gebhart/patrepeval huggingface dataset:
Molecular Analysis of Dasatinib Resistance Mechanisms in CML Patients Identifies Novel BCR-ABL Mutations Predicted To Retain Sensitivity to Imatinib: Rationale for Combination Tyrosine Kinase Inhibitor Therapy. (2005)

Abstract Point mutations within the BCR-ABL kinase domain represent the most common mechanism of resistance to imatinib in patients with CML. Preclinical studies have shown that dasatinib (BMS-354825) is effective at inhibiting the kinase activity of imatinib-resistant BCR-ABL mutants with the notable exception of the T315I mutation, which remains highly resistant to imatinib, dasatinib, and AMN107 (Gorre et al, Science 2001; Shah et al, Science 2004; Weisberg et al, Cancer Cell, 2005). Clinical data from Phase I and II studies of dasatinib in CML confirms the in vitro findings. Each of three imatinib-resistant patients bearing the T315I mutation (CP=1; AP=2) did not achieve objective hematologic or cytogenetic responses during treatment with dasatanib on a Phase I study. Additionally, each of two phase II patients with the T315I mutation (CP=1; LBC=1) treated at UCLA showed no evidence of objective response. We have also detected the T315I mutation in each of two cases of acquired resistance in a phase II (LBC =2) study, and in seven of nine patients with acquired resistance to dasatinib in phase I and II studies (CP=1; MBC=3; LBC=2; Ph+ ALL=1). Notably, we detected a novel BCR-ABL mutation, T315A, in one of the two patients who relapsed without a detectable T315I mutation. The patient is a 53 year-old female whose chronic phase CML had progressed to myeloid blast phase while being treated with imatinib. The imatinib-resistant mutation M244V was identified prior to dasatinib treatment. The patient achieved a major hematologic response (&amp;lt;5% blasts with partial recovery of peripheral blood counts) on dasatinib 90 mg orally given twice daily, but relapsed with MBC after six months. Sequence analysis of the BCR-ABL kinase domain at the time of relapse revealed the presence of the imatinib-resistant mutation M244V as well as the novel mutation T315A. This finding is of particular interest because T315A and several other novel BCR-ABL mutations were recently recovered in a saturation mutagenesis study designed to define potential mechanisms of dasatinib resistance. Remarkably, many of these mutations retain sensitivity to imatinib in vitro (Burgess et al, PNAS, 2005). Through periodic molecular monitoring of other dasatinib-treated patients, we have identified a second novel BCR-ABL mutant, F317I, that developed in an imatinib-resistant CP patient after 9 months of treatment. Similar to T315A, F317I was isolated in the saturation mutagenesis screen for dasatinib resistance and is predicted to retain sensitivity to imatinib. Taken together, our findings implicate the T315I mutation as the principle mechanism of resistance to dasatinib, but more importantly, strongly support the use for combination kinase inhibitor therapy in CML to prevent emergence of drug resistant clones. A phase I trial to assess the safety of combining imatinib with dasatinib is planned.
The Isolation and Biologic Activities of Purified Secretory IgA and IgG Anti-Salmonella Typhimurium “O” Antibodies from Rabbit Intestinal Fluid and Colostrum (1971)

Abstract Direct contact of external secretory tissue with living, but not with dead, Salmonella typhimurium stimulated formation of high concentrations of anti-“O” antibodies in the small intestinal fluid and colostrum. Purified IgG and IgA anti-S. typhimurium “O” antibodies were isolated from these fluids and their activities measured on a molar basis. Serum and exocrine IgG molecules had identical complement-dependent bactericidal, opsonization and PCA reactions. Exocrine IgA antibodies showed little or no activity in these biologic assays but did exert a similar suppressive effect upon antibody formation after intravenous injection or oral administration, as did exocrine IgG antibodies. Both IgA and IgG molecules had similar specific agglutination activities.
Acoustic fiber sensor arrays (2004)

The acoustic fiber sensor arrays that have been developed over the past two decades for oil exploration and other applications can support hundreds of fiber hydrophones per fiber pair and exhibit exceptional properties, including shot-noise-limited sensitivities better than 1 &mu;rad/&radic;Hz, high stability, and dynamic ranges well in excess of 130 dB. This article reviews the main configurations reported to date, which are based on ladder architectures utilizing either Mach-Zehnder or Sagnac interferometric sensors and time-domain multiplexing. The emphasis is placed on their principles, performance characteristics, and relative advantages regarding such key issues as signal fading, polarization-induced fading, frequency response, sensitivity, and the number of sensors that can be multiplexed on a given pair of fibers.
2P1-C04 On Haptics of Particle Aggregation (2006)

A product is chosen according to the appearance, cost, feel, etc, even with the same function. In this study, we focus on the bottled particles through a stick, which generate a different touch sensation with almost the same structure. The subjective tests and the measurement experiments are examined. The results are compared and considered.
Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams (2016)

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40-55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.
Overexpression of Brucella putative glycosyltransferase WbkA in B. abortus RB51 leads to production of exopolysaccharide (2015)

Brucella spp. are Gram-negative, facultative intracellular bacteria that cause brucellosis in mammals. Brucella strains containing the O-polysaccharide in their cell wall structure exhibit a smooth phenotype whereas the strains devoid of the polysaccharide show rough phenotype. B. abortus strain RB51 is a stable rough attenuated mutant which is used as a licensed live vaccine for bovine brucellosis. Previous studies have shown that the wboA gene, which encodes a glycosyltransferase required for the synthesis of O-polysaccharide, is disrupted in B. abortus RB51 by an IS711 element. Although complementation of strain RB51 with a functional wboA gene results in O-polysaccharide synthesis in the cytoplasm, it does not result in smooth phenotype. The aim of this study was to determine if overexpression of Brucella WbkA or WbkE, two additional putative glycosyltransferases essential for O-polysaccharide synthesis, in strain RB51 would result in the O-polysaccharide synthesis and smooth phenotype. Our results demonstrate that overexpression of wbkA or wbkE gene in RB51 does not result in O-polysaccharide expression as shown by Western blotting with specific antibodies. However, wbkA, but not wbkE, overexpression leads to the development of a clumping phenotype and the production of exopolysaccharide(s) containing mannose, galactose, N-acetylglucosamine, and N-acetylgalactosamine. Moreover, we found that the clumping recombinant strain displays increased adhesion to polystyrene plates. The recombinant strain was similar to strain RB51 in its attenuation characteristic and in its ability to induce protective immunity against virulent B. abortus challenge in mice.
Effective Change Management in Modern Enterprises (2015)

Modern enterprises are constantly under change in the effort to enhance their internal operations and become more competitive in the market. A change process is always a challenge, and its success needs to consider multi-angled approaches, as it affects all involved stakeholders. The way changes are tack- led is fundamental to the success and survivability of an enterprise. Change is interwoven with risks, and therefore it has to be effectively managed in order to be successful. This work presents an effort to identify the key factors that should be con- sidered in order to lead to effective change management in modern enter- prises, and quantify their relationship to it. The theoretical investigation re- veals that key factors often considered, both in theory and in practical change management strategies, include Employee, Leadership, Training &amp;amp; Develop- ment, Reward &amp;amp; Recognition, Culture, Politics, Information Systems. Driven by these findings, a model is proposed that depicts their correlation towards effective change management. Subsequently, a survey is conducted, and sta- tistical analysis is performed to the empirical data collected, in order to eval- uate the proposed model and its hypotheses. The empirical results indicate that all selected key factors, contribute towards achieving effective change management as hypothesized. The results of this work, may benefit enterprise managers planning, exe- cuting and assessing change processes, as proper considerations of the factors discussed throughout this work may increase the chances of the change pro- cess success, resulting in a better performing and competitive enterprise.
Waveform-Domain NOMA: The Future of Multiple Access (2020)

This paper introduces a novel non-orthogonal multiple access (NOMA) concept named waveform-domain NOMA, which proposes the coexistence of different waveforms in the same resource element (RE). Regarding the demands of each user equipments (UEs), appropriate waveforms are assigned intelligently and decoded at the receiver side properly. Since the performance gain of power-domain NOMA compared to multi-user multiple-input-multiple-output (MU-MIMO) degrades in the case of successive interference cancellation (SIC) and channel estimation errors, NOMA is not considered as a work-item in 3GPP anymore. The novel waveform-domain NOMA concept provides a remedy for the problems of the power-domain NOMA scheme as well as flexibility in terms of reliability, latency, and energy efficiency. To mitigate SIC errors, low-density parity-check (LDPC) codes aided soft interference cancellation technique is used. As numerically evaluated, the proposed waveform-domain NOMA scheme outperforms the conventional power-domain NOMA in the power-balanced scenario.
787. Engineered Fok I Heterodimers for Enhanced Zinc Finger Nuclease Specificity (2006)

Zinc finger nucleases have been shown to be effective tools for high-frequency genome editing with potential therapeutic applications (Urnov et al., Nature 435:646-651). Such nucleases are created by fusing the cleavage domain of the type IIs restriction enzyme Fok I to engineered zinc finger proteins. One limitation of this architecture is that the natural Fok I cleavage domain must dimerize in order to cleave DNA; therefore two different zinc finger protein-Fok I fusions are required to introduce a double-stranded break at an asymmetric target site. As a consequence, use of this technology for genome editing may expose the cell to three different nuclease species – the desired heterodimer as well as two homodimers which are irrelevant to the desired process but which may still contribute to off-target cleavage events. Creating Fok I cleavage domain variants that do not function as homodimers would eliminate the possibility of off-target cutting by these species and would also increase the availability of the desired heterodimer. In order to develop such variants, we used a process of iterative structure-based design and screening in which candidate designs were tested for their ability to cleave DNA in vitro and for their ability to potentiate gene correction in a reporter cell line. A pair of nuclease variants, each containing two mutations at the dimerization interface, were developed that worked well when paired together, but were severely impaired when paired with a second copy of themselves. These mutant cleavage domains were substituted for the wild-type FokI cleavage domains in the reagents used by Urnov et al. and tested for their ability to induce sequence alterations at the endogenous human common gamma chain gene. In this system we observed that a heterodimer of our designed cleavage domains was as active as wild type Fok I at stimulating gene correction while inducing significantly fewer overall DNA cutting events. Moreover, homodimers of the designed Fok I cleavage domain variants were completely inactive. These studies demonstrate that we have successfully developed Fok I cleavage domain variants that function as obligate heterodimers. These variants should be broadly useful for increasing the potency and specificity of designed zinc finger nucleases.
A novel TCAD-based methodology to minimize the impact of parasitic structures on ESD performance (2010)

During an ESD event, breakdown of a parasitic bipolar transistor can lead to chip failure. For a variety of ESD protection networks, it is demonstrated that TCAD simulations correctly predict the stress level at which failure occurs due to bipolar breakdown. A procedure to characterize the interaction between any two N-type diffusions and the ESD cells to which they are connected is presented.
A trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification (2017)

Tumor necrosis factor-α (TNF) exerts its biological effect through two types of receptors, p55 TNF receptor (TNFR1) and p75 TNF receptor (TNFR2). An inflammatory response is known to be induced mainly by TNFR1, whereas an anti-inflammatory reaction is thought to be mediated by TNFR2 in some autoimmune diseases. We have been investigating the use of an antagonistic TNF mutant (TNFR1-selective antagonistic TNF mutant (R1antTNF)) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality. Here, we aimed to further improve and optimize the activity and behavior of this mutant protein both <i>in vitro</i> and <i>in vivo</i> Specifically, we examined a trimeric structural fusion of R1antTNF, formed via the introduction of short peptide linkers, as a strategy to enhance bioactivity and molecular stability. By comparative analysis with R1antTNF, the trimeric fusion, referred to as single-chain R1antTNF (scR1antTNF), was found to retain <i>in vitro</i> molecular properties of receptor selectivity and antagonistic activity but displayed a marked increase in thermal stability. The residence time of scR1antTNF <i>in vivo</i> was also significantly prolonged. Furthermore, molecular modification using polyethylene glycol (PEG) was easily controlled by limiting the number of reactive sites. Taken together, our findings show that scR1antTNF displays enhanced molecular stability while maintaining biological activity compared with R1antTNF.
Following the dynamics of matter with femtosecond precision using the X-ray streaking method (2015)

X-ray Free Electron Lasers (FELs) can produce extremely intense and very short pulses, down to below 10 femtoseconds (fs). Among the key applications are ultrafast time-resolved studies of dynamics of matter by observing responses to fast excitation pulses in a pump-probe manner. Detectors with sufficient time resolution for observing these processes are not available. Therefore, such experiments typically measure a sample's full dynamics by repeating multiple pump-probe cycles at different delay times. This conventional method assumes that the sample returns to an identical or very similar state after each cycle. Here we describe a novel approach that can provide a time trace of responses following a single excitation pulse, jitter-free, with fs timing precision. We demonstrate, in an X-ray diffraction experiment, how it can be applied to the investigation of ultrafast irreversible processes.
Molecular Determinants of Vanilloid Sensitivity in TRPV1 (2004)

Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [(3)H]RTX binding in membranes prepared from their dorsal root ganglia. We have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homology to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here we identify key residues (Met(547) and Thr(550)) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [(3)H]RTX binding and competitive antagonist binding to rabbit TRPV1. We also show that these residues differentially affect ligand recognition as well as the assays of functional response versus ligand binding. Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders.
Discovery, isolation, heterologous expression and mode-of-action studies of the antibiotic polyketide tatiomicin from Amycolatopsis sp. DEM30355 (2022)

A genomic and bioactivity informed analysis of the metabolome of the extremophile Amycolatopsis sp. DEM30355 has allowed for the discovery and isolation of the polyketide antibiotic tatiomicin. Identification of the biosynthetic gene cluster was confirmed by heterologous expression in Streptomyces coelicolor M1152. Structural elucidation, including absolute stereochemical assignment, was performed using complementary crystallographic, spectroscopic and computational methods. Tatiomicin shows antibiotic activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Cytological profiling experiments suggest a putative antibiotic mode-of-action, involving membrane depolarisation and chromosomal decondensation of the target bacteria.
New Composite MoS2–C60 Crystals (2005)

New MoS2–C60 composite layered crystals built of alternating MoS2 and C60 molecular layers and with unusual diffraction contrast (see Figure) have been grown via a catalyzed transport reaction using fullerene C60. A model structure of these layered composites is proposed based on transmission electron microscopy, electron diffraction, X-ray diffraction, and photoelectron spectroscopy. A growth mechanism is proposed based on electrostatic interactions, considering optical absorption by MoS2 and possible charge transfer to C60.
Concise Synthesis of Conformationally Constrained Pybox Ligands (1996)

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTConcise Synthesis of Conformationally Constrained Pybox LigandsIan W. Davies, Linda Gerena, Nu Lu, Robert D. Larsen, and Paul J. ReiderView Author Information Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065 Cite this: J. Org. Chem. 1996, 61, 26, 9629–9630Publication Date (Web):December 27, 1996Publication History Received20 August 1996Published online27 December 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/jo9616264https://doi.org/10.1021/jo9616264brief-reportACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views3964Altmetric-Citations63LEARN 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 SUBJECTS:Aldol reactions,Dehydration,Ligands Get e-Alerts
Digital Integrated Circuits on an E-Mode GaN Power HEMT Platform (2017)

GaN-based digital integrated circuits (ICs) are realized on a 6-inch GaN-on-Si power high-electron-mobility transistor (HEMT) platform by monolithic integration of enhancement/depletion-mode HEMTs using a 0.5-μm gate technology. A direct-coupled FET logic inverter and a 101-stage ring oscillator are fabricated and characterized. The inverter exhibits a large input voltage swing, wide noise margin, and high temperature stability, while the ring oscillator features a small propagation delay of 0.1 ns/stage under a supply voltage of 4 V. These digital ICs can operate properly up to at least 200 °C and show great potential for GaN smart power IC applications.
Attachment Rate of the Inferior Alveolar Nerve to Buccal Plate During Bilateral Sagittal Split Osteotomy Influences Self-Reported Sensory Impairment (2014)

This study was aimed to investigate a modified buccal osteotomy technique and whether the integrity of the lingual part of the lower border influences the attachment of the neurovascular bundle to the proximal segment of the mandible during a sagittal split osteotomy without increasing the number of bad splits. The presence of self-reported sensibility disturbance in the lower lip at the last follow-up visit was assessed. This study included 220 and 133 patients with bilateral sagittal split osteotomy undergoing the classical and the new modified buccal osteotomy techniques, respectively. In the new technique, the lower border is divided into a lingual fragment that remains incorporated in the tooth-bearing fragment and a buccal fragment that comes with the proximal fragment (buccal plate). In the classical technique, the inferior alveolar nerve was attached to the proximal segment of the mandible in more than one third of operation sites (36.36% on the right and 40.91% on the left) compared with less than one fourth of the operation sites using the new technique (9.73% on the right and 23.01% on the left). The overall figure of self-reported changed sensibility was 09.40% (12/128) in the new technique compared to 15.12% in the classical technique. We present a suitable improvement to the classical buccal osteotomy technique that allows less manipulation and injury of the inferior alveolar nerve with consequent reduction in self-reported postoperative changes in lower lip sensation