gebhart/patrepeval huggingface dataset:
Glucose analogue inhibitors of glycogen phosphorylase: from crystallographic analysis to drug prediction using GRID force-field and GOLPE variable selection (1995)

Several inhibitors of the large regulatory enzyme glycogen phosphorylase (GP) have been studied in crystallographic and kinetic experiments. GP catalyses the first step in the phosphorylysis of glycogen to glucose-l-phosphate, which is utilized via glycolysis to provide energy to sustain muscle contraction and in the liver is converted to glucose. alpha-D-Glucose is a weak inhibitor of glycogen phosphorylase form b (GPb, K(i) = 1.7 mM) and acts as a physiological regulator of hepatic glycogen metabolism. Glucose binds to phosphorylase at the catalytic site and results in a conformational change that stabilizes the inactive T state of the enzyme, promoting the action of protein phosphatase 1 and stimulating glycogen synthase. It has been suggested that in the liver, glucose analogues with greater affinity for glycogen phosphorylase may result in a more effective regulatory agent. Several N-acetyl glucopyranosylamine derivatives have been synthesized and tested in a series of crystallographic and kinetic binding studies with GPb. The structural results of the bound enzyme-ligand complexes have been analysed together with the resulting affinities in an effort to understand and exploit the molecular interactions that might give rise to a better inhibitor. Comparison of the N-methylacetyl glucopyranosylamine (N-methylamide, K(i) = 0.032 mM) with the analogous beta-methylamide derivative (C-methylamide, K(i) = 0.16 mM) illustrate the importance of forming good hydrogen bonds and obtaining complementarity of van der Waals interactions. These studies also have shown that the binding modes can be unpredictable but may be rationalized with the benefit of structural data and that a buried and mixed polar/non-polar catalytic site poses problems for the systematic addition of functional groups. Together with previous studies of glucose analogue inhibitors of GPb, this work forms the basis of a training set suitable for three-dimensional quantitative structure-activity relationship studies. The molecules in the training set are void of problems and potential errors arising from the alignment and bound conformations of each of the ligands since the coordinates were those determined experimentally from the X-ray crystallographic refined ligand-enzyme complexes. The computational procedure described in this work involves the use of the program GRID to describe the molecular structures and the progam GOLPE to obtain the partial least squares regression model with the highest prediction ability. The GRID/GOLPE procedure performed using 51 glucose analogue inhibitors of GPb has good overall predictivity [standard deviation of error predictions (SDEP) = 0.98 and Q(2) = 0.76] and has shown good agreement with the crystallographic and kinetic results by reliably selecting regions that are known to affect the binding affinity.
Hepadnaviral replication in HBV-transgenic mice lacking the surface antigen (HBsAg) is controlled by toll-like receptor 3-induced immune responses (2014)

Background and aims: It is likely that HBV surface antigen (HBsAg) impairs toll-like receptor (TLR) signaling leading to an attenuation of innate and adaptive immune responses. Here, we aimed to analyze TLR3 signaling in HBV transgenic mice lacking the HBs antigen (1.4 tgHBV-s-mut).
Gene expression profiling in drug discovery and development. (1999)

Recent advances in technology, especially the merger between molecular biology, automation technology and computer science, are rapidly changing the manner in which pharmaceutical companies will discover new drug targets and develop new therapeutic drugs. One example of such a merger between different disciplines has been the development of technology platforms, such as cDNA microarrays and oligonucleotide arrays, allowing the generation of comprehensive gene expression profiles in a previously insurmountable throughput. Hereby, the major limitation is currently shifting from the efficient generation of biological information to the extraction of biological knowledge. However, given the foreseeable developments in data mining technologies and diverse computational biology tools, it can be anticipated that this information will foster the effectiveness to develop new and hopefully better drugs.
Recognition of corn defense chitinases by fungal polyglycine hydrolases (2017)

Polyglycine hydrolases (PGH)s are secreted fungal endoproteases that cleave peptide bonds in the polyglycine interdomain linker of ChitA chitinase, an antifungal protein from domesticated corn (Zea mays ssp. mays). These target-specific endoproteases are unusual because they do not cut a specific peptide bond but select one of many Gly-Gly bonds within the polyglycine region. Some Gly-Gly bonds are cleaved frequently while others are never cleaved. Moreover, we have previously shown that PGHs from different fungal pathogens prefer to cleave different Gly-Gly peptide bonds. It is not understood how PGHs selectively cleave the ChitA linker, especially because its polyglycine structure lacks peptide sidechains. To gain insights into this process we synthesized several peptide analogs of ChitA to evaluate them as potential substrates and inhibitors of Es-cmp, a PGH from the plant pathogenic fungus Epicoccum sorghi. Our results showed that part of the PGH recognition site for substrate chitinases is adjacent to the polyglycine linker on the carboxy side. More specifically, four amino acid residues were implicated, each spaced four residues apart on an alpha helix. Moreover, analogous peptides with selective Gly->sarcosine (N-methylglycine) mutations or a specific Ser->Thr mutation retained inhibitor activity but were no longer cleaved by PGH. Additonally, our findings suggest that peptide analogs of ChitA that inhibit PGH activity could be used to strengthen plant defenses.
The Incorporation of Photonic Transmitter-Mixer with Si/Ge Based Electrical Comb Line Generator for W-band Ultra-Wideband (UWB) Wireless Data Transmission (2012)

By combing Si/Ge avalanche photodiodes based electrical comb-line generators with photonic-transmitter-mixers, millimeter-wave short-pulse generations for photonic ultra-wideband linking at W-band with wireless transmission distance up to 12 meter and error-free 1.5Gbps data rate are demonstrated.
Degradation mechanisms in organic light-emitting devices: Metal migration model versus unstable tris(8-hydroxyquinoline) aluminum cationic model (2007)

To resolve the issue of which of the “indium migration” model and the “unstable AlQ3 cationic” model plays a more important role in luminescence degradation of organic light-emitting devices, we investigated the effect of the device structures on device operational stability. The results show that alterations in device layer structures can significantly affect the device operational stability, although they do not appear to noticeably change the magnitude of indium migrations. This suggests that the indium migration model may not play a dominant role in device degradation. On the other hand, the change in device stability with the alteration in the device structures can be plausibly explained by the unstable AlQ3 cationic model.
Interactive Peritoneum in a Haptic Surgery Illustration Environment (2009)

We describe a fully interactive, low-overhead and robust peritoneum representation allowing for probing and cutting. The peritoneum implementation has been tested within a surgical illustration environment.
Substrate binding induces structural changes in cytochrome P450cam (2009)

The binding of (+)-camphor to cytochrome P450cam (P450cam) expels a cluster of waters at the active site, raising the redox potential of the haem to an extent that allows reduction by the electron-transfer system. This binding was reported to involve no significant structural changes in the protein. Here, two ferric P450cam structures partially complexed with (+)-camphor were determined by X-ray crystallography at 1.30-1.35 A resolution, revealing the structures of the substrate-free and substrate-bound forms. (+)-Camphor binding induces rotation of Thr101 to form a hydrogen bond that acts as a hydrogen donor to a peripheral haem propionate. This bonding contributes to the redox-potential change.
100 Questions & Answers About Alzheimer's Disease (2004)

ix, 213 p. : 23 cm
Gene expression analyses of grade II gliomas and identification of rPTPβ/ζ as a candidate oligodendroglioma marker (2007)

Grade II gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes - astrocytomas, oligodendrogliomas, and oligoastrocytomas - constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPTPbeta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTPbeta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade II gliomas. Furthermore, the results from the immunohistochemical analyses of rPTPbeta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.
Poisson's ratio and angle bending in spring networks (2021)

The Poisson's ratio of a spring network system has been shown to depend not only on the geometry but also on the relative strength of angle-bending forces in comparison to the bond-compression forces in the system. Here we derive the very simple analytic result that in systems where the spring interaction strength is equal to the bond-reorientation interaction, the Poisson's ratio identically goes to zero and is independent of the network geometry.
Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]octanes as Selective α4β2-nAChR Ligands (2014)

We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR β2 subunit-containing nAChR subtypes (β2*-nAChRs) over β4*-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2- and α4β2*-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15.
Forward-current-generated donor centers in high-voltage 4H-SiC based p-i-n diodes (2011)

High-voltage diodes based on silicon carbide of 4H polytype (4H-SiC) have been studied by the deep-level transient spectroscopy (DLTS) method. It is established that the passage of forward current leads to the activation of a donor center with an activation energy of E c − 0.2 eV and an electron capture cross section of σ n ∼ 2.0 × 10−15 cm2. The DLTS measurements reveal the appearance of this center upon the transfer of a very small charge through the diode, under the conditions where the forward voltage drop on the diode remains almost unchanged. A possible nature of the observed phenomenon is discussed.
LETTERS/COMMENTARY (2007)

At the “Second International Workshop on Seizure Prediction” held recently in Washington, DC, under the co-sponsorship of NIH/NINDS and the AES, the importance of prospectively comparing the therapeutic efficacy of “closed-” vs. “open-loop” brain electrical stimulation was identified as an important research aim, and the meaning of these terms was briefly debated. Therapies that utilize any type of feedback, including patient seizure diaries, are “closed-loop”. The term “open-loop” was adopted for description of clinical trials with devices lacking automated means for (a) detecting seizures, quantifying their severity, and logging these data; and (b) triggering delivery of therapy based on seizure detections. As currently used, the term “open loop” may create confusion since the therapies to which it is applied rely on patient diary-feedback. The following clarification may be useful: Closed-loop therapy: Any therapy that uses a feedback loop. The feedback may be real-time or delayed (off-line); for both these options, the feedback may be automated or manual, objective or subjective, and may be used to trigger therapy delivery or to adjust parameters or dose. Open-loop therapy: Any therapy that operates without any feedback loop. Recent trials that use automated seizure detection to trigger electrical stimulation directly to the brain (Osorio et al., 2005; Bergey et al., 2006) are examples of automated real-time closed-loop. One of these trials (Osorio et al., 2005) provides real-time automated therapy delivery and objective quantitative assessment of response, while the other (Bergey et al., 2006) provides only automated therapy (as assessment is based on seizure diaries). Vagus nerve stimulation with the neurocybernetic prosthesis (Cyberonics, Houston, TX, U.S.A.), exemplifies two closed-loop modalities: (1) real-time manual closed loop, when the magnet is used to activate the generator in response to an “aura”; and (2) delayed closed loop, when device parameter changes are based upon subjective feedback in the form of seizure diaries. With these definitions in place, the incorrectly stated and irrelevant/futile aim of comparing “open-loop” vs. “closed-loop” therapies should be re-framed. With respect to brain stimulation studies, we offer the following formulation: The aim is to compare efficacy (and adverse events) of therapies that use either continuous, periodic, or random brain electrical stimulation to that of therapies based on contingent stimulation (i.e., in response to) seizure detections. This would be a worthwhile endeavor that should be pursued using objective and quantifiable assessment means such as seizure detection algorithms, instead of patient seizure diaries; diaries are inherently and grossly inaccurate (Blum et al., 1996), provide information only about seizures with clinical manifestations (a small fraction of all recorded seizures) (Osorio et al., 2002), and do not quantify intensity, duration, and extent of spread.
Cosmetic Outcome and Breast Morbidity in Breast-Conserving Treatment (2002)

A total of 266 recurrence-free breast cancer patients from the randomized DBCG-82TM breast conservation trial were called in for a follow-up investigation to study the impact of surgical and radiation treatment factors on the cosmetic and functional outcome after breast conservation. The patients were interviewed and examined after a median follow-up time of 6.6 years, and 194 of them (73%) regarded the cosmetic result as excellent or good. Morbidity assessments showed that breast fibrosis, skin telangiectasia, and breast retraction were significantly associated with a less satisfactory cosmetic result. On univariate analysis, it was found that treatment with a direct anterior electron field produced more morbidity and inferior cosmetic outcomes compared with tangential photon treatment, while increasing breast size was associated with increased breast retraction and breast fibrosis. Treatment characteristics that emerged as independent prognostic factors of a poor cosmetic outcome on multivariate analysis were the use of a direct anterior electron field (OR = 2.15, CI 1.25-3.70) and adjuvant systemic therapy (OR = 2.13, 1.22-3.71). A significant but relatively low level of concordance was found between the patients' and the clinician's evaluations of cosmetic results but self-assessments of breast morbidity and psychological distress were significantly related to the observed treatment-induced side effects after breast-conserving treatment, indicating that subjective perceptions and observations as reported by the patients are relevant for the identification of treatment factors that impact on normal tissue reactions.
Antibody‐Based Therapeutics in Oncology (2017)

This chapter describes the application of monoclonal antibody (mAb)-based selectivity in the context of cell-surface receptor targeting of solid tumors and immune cell-tumor cell interactions through blockade of T-cell inhibitory pathways or activation of co-stimulation pathways. The development of mAbs as immune modulators to elicit potent cancer immunotherapy broadly fits into two classes: co-stimulatory agonists and check-point inhibitory antagonists. Intrinsic to both classes is the concept that T cells express both co-stimulatory and inhibitory molecules that form potent immunomodulatory axes that can be harnessed to generate antitumor immunity. The chapter also discusses leveraging of bispecific antibody (BsAb)-based platforms to fully exploit targeting of such networks. The chapter focuses on antibody-based therapeutics that have reached the stage of clinical evaluation. Receptor crosstalk, modification of receptor structure, and utilization of alternative downstream signaling pathways are the main resistance pathways to compensate for the loss of receptor functions in cancer cells.
Penetrating an operating system: a study of VM/370 integrity (1976)

The virtual machine architecture embodied in wm/370 greatly simplifies an operating system in most areas and hence increases the probability of correct implementation and resistance to penetration. The control program is not concerned with user files or multiple access methods. It simulates a machine with a fixed number of buttons and instructions that require interpretation. The choice of System/370 Principles of Operation as a user interface provides a well understood and well documented interface. The result is a system that is smaller and simpler, with fewer opportunities for error. The simplicity enhances the probability of obtaining security. The exception area is the support of input/output.
Relating the morphology of a poly(p-phenylene vinylene)/methanofullerene blend to bulk heterojunction solar cell performance (2004)

Few techniques are available where the morphology of blends can be determined in all three dimensions on a nanometer scale. Here we describe the use of a combination of techniques to resolve the morphology both laterally and vertically in spin cast films of a poly(<i>p</i>-phenylene vinylene)/methanofullerene blend. These blends are used as photoactive films in plastic bulk heterojunction solar cells where the performance strongly depends on the molecular morphology. In addition to depth profiling by dynamic time-of-flight secondary ion mass spectrometry (TOF-SIMS), tapping-mode atomic force microscopy (TM-AFM), transmission electron microscopy (TEM), absorption and emission spectroscopy and time-correlated single photon counting fluorescence measurements were used to investigate the morphology of ~100 nm thick spin cast composites with varying composition of 1-(3-methoxycarbonyl)propyl-1-phenyl-[6,6]-methanofullerene (PCBM) and poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene] (MDMO-PPV). Combining all results showed clustering of PCBM into rather pure separate domains in a matrix of ~50 wt% MDMO-PPV for composites with PCBM concentrations 80-100 wt%, and no spontaneous stratification. Electrical characterization, under illumination and in the dark, of the composite devices revealed the percolation threshold for electron transport and showed a reduction in recombination-limitation for the photocurrent of these solar cells as a result of an improved charge transport and collection efficiency with increasing fullerene concentration.
Fecal and Urinary Obstruction by a Stone in Ureterosigmoidostomy (2003)

No AccessJournal of UrologyCLINICAL UROLOGY: Case Reports1 Aug 2003Fecal and Urinary Obstruction by a Stone in Ureterosigmoidostomy JOSÉ PLACER, RAMÓN CORTADELLAS, FELIX GRASES, and ANTONI GELABERT-MAS JOSÉ PLACERJOSÉ PLACER More articles by this author , RAMÓN CORTADELLASRAMÓN CORTADELLAS More articles by this author , FELIX GRASESFELIX GRASES More articles by this author , and ANTONI GELABERT-MASANTONI GELABERT-MAS More articles by this author View All Author Informationhttps://doi.org/10.1097/01.ju.0000075142.14770.78AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Fecal and Urinary Obstruction by a Stone in Ureterosigmoidostomy." The Journal of Urology, 170(2), p. 516 References 1 : Unique urinary-fecal calculus after cystectomy and ureterosigmoidostomy. J Urol1989; 142: 1314. Abstract, Google Scholar 2 : Selective minimally invasive management of calculi in patients with urinary diversions. J Urol1994; 152: 1091. Link, Google Scholar 3 : Lithotripsy of urinary concrement in the sigmoid after ureterosigmoidostomy. Endoscopy1985; 17: 38. Google Scholar From the Department of Urology, Hospital del Mar, IMAS-Universitat Autònoma de Barcelona (JP, RC, AG-M), Barcelona and Laboratory of Renal Lithiasis Research, Faculty of Sciences, Universitat de les Illes Balears (FG), Palma de Mallorca, Spain© 2003 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 170Issue 2August 2003Page: 516 Advertisement Copyright & Permissions© 2003 by American Urological Association, Inc.Keywordsurinary reservoirs, continenturinary diversionurinary calculiMetricsAuthor Information JOSÉ PLACER More articles by this author RAMÓN CORTADELLAS More articles by this author FELIX GRASES More articles by this author ANTONI GELABERT-MAS More articles by this author Expand All Advertisement PDF downloadLoading ...