gebhart/patrepeval huggingface dataset:
Novel HSP90 Inhibitor NVP-HSP990 Targets Cell-Cycle Regulators to Ablate Olig2-Positive Glioma Tumor–Initiating Cells (2013)

Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor-initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.
Quick Assembly of 1,4-Diphenyltriazoles as Probes Targeting β-Amyloid Aggregates in Alzheimer's Disease (2007)

Accumulation of beta-amyloid aggregates (Abeta) in the brain is linked to the pathogenesis of Alzheimer's disease (AD). We report a novel approach for producing 1,4-diphenyltriazoles as probes for targeting Abeta aggregates in the brain. The imaging probes, a series of substituted tricyclic 1,4-diphenyltriazoles showing excellent binding affinities to Abeta aggregates (Ki = 4-30 nM), were conveniently assembled by "click chemistry." Two radioiodinated probes, [125I]10a and [125I]10b, and two radiofluorinated probes, [18F]17a and [18F]17b, exhibited moderate lipophilicities and showed excellent initial brain penetrations and fast washouts from the normal mouse brain. In vitro autoradiography of postmortem AD brain sections and homogenates showed that these triazoles were binding to Abeta plaques. Preliminary results strongly suggest that use of click chemistry, which led to a 1,4-diphenyltriazole-based core, is a highly convenient and flexible approach for assembling novel imaging agents for targeting Abeta aggregates in senile plaques in the living human brain.
Glucosylceramide synthase activity in murine epidermis: quantitation, localization, regulation, and requirement for barrier homeostasis (1998)

Ceramides, which derive from the hydrolysis of glucosylceramide (GlcCer), are the predominant lipid species in the stratum corneum and are critical for epidermal permeability barrier homeostasis. UDP-glucose:ceramide glucosyltransferase (GlcCer synthase) (EC 2.4.1.80) catalyzes the glucosylation of ceramide to form GlcCer. Recently, we demonstrated a progressive increase in GlcCer synthase expression during fetal barrier development, while others have reported increased GlcCer synthase activity with differentiation of cultured human keratinocytes. To further delineate the role of GlcCer synthase in barrier homeostasis, we determined GlcCer synthase activity and localization in hairless mouse epidermis, both under basal conditions and after acute barrier perturbation. Under basal conditions, GlcCer synthase activity localizes predominantly (approximately 80%) to the dithiothreitol-separated outer epidermis; i.e., 6.2+/-0.6 versus 1.2+/-0.1 pmol/min/mg for outer vs. lower epidermis, respectively (P < 0.0001). Although acute barrier disruption does not up-regulate epidermal GlcCer synthase activity at any time point up to 24 h, GlcCer synthase is required for barrier homeostasis: topical d,1-threo-1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol (P4), a specific GlcCer synthase inhibitor, applied immediately after acute barrier disruption, causes a delay in barrier recovery attributable to specific enzyme inhibition. These findings demonstrate first, that GlcCer synthase activity predominates in the outer epidermis, consistent with an increased formation of GlcCer during barrier ontogenesis and maintenance. Second, GlcCer synthase activity is required for normal permeability barrier homeostasis. Third, baseline epidermal GlcCer synthase activity appears to accommodate acute challenges to the barrier.
Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography (2007)

Bleeding is the major adverse reaction to anticoagulants, leading to significant morbidity and even mortality. Protamine is a specific antidote for heparin yet is only partially effective for enoxaparin, and the activated factor X inhibitor fondaparinux and the direct thrombin inhibitors argatroban and bivalirudin lack specific antidotes. We evaluated the ability of recombinant activated factor VII (rFVIIa), a general hemostatic agent, to reverse the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, as measured by thromboelastography. Whole-blood samples containing each test anticoagulant, with or without rFVIIa 1.5-4.5 microg/ml, were prepared ex vivo (n >or= 48, each anticoagulant) and analyzed by thromboelastography. The thromboelastography parameters of clot initiation, propagation, rigidity and elasticity were compared for the ex-vivo samples for each anticoagulant. The reversal ability of rFVIIa was also assessed using the standard clinical assay used to monitor each anticoagulant. Thromboelastography was performed on blood from eight stably anticoagulated patients, with and without exogenous rFVIIa. For each anticoagulant, rFVIIa significantly improved and, in some cases, completely normalized all thromboelastography parameters (P < 0.001). rFVIIa significantly (P < 0.01) decreased the activated partial thromboplastin time for argatroban-containing, bivalirudin-containing, or heparin-containing blood yet did not affect the anti-activated factor X levels for enoxaparin-containing or fondaparinux-containing blood. By thromboelastography, rFVIIa exerted generally similar reversal effects on the anticoagulated patient samples as on the ex-vivo samples. In conclusion, rFVIIa effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, and should be considered for patients with excessive bleeding associated with these anticoagulants.
Discriminative Object Class Models of Appearance and Shape by Correlatons (2006)

This paper presents a new model of object classes which incorporates appearance and shape information jointly. Modeling objects appearance by distributions of visual words has recently proven successful. Here appearancebased models are augmented by capturing the spatial arrangement of visual words. Compact spatial modeling without loss of discrimination is achieved through the introduction of adaptive vector quantized correlograms, which we call correlatons. Efficiency is further improved by means of integral images. The robustness of our new models to geometric transformations, severe occlusions and missing information is also demonstrated. The accuracy of discrimination of the proposed models is assessed with respect to existing databases with large numbers of object classes viewed under general conditions, and shown to outperform appearance-only models.
Poster Presentations, pp. 80–103 (2008)

We have previously described 4 GHTD children with severe growth delay and impaired phosphorylation of STAT3 who responded to hGH therapy. These children showed over-expression of the negative regulator CIS. Objective: To examine the association of protein degradation of the GH receptor (GHR) and the cellular localization of GHR due to CIS over-expression as possible molecular mechanisms of GHTD. Methods: In fibroblasts from gingival biopsies of 4 controls and 4 GHTD patients we studied by immunofluorescent microscopy (IF) the expression and localization of GHR, Ub and CIS at basal level and after induction with 200ng/ml or 1000ng/ml GH with or without 15M of the proteasome inhibitor lactacystin. Proteasome activity was studied by Proteasome-Glo Cell Based Assay. Results: 1) Significant differences in the localization of the GHR were found by IF: The control's fibroblasts (C) showed both membrane and cytoplasmic localization of GHR in contrast to the GHTD fibroblasts (GF) that had mainly cytoplasmic localization of GHR near the nucleus, 2) induction with 200 or 1000 ng/ml hGH did not cause any changes in the localization of GHR in the GF, 3) induction with lactacystin or with lactacystin/hGH changed the localization of GHR in the GF to mainly membrane accumulation without the previously seen cytoplasmic accumulation. 4) Over-expression of CIS and Ub protein were observed also by IF in GHTD fibroblasts. 5) The GF at baseline showed 50% increase of the proteasome activity in comparison to the C. Treatment of the GF cells with 15M lactacystin decreased the proteasome activity to the level of the control fibroblasts. Conclusions: It appears that increased protein degradation of GHR/JAK2 in GHTD via the proteasome is probably mediated by the over-expression of CIS protein acting as a ubiquitin ligase. This results in reduced availability of membrane GHR, which is possibly the main cause of the pathological GH signalling in GHTD children.
Wifi bluetooth based combined positioning algorithm (2012)

Nowadays positioning have become very important for many services (Localization based services) and positioning have become more accurate, despite, there are some territories that basic positioning systems like GPS or even hybrid ones like GPS-WiFi or GPS-WiFi-gsm can’t cover, specially indoor enviroments. In this paper we propose a positioning method merging WLAN and Bluetooth technologies based on trilateration technique. Simulated sceneario demostrate accuracy gains, even when we use a high signal attenuation parameter. A simulated sceneario taken from a real home with the real WLAN and Bluetooth stations validates our WLAN-Bluetooth method. Firstly we calculate each equation from each available station, then we decide how to overdetermine the generated equation system in a reason of 4 to 1 (4 equations for one unknown) and finally solve the system using mathematical methods. This work is a step more to better position in indoor enviroments and localization based services.
Efficacy of CD101, a Novel Echinocandin, in Mouse Models of Aspergillosis and Azole-Resistant Disseminated Candidiasis (2016)

Abstract Background: CD101 is a novel echinocandin with long-acting pharmacokinetics and exceptional stability in development for prevention and treatment of serious fungal infections. The in vivo efficacy of CD101 was evaluated using neutropenic mouse models of azole-resistant candidiasis and aspergillosis. Methods: An azole-resistant strain of Candida albicans (R357; resistant to fluconazole [Flu], voriconazole, and posaconazole but susceptible to amphotericin B [AmB] and echinocandins) isolated from human blood was used for the mouse candidiasis model. A test strain of Aspergillus fumigatus (ATCC 13073) was used for the mouse aspergillosis model. Mice were rendered neutropenic by cyclophosphamide and then infected by injections of C. albicans (105 CFU/mouse) or A. fumigatus (104 CFU/mouse) into the tail vein. Test articles were administered starting 2 hours after infection. In the mouse candidiasis model, groups of 5 mice each received one dose of AmB (3 mg/kg IV), Flu (20 mg/kg orally), or CD101 (3, 10 or 30 mg/kg by intraperitoneal administration [IP]). After 72 hours post-infection, mice were euthanized and C. albicans counts in kidney tissue (CFU/g) were measured. In the mouse aspergillosis model, groups of 10 mice each received one dose ofAmB (2 mg/kg IP) or CD101 (2 mg/kg IV and IP). Survival was monitored daily for 10 days. Differences between vehicle and test article groups were assessed for significance by one-way ANOVA followed byDunnett's test and Fisher's Exact test in the candidiasis and aspergillosis models, respectively. Results: One dose of CD101 3 mg/kg produced a &gt;99.9% (or &gt; 3-log; P&lt;0.001) reduction in C. albicans CFU compared with vehicle through at least 72hours post-dose following a single IP dose.AmB showed similar, albeit less robust, efficacy (&gt;99% or &gt;2-log reduction in CFU; P&lt;0.05), whereas fluconazole was less efficacious (83.9% or &lt;2-log reduction in CFU). In the aspergillosis model, CD101 administered 2 mg/kg IV or IP showed similar efficacy to that ofAmB 2 mg/kg IP, both with significantly longer survival than vehicle (P&lt;0.05; Figure). Conclusions: A single dose of CD101 3 mg/kg produced significant reduction in C. albicans burden compared with vehicle (P&lt;0.001) in the neutropenic mouse model of azole-resistant candidiasis, demonstrating efficacy comparable, if not better, to that of AmB at the same dose. One dose of CD101 also demonstrated efficacy in the mouse model of aspergillosis. These data support the continued development of CD101 for treatment of serious infections caused by Candida, including azole-resistant strains, and Aspergillus spp. Figure Percent Survival in a Neutropenic Mouse Model of Aspergillosis Figure. Percent Survival in a Neutropenic Mouse Model of Aspergillosis Disclosures Ong: Cidara Therapeutics, Inc.: Employment. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder. Miesel:Eurofins Panlabs: Employment; Cidara Therapeutics, Inc: Research Funding.
Imaging and therapy of gastrointestinal cancers with radiolabeled antibodies. (1991)

Radiolabeled antibodies are gaining in application for the imaging and therapy of cancers. Much progress has been made in the use of these new biological reagents for tumors of the gastrointestinal system, and the current status, problems and prospects are reviewed in this paper. It is apparent that murine monoclonal antibodies against cancer-associated antigens are safe and useful for revealing a high percentage of sites of tumor, including some missed by conventional radiological methods. Tumors as small as 0.5 cm can be disclosed, even in organs that are difficult for CT scan interpretation. Major advances in cancer imaging have involved the use of antibody fragments and simple, direct labeling methods for 99mTc, the most widely used radionuclide in nuclear medicine. The use of radiolabeled antibodies for cancer therapy has been a more difficult endeavor, particularly because of the delivery of inadequate rad doses to tumor. Advances include humanization of monoclonal antibodies and the improved attachment of therapeutic radionuclides, such as 90Y and 186Re or 188Re.
Amino Acid Sequence Similarity Between Rabies Virus Glycoprotein and Snake Venom Curaremimetic Neurotoxins (1984)

Evidence was presented earlier that a host-cell receptor for the highly neurotropic rabies virus might be the acetylcholine receptor. The amino acid sequence of the glycoprotein of rabies virus was compared by computer analysis with that of snake venom curaremimetic neurotoxins, potent ligands of the acetylcholine receptor. A statistically significant sequence relation was found between a segment of the rabies glycoprotein and the entire sequence of long neurotoxins. The greatest identity occurs with residues considered most important in neurotoxicity, including those interacting with the acetylcholine binding site of the acetylcholine receptor. Because of the similarity between the glycoprotein and the receptor-binding region of the neurotoxins, this region of the viral glycoprotein may function as a recognition site for the acetylcholine receptor. Direct binding of the rabies virus glycoprotein to the acetylcholine receptor could contribute to the neurotropism of this virus.
Zero-current-switching multilevel modular switched-capacitor dc-dc converter (2009)

This paper presents a quasi-resonant technique for multilevel modular switched-capacitor circuit (MMSCC) to achieve zero-current-switching (ZCS) without increasing cost and sacrificing reliability. This zero-current-switching multilevel modular switched-capacitor circuit (ZCS-MMSCC) employs the stray inductance existing in the circuit as the resonant inductor to resonate with the capacitor and provide low dv/dt and low switching loss for the device. The ZCS-MMSCC does not utilize any additional components to achieve ZCS and solves the current and voltage spike problem during the switching transition, thus leading to reliable and high efficiency advantages over traditional MMSCC. Furthermore, the ZCS-MMSCC reduces the capacitance needed the circuit; in this case, the bulky capacitors present in traditional MMSCC to attain high efficiency is not necessary any more. A 150 W four-level ZCS-MMSCC prototype has been built. Simulation and experimental results are given to demonstrate the validity and features of the soft switching switched-capacitor circuit.
Imaging of Renal Trauma: A Comprehensive Review (2001)

Computed tomography (CT) is the modality of choice in the evaluation of blunt renal injury. Intravenous urography is used primarily for gross assessment of renal function in hemodynamically unstable patients. Selective renal arteriography or venography can provide detailed information regarding vascular injury. Retrograde pyelography is valuable in assessing ureteral and renal pelvic integrity in suspected ureteropelvic junction injury. Ultrasonography is useful in detecting hemoperitoneum in patients with suspected intraperitoneal injury but has limited value in evaluating those with suspected extraperitoneal injury. Occasionally, radionuclide renal scintigraphy or magnetic resonance imaging may prove helpful. Renal injuries can be classified into four large categories based on imaging findings. Category I renal injuries include minor cortical contusion, subcapsular hematoma, minor laceration with limited perinephric hematoma, and small cortical infarct. Category II lesions include major renal lacerations extending to the medulla with or without involvement of the collecting system and segmental renal infarct. Category III lesions are catastrophic renal injuries and include multiple renal lacerations and vascular injury involving the renal pedicle. Category IV injuries are ureteropelvic junction injuries. CT is particularly useful in evaluating traumatic injuries to kidneys with preexisting abnormalities and can help assess the extent of penetrating injuries in selected patients with limited posterior stab wounds. Integration of the imaging findings in renal injury with clinical information is critical in developing a treatment plan.
Less-Than-Additive Epistatic Interactions of Quantitative Trait Loci in Tomato (1996)

Epistasis plays a role in determining the phenotype yet quantitative trait loci (QTL) mapping has uncovered little evidence for it. To address this apparent contradiction, we analyzed interactions between individual Lycopersicon pennellii chromosome segments introgressed into an otherwise homogeneous genetic background of L. esculentum (cv. M82). Ten different homozygous introgression lines, each containing from 4 to 58 cM of introgressed DNA, were crossed in a half diallele scheme. The 45 derived double heterozygotes were evaluated in the field for four yield-associated traits, along with the 10 single heterozygotes and M82. Of 180 (45 x 4) tested interactions, 28% were epistatic (P < 0.05) on both linear and geometric scales. The detected epistasis was predominantly less-than-additive, i.e., the effect of the double heterozygotes was smaller than the sum of the effects of the corresponding single heterozygotes. Epistasis was also found for homozygous linked QTL affecting fruit mass and total soluble solids. Although the frequency of epistasis was high, additivity was the major component in the interaction of pairs of QTL. We propose that the diminishing additivity of QTL effects is amplified when more loci are involved; this mode of epistasis may be an important factor in phenotype canalization and in breeding.
Identification of the Plasticity-Relevant Fucose-α(1−2)-Galactose Proteome from the Mouse Olfactory Bulb (2009)

Fucose-alpha(1-2)-galactose [Fucalpha(1-2)Gal] sugars have been implicated in the molecular mechanisms that underlie neuronal development, learning, and memory. However, an understanding of their precise roles has been hampered by a lack of information regarding Fucalpha(1-2)Gal glycoproteins. Here, we report the first proteomic studies of this plasticity-relevant epitope. We identify five classes of putative Fucalpha(1-2)Gal glycoproteins: cell adhesion molecules, ion channels and solute carriers/transporters, ATP-binding proteins, synaptic vesicle-associated proteins, and mitochondrial proteins. In addition, we show that Fucalpha(1-2)Gal glycoproteins are enriched in the developing mouse olfactory bulb (OB) and exhibit a distinct spatiotemporal expression that is consistent with the presence of a "glycocode" to help direct olfactory sensory neuron (OSN) axonal pathfinding. We find that expression of Fucalpha(1-2)Gal sugars in the OB is regulated by the alpha(1-2)fucosyltransferase FUT1. FUT1-deficient mice exhibit developmental defects, including fewer and smaller glomeruli and a thinner olfactory nerve layer, suggesting that fucosylation contributes to OB development. Our findings significantly expand the number of Fucalpha(1-2)Gal glycoproteins and provide new insights into the molecular mechanisms by which fucosyl sugars contribute to neuronal processes.
Thermal infrared imaging in psychophysiology: Potentialities and limits (2014)

Functional infrared thermal imaging (fITI) is considered an upcoming, promising methodology in the emotional arena. Driven by sympathetic nerves, observations of affective nature derive from muscular activity subcutaneous blood flow as well as perspiration patterns in specific body parts. A review of 23 experimental procedures that employed fITI for investigations of affective nature is provided, along with the adopted experimental protocol and the thermal changes that took place on selected regions of interest in human and nonhuman subjects. Discussion is provided regarding the selection of an appropriate baseline, the autonomic nature of the thermal print, the experimental setup, methodological issues, limitations, and considerations, as well as future directions.
Affinity-Driven Peptide Selection of an NFAT Inhibitor More Selective Than Cyclosporin A (1999)

The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide libraries based on the calcineurin docking motif of NFAT. This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are less toxic than current drugs.