gebhart/patrepeval huggingface dataset:
New developments for antibody-drug conjugate-based therapeutic approaches (2016)

The clinical success of Adcetris(®) (brentuximab vedotin) and Kadcyla(®) (ado-trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window.
From molecules to mammals: what's NOS got to do with it? (2003)

Nitric oxide synthases (NOSs) generate nitric oxide (NO) and the by-product l-citrulline, via the catalytic combination of l-arginine and molecular oxygen. In mammals, there are three NOS genes: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). The molecular structure, enzymology and pharmacology of these enzymes have been well defined, and reveal critical roles for the NOS system in a variety of important processes. The studies of NOS enzymes using knockout and transgenic mouse models have provided an invaluable contribution, highlighting critical roles in neuronal, renal, pulmonary, gastro-intestinal, skeletal muscle, reproductive and cardiovascular biology. This review will outline the data gleaned from complementary knockout and transgenic over-expression models in mice, and focus on the interactions between NOS enzymes and pathophysiology of the vascular system. These studies are a paradigm for the near future, which will involve the translation of an enormous amount of genomic data into physiological insights that penetrate the realms of both health care and biology.
Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease (2017)

Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer's disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.
Genotyping of Burkholderia mallei from an Outbreak of Glanders in Bahrain Suggests Multiple Introduction Events (2014)

High-resolution genotyping and comparative whole genome analysis revealed the same phylogenetic patterns among our samples. The close relationship of the Dubai/UAE B. mallei populations to each other may be indicative of a similar geographic origin that has yet to be identified for the infecting strains. The recent emergence of glanders in combination with worldwide horse trading might pose a new risk for human infections.
Oxidized phospholipids as modulators of inflammation in atherosclerosis (2003)

During inflammatory processes biologically active lipid oxidation products accumulate that modulate the inflammatory process and may determine the fate and outcome of the body's reaction in acute inflammation during host defense. Oxidized phospholipids may induce and propagate chronic inflammatory processes; however, evidence is accumulating that cells and tissues respond towards these oxidatively formed stress signals also by activation of anti-inflammatory, cytoprotective reactions.
Pharmacological modulation of voltage-gated potassium channels as a therapeutic strategy (2010)

Development of new drugs that target Kv channels continue to be of great interest but is proving to be challenging. Nevertheless, opportunities for Kv channel modulators to have an impact on a wide range of disorders in the future remain an exciting prospect.
Appraisal of ethylene production as a test for defoliants (1975)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAppraisal of ethylene production as a test for defoliantsDavid T. Webb, Robert A. Darrow, and Gerald R. LeatherCite this: J. Agric. Food Chem. 1975, 23, 6, 1113–1115Publication Date (Print):November 1, 1975Publication History Published online1 May 2002Published inissue 1 November 1975https://pubs.acs.org/doi/10.1021/jf60202a007https://doi.org/10.1021/jf60202a007research-articleACS PublicationsRequest reuse permissionsArticle Views49Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Pharmacodynamics of Fluconazole in a Murine Model of Systemic Candidiasis (1998)

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.
Immune modulation by the cholera-like enterotoxins (2002)

The role of cholera toxin and heat-labile enterotoxin in the pathogenesis of diarrhoeal disease has been well documented for many years. In addition to these deleterious effects, a wealth of data is accumulating that suggests that these toxins and their subunits might be used to modulate immune responses in a variety of beneficial ways. In this regard, the toxins can boost immune responses to unrelated antigens, leading to the possibility of their use in the generation of improved vaccines to a variety of pathogens. Furthermore, recent evidence suggests that recombinant preparations of the nontoxic B subunits of the toxins have distinct immunomodulatory activities, with potential applications to the treatment of autoimmune and inflammatory diseases. This article reviews our current understanding of the mechanisms of immune modulation by these fascinating proteins.
Microfluidic probe: a new tool for integrating microfluidic environments and electronic wafer-probing (2009)

We demonstrate a new tool for integrating microfluidic channels with commonly used electronic probing techniques. The "microfluidic probe" allows rapid and repeatable fluidic and electronic addressing of small die sites on a variety of substrate types without the need for permanent modification or dicing of the device wafers. We also use the probe to demonstrate locally patterned chemical modification of a substrate. The probes are easily fabricated using standard soft-lithography and basic machining making this a widely accessible technique for electronics and fluidics researchers.
Triplet-triplet extinction coefficients via energy transfer (1971)

The triplet-triplet extinction coefficients of seventeen compounds have been determined in cyclohexane and benzene at room temperature by a method involving energy transfer. Large changes in extinction coefficient at the wavelength maximum Îµ(λmax) were observed upon changing solvent from cyclohexane to benzene. Values of Îµ(λmax) were determined relative to a value of Îµ(λmax) for the ketyl radical (ϕ2ĊOH) of 3220 M–1 cm–1 in water, assuming no change of oscillator strength with solvent. A number of triplet transfer rates, and other reactivities of benzophenone triplet and ketyl radicals, were also estimated.
Leucine degradation and release of glutamine and alanine by adipose tissue. (1980)

Adipose tissue from fed rats rapidly degrades [l14C]leucine to 14C02. This process is stimulated by glucose (but not by pyruvate) and by insulin, which also enhances the degradation of isoleucine and valine. Fasting and protein deficiency markedly reduced the catabolism of [l-‘4C]leucine in epididymal fat pads by decreasing the decarboxylation of a-ketoisocaproic acid and the transamination of leucine. In tissue homogenates, the rates of these reactions decreased by 63 and 47%, respectively, after 2 days of food deprivation. Within only 1 day of food deprivation, total decarboxylation of leucine in tissue homogenates was 73% slower. In adipose tissue from the fasted animals, leutine oxidation was also stimulated by glucose but not by insulin. In fat pads from fed (but not fasted) rats, leucine decreased the oxidation of pyruvate and thus may spare use of glucose-derived acetyl coenzyme A for lipogenesis. When fed and fasted rats were injected with [1-14CJleucine, their rates of expiration of 14C02 did not differ, but when they were injected with p-‘4C]leucine, 14C02 expiration was greater in the fasted rats. Therefore, food deprivation did not affect the total amount of leucine degradation by the organism but seemed to increase the oxidation of leucine by muscle, while decreasing its conversion to triglycerides. The incubated fat pads appear to synthesize and release large amounts of glutamine and smaller quantities of alanine and glutamate. Addition of leucine increased release into the medium of glutamine and, to a lesser extent, that of alanine and glutamate (without affecting tissue protein balance or the release of other amino acids). In fasting, when degradation of leucine fell, the accumulation of glutamine and alanine in the medium decreased. Isoleucine and valine were degraded more slowly than leucine and stimulated glutamine and alanine release to a lesser extent. In adipose tissue, as in muscle, production of glutamine, as well as alanine and glutamate, seems to be the route for disposal of amino groups released in the transamination of branched-chain amino acids.
Fluorescence Resonance Energy Transfer Between Quantum Dot Donors and Dye-Labeled Protein Acceptors (2003)

We used luminescent CdSe-ZnS core-shell quantum dots (QDs) as energy donors in fluorescent resonance energy transfer (FRET) assays. Engineered maltose binding protein (MBP) appended with an oligohistidine tail and labeled with an acceptor dye (Cy3) was immobilized on the nanocrystals via a noncovalent self-assembly scheme. This configuration allowed accurate control of the donor-acceptor separation distance to a range smaller than 100 A and provided a good model system to explore FRET phenomena in QD-protein-dye conjugates. This QD-MBP conjugate presents two advantages: (1) it permits one to tune the degree of spectral overlap between donor and acceptor and (2) provides a unique configuration where a single donor can interact with several acceptors simultaneously. The FRET signal was measured for these complexes as a function of both degree of spectral overlap and fraction of dye-labeled proteins in the QD conjugate. Data showed that substantial acceptor signals were measured upon conjugate formation, indicating efficient nonradiative exciton transfer between QD donors and dye-labeled protein acceptors. FRET efficiency can be controlled either by tuning the QD photoemission or by adjusting the number of dye-labeled proteins immobilized on the QD center. Results showed a clear dependence of the efficiency on the spectral overlap between the QD donor and dye acceptor. Apparent donor-acceptor distances were determined from efficiency measurements and corresponding Förster distances, and these results agreed with QD bioconjugate dimensions extracted from structural data and core size variations among QD populations.
Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding (2011)

Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ∼ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases.
Variation in Expression of hsp27 Messenger Ribonucleic Acid during the Cycle of the Seminiferous Epithelium and Co-Localization of hsp27 and Microfilaments in Sertoli Cells of the Rat1 (1996)

The purpose of these studies was to define expression of hsp27 mRNA during the cycle of the seminiferous epithelium and to determine the distribution of hsp27 protein in the rat testis. To study hsp27 mRNA expression, a rat hsp27 cDNA was isolated and sequenced (GenBank no. M86389). The cDNA was used in Northern blot analysis to estimate the relative levels of hsp27 mRNA in rat seminiferous tubule segments selected for different stages of the cycle of the seminiferous epithelium. The level of hsp27 mRNA was low during stages IX-XII of the cycle of the seminiferous epithelium. Approximately 15-fold higher levels of hsp27 mRNA were expressed during stages II-VI, with intermediate levels being expressed during stages XIII-I and VII-VIII. No effect of FSH on hsp27 mRNA expression was detected in cultured Sertoli cells, suggesting that hsp27 synthesis in Sertoli cells is not directly regulated by FSH. The distribution of hsp27 was also studied by use of immunofluorescence in frozen sections of rat testis, in isolated seminiferous tubules, in primary cultures of Sertoli cells isolated from 19-26-day-old rats, in peritubular myoid cells from 26-day-old rats, and in several cell lines. Microfilaments were localized in similar preparations by using rhodamine-phalloidin or BODIPY-phallicidin (Molecular Probes, Eugene, OR). The hsp27 was co-localized with micro-filaments in Sertoli cells from 20-day-old and older rats, but not in Sertoli cells from younger rats. In other cell types, hsp27 was diffusely distributed throughout the cytoplasm. These results demonstrate that hsp27 expression varies with the cycle of the seminiferous epithelium and provide the first direct morphological evidence that hsp27 is associated with microfilaments in a normal, intact tissue. They also suggest that Sertoli cell micro-filaments, by virtue of their associated hsp27, may be different in composition and function from microfilaments of peritubular myoid cells and many other cell types.
Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics (2016)

We have used the site-directed spectroscopies of time-resolved fluorescence resonance energy transfer (TR-FRET) and double electron-electron resonance (DEER), combined with complementary molecular dynamics (MD) simulations, to resolve the structure and dynamics of cardiac myosin-binding protein C (cMyBP-C), focusing on the N-terminal region. The results have implications for the role of this protein in myocardial contraction, with particular relevance to β-adrenergic signaling, heart failure, and hypertrophic cardiomyopathy. N-terminal cMyBP-C domains C0-C2 (C0C2) contain binding regions for potential interactions with both thick and thin filaments. Phosphorylation by PKA in the MyBP-C motif regulates these binding interactions. Our spectroscopic assays detect distances between pairs of site-directed probes on cMyBP-C. We engineered intramolecular pairs of labeling sites within cMyBP-C to measure, with high resolution, the distance and disorder in the protein's flexible regions using TR-FRET and DEER. Phosphorylation reduced the level of molecular disorder and the distribution of C0C2 intramolecular distances became more compact, with probes flanking either the motif between C1 and C2 or the Pro/Ala-rich linker (PAL) between C0 and C1. Further insight was obtained from microsecond MD simulations, which revealed a large structural change in the disordered motif region in which phosphorylation unmasks the surface of a series of residues on a stable α-helix within the motif with high potential as a protein-protein interaction site. These experimental and computational findings elucidate structural transitions in the flexible and dynamic portions of cMyBP-C, providing previously unidentified molecular insight into the modulatory role of this protein in cardiac muscle contractility.
Selective Transfer of Individual Human Chromosomes to Recipient Cells (1985)

Two hypoxanthine phosphoribosyltransferase-deficient human cell lines, D98/AH-2 and HT1080-6TG, were stably transfected with pSV2 gpt, a plasmid containing the selectable marker Escherichia coli xanthine-guanine phosphoribosyl transferase (Eco gpt). Hypoxanthine-aminopterin-thymidine-resistant transformants arose with a frequency of ca. 10(-6) and contained mostly single, but occasionally multiple, copies of the plasmid sequences. These transformants actively express the Eco gpt marker. Single chromosomes from two different HT1080 gpt transformants and one D98 gpt transformant, containing the integrated plasmid sequences, were transferred via microcell-mediated chromosome transfer to hypoxanthine phosphoribosyl transferase-deficient mouse A9 cells. The transferred human chromosomes were identified as 2, 4, and 22, by using a combination of G-11 staining, G-banding, isoenzyme analysis, and in situ hybridization. This system is being used to create a library of interspecies microcell hybrid clones, each clone containing a unique single human chromosome in a mouse background. The complete library will represent the entire human karyotype.
Specific antigen of murine erythroblasts (1976)

A new antigan has been revealed by means of antisera against Rauscher virus in mice with Rauscher virus-induced leukemia. This antigen appears to be different from both Rauscher type-specific antigen and MULV-gs-1 (p-30), as shown by studies of electrophoretic mobility and immunochemical specificity. Except in leukemic mice it was also found in low levels in both serum and spleen extracts of healthy mice of a number of strains. Furthermore, this antigen was regularly demonstrated by immunofluorescence on the surface of erythroblasts, but not on the surface of erythrocytes, lymphocytes, polymorphonuclear cells and thymocytes, and was shown to be different from fetal hemoglobin. Therefore, it is referred to as antigen of erythroblasts (Ag-Eb), which seems to represent a surface marker for a certain differentiation stage of erythroid cells.
Three-dimensional object-distortion-tolerant recognition for integral imaging using independent component analysis (2009)

Independent component analysis (ICA) aims at extracting unknown components from multivariate data assuming that the underlying components are mutually independent. This technique has been successfully applied to the recognition and classification of objects. We present a method that combines the benefits of ICA and the ability of the integral imaging technique to obtain 3D information for the recognition of 3D objects with different orientations. Our recognition is also possible when the 3D objects are partially occluded by intermediate objects.
Stimulus Specificity of Phase-Locked and Non-Phase-Locked 40 Hz Visual Responses in Human (1996)

Considerable interest has been raised by non-phase-locked episodes of synchronization in the gamma-band (30-60 Hz). One of their putative roles in the visual modality is feature-binding. We tested the stimulus specificity of high-frequency oscillations in humans using three types of visual stimuli: two coherent stimuli (a Kanizsa and a real triangle) and a noncoherent stimulus ("no-triangle stimulus"). The task of the subject was to count the occurrences of a curved illusory triangle. A time-frequency analysis of single-trial EEG data recorded from eight human subjects was performed to characterize phase-locked as well as non-phase-locked high-frequency activities. We found in early phase-locked 40 Hz component, maximal at electrodes Cz-C4, which does not vary with stimulation type. We describe a second 40 Hz component, appearing around 280 msec, that is not phase-locked to stimulus onset. This component is stronger in response to a coherent triangle, whether real or illusory: it could reflect, therefore, a mechanism of feature binding based on high-frequency synchronization. Because both the illusory and the real triangle are more target-like, it could also correspond to an oscillatory mechanism for testing the match between stimulus and target. At the same latencies, the low-frequency evoked response components phase-locked to stimulus onset behave differently, suggesting that low- and high-frequency activities have different functional roles.