification of one member of the family as the receptor for alpha-latrotoxin. This toxin is a component of the venom from black widow spiders; it binds to presynaptic nerve terminals and triggers massive neurotransmitter release. Neurexins contain single transmembrane regions and extracellular domains with repeated sequences similar to sequences in laminin A, slit, and agrin, proteins that have been implicated in axon guidance and synaptogenesis. An antibody to neurexin I showed highly concentrated immunoreactivity at the synapse. The polymorphic structure of the neurexins, their neural localization, and their sequence similarity to proteins associated with neurogenesis suggest a function as cell recognition molecules in the nerve terminal.
Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograft and in Monkeys (2005)

The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.
Steroid antagonists and receptor-associated proteins (1994)

Journal Article Steroid antagonists and receptor-associated proteins Get access Marie-Claire Lebeau, Marie-Claire Lebeau INSERM U 33, 80 rue du Général Leclerc94276 Bicêtre Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Etienne Emile Baulieu Etienne Emile Baulieu INSERM U 33, 80 rue du Général Leclerc94276 Bicêtre Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Reproduction, Volume 9, Issue suppl_2, 1 June 1994, Pages 11–21, https://doi.org/10.1093/humrep/9.suppl_2.11 Published: 01 June 1994
Chemical strategies for bicyclic peptide formation (2015)

The chemical constraint of proteins has been demonstrated to improve the binding affinity of peptide ligands as well as improving properties such as cell penetrability and resistance to proteases. In this work two new chemical methodologies are presented for such constraint, widening the diversity of peptide structures available starting from a single linear peptide sequence. The combination of these chemical modifications with a library of peptide sequences access new classes of constrained peptides which bind protein surfaces. Such molecules could potentially be used in similar applications to antibodies: therapeutics, diagnostics, and molecular biology research tools.&#13;\n&#13;\nA two-step strategy to produce stereochemically diverse bicyclic peptides has been developed where the first step involves the conversion of multiple cysteine residues to dehydroalanines. The application of methyl 2,5-dibromovalerate proved superior for this transformation when compared to other chemical modification methodologies. The second step of the strategy involved cyclisation via nucleophilic attack at the dehydroalanine residues by a small molecule core bearing multiple thiol functional groups – generating an alkylated L- or D- cysteine in the peptide sequence. The effect of scrambling the stereochemistry at each of these positions is exemplified via the use of a human plasma kallikrein inhibitor PK15 as a model system.&#13;\n&#13;\nAn alternative strategy to create diverse bicyclic peptides involved the synthesis of a new core molecule based upon Barbas reagent. The core molecule bearing three 2 mesyl 1,3,4 oxadiazole moieties cyclised peptides containing three cysteines efficiently - constraining peptide loops in distinctly different structures from other established core molecules. Attempts were made to create a phagemid-encoded phage display library of peptides to subsequently modify with these chemical methodologies.&#13;\n&#13;\nA phage display library of Adhirons was screened for binders to the antifungal drug posaconazole. Adhirons are a non-antibody binding protein scaffold bearing variable peptide loops. The screening relied upon chemical derivatisation of the posaconazole structure to enable both screening and hit characterisation.&#13;\n
DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA·TTC repeats in Friedreich's ataxia (2006)

The DNA abnormality found in 98% of Friedreich's ataxia (FRDA) patients is the unstable hyperexpansion of a GAA.TTC triplet repeat in the first intron of the frataxin gene. Expanded GAA.TTC repeats result in decreased transcription and reduced levels of frataxin protein in affected individuals. Beta-alanine-linked pyrrole-imidazole polyamides bind GAA.TTC tracts with high affinity and disrupt the intramolecular DNA.DNA-associated region of the sticky-DNA conformation formed by long GAA.TTC repeats. Fluorescent polyamide-Bodipy conjugates localize in the nucleus of a lymphoid cell line derived from a FRDA patient. The synthetic ligands increase transcription of the frataxin gene in cell culture, resulting in increased levels of frataxin protein. DNA microarray analyses indicate that a limited number of genes are significantly affected in FRDA cells. Polyamides may increase transcription by altering the DNA conformation of genes harboring long GAA.TTC repeats or by chromatin opening.