gebhart/patrepeval huggingface dataset:
Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound <i>ALK</i> Mutations in ALK-Positive Lung Cancer (2018)

The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of <i>ALK</i> mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, <i>N</i>-ethyl-<i>N</i>-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single <i>ALK</i> mutations. In similar screens with EML4-ALK containing single <i>ALK</i> resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound <i>ALK</i> mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound <i>ALK</i> mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of <i>ALK</i> mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound <i>ALK</i> mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.<b>Significance:</b> Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound <i>ALK</i> mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. <i>Cancer Discov; 8(6); 714-29. ©2018 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 663</i>.
Computational Methods for Understanding Mass Spectrometry–Based Shotgun Proteomics Data (2018)

Computational proteomics is the data science concerned with the identification and quantification of proteins from high-throughput data and the biological interpretation of their concentration changes, posttranslational modifications, interactions, and subcellular localizations. Today, these data most often originate from mass spectrometry–based shotgun proteomics experiments. In this review, we survey computational methods for the analysis of such proteomics data, focusing on the explanation of the key concepts. Starting with mass spectrometric feature detection, we then cover methods for the identification of peptides. Subsequently, protein inference and the control of false discovery rates are highly important topics covered. We then discuss methods for the quantification of peptides and proteins. A section on downstream data analysis covers exploratory statistics, network analysis, machine learning, and multiomics data integration. Finally, we discuss current developments and provide an outlook on what the near future of computational proteomics might bear.
Treatment with metformin of non-diabetic men with hypertension, hypertriglyceridaemia and central fat distribution: the BIGPRO 1.2 trial (2000)

The consistency of the two BIGPRO trials supports the conclusion that metformin affects several cardiovascular risk factors favourably in non-diabetic subjects with a central fat distribution.
Performance Analysis of Circuit Switched Multi-Service Multi-Rate Networks With Alternative Routing (2013)

We consider a circuit-switched multiservice network with non-hierarchical alternative routing and trunk reservation. Based on the fundamental concept of overflow priority classification approximation (OPCA), we develop two approximations for the estimation of the blocking probability: OPCA and service-based OPCA. We also apply the classical Erlang fixed-point approximation (EFPA) for the estimation of the blocking probability in the network and propose the more conservative max (EFPA, service-based OPCA) as a reasonably accurate evaluation. We compare the approximations with simulation results and discuss the accuracy of the blocking probabilities for the various traffic classes under different system parameter values such as service rates, bandwidth requirements, number of channels per trunk, maximum allowable number of alternative paths and trunk reservation. We also discuss the robustness of the approximations to the shape of the holding time distribution and their performances under asymmetrical cases. We illustrate that when the approximations are used for network dimensioning, their error is acceptable. We further demonstrate that the approximations can be applied in large networks such as the CORONET.
WarpPool (2015)

Although graphics processing units (GPUs) are capable of high compute throughput, their memory systems need to supply the arithmetic pipelines with data at a sufficient rate to avoid stalls. For benchmarks that have divergent access patterns or cause the L1 cache to run out of resources, the link between the GPU's load/store unit and the L1 cache becomes a bottleneck in the memory system, leading to low utilization of compute resources. While current GPU memory systems are able to coalesce requests between threads in the same warp, we identify a form of spatial locality between threads in multiple warps. We use this locality, which is overlooked in current systems, to merge requests being sent to the L1 cache. This relieves the bottleneck between the load/store unit and the cache, and provides an opportunity to prioritize requests to minimize cache thrashing. Our implementation, WarpPool , yields a 38% speedup on memory throughput-limited kernels by increasing the throughput to the L1 by 8% and the reducing the number of L1 misses by 23%. We also demonstrate that WarpPool can improve GPU programmability by achieving high performance without the need to optimize workloads' memory access patterns. A Verilog implementation including place-androute shows WarpPool requires 1.0% added GPU area and 0.8% added power.
High affinity of sigma<sub>1</sub>‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C<sub>8</sub>–C<sub>7</sub> isomerase (1997)

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C8-C7 isomerase (ERG2 protein). Pharmacologically-but not structurally-the sigma 1-site is also related to the emopamil binding protein, the mammalian sterol C8-C7 isomerase. We therefore investigated if sterol C8-C7 isomerase inhibitors are high affinity ligands for the (+)-[3H]-pentazocine labelled sigma 1-binding site. 2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma 1-binding sites were the agricultural fungicide fenpropimorph (Ki 0.005 nM), the antihypocholesterinaemic drugs triparanol (Ki 7.0 nM), AY-9944 (Ki, 0.46 nM) and MDL28,815 (Ki 0.16 nM), the enantiomers of the ovulation inducer clomiphene (Ki 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (Ki 26 nM). 3. Except for tamoxifen these affinities are essentially identical with those for the [3H]-ifenprodil labelled sterol C8-C7 isomerase of S. cerevisiae. This demonstrates that sigma 1-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma 1-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.
Unusual conformational stability of a sterically crowded atropisomer of methyl[α<sup>4</sup>-5,10,15,20-tetrakis(2′-phenylphenyl)porphyrinato]aluminium: a possibility of CH–π bonding interactions in organometallic porphyrin systems (1995)

Through conformational studies on the topologically well-defined atropisomeric systems of organo-aluminium and -cobalt porphyrins, e.g. methyl[α4-5,10,15,20-tetrakis(2′-phenylphenyl)porphyrinato]aluminium (α4-1a), the presence of intramolecular CH–π bonding interactions are indicated between alkyl groups bonded to the central metal atoms and aromatic rings located at the ortho position of the meso phenyl substituents upon proximal orientation.
Frameshift Mutants of β Amyloid Precursor Protein and Ubiquitin-B in Alzheimer's and Down Patients (1998)

The cerebral cortex of Alzheimer's and Down syndrome patients is characterized by the presence of protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads. These structures were shown to contain forms of beta amyloid precursor protein and ubiquitin-B that are aberrant (+1 proteins) in the carboxyl terminus. The +1 proteins were not found in young control patients, whereas the presence of ubiquitin-B+1 in elderly control patients may indicate early stages of neurodegeneration. The two species of +1 proteins displayed cellular colocalization, suggesting a common origin, operating at the transcriptional level or by posttranscriptional editing of RNA. This type of transcript mutation is likely an important factor in the widely occurring nonfamilial early- and late-onset forms of Alzheimer's disease.
Optimization of Substituted <i>N</i>-3-Benzylimidazoquinazolinone Sulfonamides as Potent and Selective PDE5 Inhibitors (2000)

A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.
Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease (2005)

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.
Modeling Task-Based vs. Affect-based Feedback Behavior in Pedagogical Agents: An Inductive Approach (2009)

Affect has been the subject of increasing attention in cognitive accounts of learning. Many intelligent tutoring systems now seek to adapt pedagogy to student affective and motivational processes in an effort to increase the effectiveness of tutorial interaction and improve learning outcomes. However, the majority of research on tutorial feedback has focused on pedagogical content, often at the expense of the affective component of the learning process. It is unclear under which circumstances it is more appropriate to focus directly on student affect and when support is best offered through task-related feedback. This paper proposes an inductive framework for modeling task-based and affect-based feedback to inform the behavior of pedagogical agents within a narrative-centered learning environment.
Consensus Development at NIH: What Went Wrong (1993)

A close observer identifies the Science Court concept as inspiring consensus development conferences at the National Institutes of Health and describes the extent to which they have followed the model. Professor Jacoby also argues that, if the model were more closely followed, conference objectives would be better realized.
Walk-Unlock: Zero-Interaction Authentication Protected with Multi-Modal Gait Biometrics (2016)

Zero-interaction authentication (ZIA) refers to a form of user-transparent login mechanism using which a terminal (e.g., a desktop computer) can be unlocked by the mere proximity of an authentication token (e.g., a smartphone). Given its appealing usability, ZIA has already been deployed in many real-world applications. However, ZIA contains one major security weakness - unauthorized physical access to the token, e.g., during lunch-time or upon theft, allows the attacker to have unfettered access to the terminal. In this paper, we address this gaping vulnerability with ZIA systems by (un)locking the authentication token with the user's walking pattern as she approaches the terminal to access it. Since a user's walking or gait pattern is believed to be unique, only that user (no imposter) would be able to unlock the token to gain access to the terminal in a ZIA session. While walking-based biometrics schemes have been studied in prior literature for other application settings, our main novelty lies in the careful use of: (1) multiple sensors available on the current breed of devices (e.g., accelerometer, gyroscope and magnetometer), and (2) multiple devices carried by the user (in particular, an "in-pocket" smartphone and a "wrist-worn" smartwatch), that all capture unique facets of user's walking pattern. Our contributions are three-fold. First, we introduce, design and implement WUZIA ("Walk-Unlock ZIA"), a multi-modal walking biometrics approach tailored to enhance the security of ZIA systems (still with zero interaction). Second, we demonstrate that WUZIA offers a high degree of detection accuracy, based on multi-sensor and multi-device fusion. Third, we show that WUZIA can resist active attacks that attempt to mimic a user's walking pattern, especially when multiple devices are used.
Is Noise Always Bad? Exploring the Effects of Ambient Noise on Creative Cognition (2012)

This paper examines how ambient noise, an important environmental variable, can affect creativity. Results from five experiments demonstrate that a moderate (70 dB) versus low (50 dB) level of ambient noise enhances performance on creative tasks and increases the buying likelihood of innovative products. A high level of noise (85 dB), on the other hand, hurts creativity. Process measures reveal that a moderate (vs. low) level of noise increases processing difficulty, inducing a higher construal level and thus promoting abstract processing, which subsequently leads to higher creativity. A high level of noise, however, reduces the extent of information processing and thus impairs creativity.
Perspective-consistent multifocus multiview 3D reconstruction of small objects (2019)

Image-based 3D reconstruction or 3D photogrammetry of small-scale objects including insects and biological specimens is challenging due to the use of high magnification lens with inherent limited depth of field, and the object's fine structures and complex surface properties. Due to these challenges, traditional 3D reconstruction techniques cannot be applied without suitable image pre-processings. One such preprocessing technique is multifocus stacking that combines a set of partially focused images captured from the same viewing angle to create a single in-focus image. Traditional multifocus image capture uses a camera on a macro rail. Furthermore, the scale and shift are not properly considered by multifocus stacking techniques. As a consequence, the resulting in-focus images contain artifacts that violate perspective image formation. A 3D reconstruction using such images will fail to produce an accurate 3D model of the object. This paper shows how this problem can be solved effectively by a new multifocus stacking procedure which includes a new Fixed-Lens Multifocus Capture and camera calibration for image scale and shift. Initial experimental results are presented to confirm our expectation and show that the camera poses of fixed-lens images are at least 3-times less noisy than those of conventional moving lens images.
Synthesis of Diaryl Ethers, Diaryl Thioethers, and Diarylamines Mediated by Potassium Fluoride−Alumina and 18-Crown-6:  Expansion of Scope and Utility<sup>1</sup> (1998)

An efficient alternative to the Ullmann ether synthesis of diaryl ethers, diaryl thioethers, and diarylamines involving the S(N)Ar addition of a phenol, thiophenol, or aniline to an appropriate aryl halide, mediated by potassium-fluoride alumina and 18-crown-6 in acetonitrile or DMSO, is described. Expansion of the reaction conditions to include DMSO as solvent has resulted in a far greater range of substitution patterns permitted on the electrophile. For example, it was found that electronically unfavorable 3-chlorobenzonitrile could be condensed with 3-methoxyphenol to form the corresponding diaryl ether in 66% yield, a combination not normally amenable to Ullmann coupling. Electron-withdrawing groups present on the electrophile may be as diverse as nitro, cyano, formyl, acetyl, ester, amide, and even aryl. The method features a simple reaction procedure that provides products in generally good to excellent purified yields.
Alzheimer's β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid (2012)

β-Amyloid protein (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. BACE1 is the rate-limiting enzyme for Aβ production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for Aβ generation, BACE1 plays multiple physiological roles including the regulation of synaptic functions. Here, we found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels, whereas downregulation of BACE1 has the opposite effect. We showed that BACE1's effect is independent of its activity for Aβ production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human Aβ. Furthermore, we demonstrated that BACE1 interacts via its transmembrane domain with adenylate cyclase, resulting in reduction of cellular cAMP levels and thus PKA inactivation and reduced CREB phosphorylation. Our study suggests that in addition to its function as the β-secretase to produce Aβ, BACE1 may contribute to the memory and cognitive deficits typical of AD by regulating the cAMP/PKA/CREB pathway, which is important for memory functions.
HPLC of flavanones and chalcones in different species and clones of Salix. (2013)

The SPE-HPLC method was developed to determine an isosalipurposide (5) and its derivative, 6"-O-p-coumaroyl ester (6) in the bark of eight taxa (I-VIII) belonging to three species of the genus Salix and originating from a natural habitat or cultivated for pharmaceutical purposes. The chalcones were separated by HPLC under gradient elution with the concentration of ACN increasing from 20% to 50% in 0.1% aqueous H3PO, (tG 15 min). The content of both compounds was determined by an external standardization with the use of isoliquiritigenin (7) as a reference substance - a commercially available chalcone, and also isosalipurposide (5) and its derivative, 6"-O-p-coumaroyl ester (6). The latter compound was isolated from the bark of Salix daphnoides (IV) by a CC and semi-preparative HPLC and its structure was elucidated by MS and NMR spectra. It was stated that 6"-O-p-coumaroylisosalipurposide (6), in addition to isosalipurposide (5), is a characteristic flavonoid for the S. daphnoides species. Moreover, the presence of these two chalcones was confirmed in the bark of S. acutifolia (I). Differences were observed in the results obtained from a quantitative analysis due to the type of reference substance used. The content of chalcones was varied and dependent on the species selected for analysis, namely from 22.01/21.08 mg/g in S. daphnoides clone 1095 (III) to 2.47/2.44 mg/g in S. daphnoides (II), collected from a natural habitat. Isosalipurposide (5) was determined in all the investigated species and clones of Salix, besides a number of naringenin derivatives. Separation of all flavonoids: flavanones - naringenin (1), naringenin (+)-5-O-glucoside (2), (-)-5-O-glucoside (3), 7-O-glucoside (4) and chalcones (5 and 6) was performed under gradient elution with the same solvents and changes in ACN concentration from 2% to 37% (tG 60 min). The total amount of flavanones ranged from 4.69 mg/g in S. purpurea clone 1132 (VII) to 41.93 mg/g in S. purpuea (VIII) from Herbapol Wrocław.
PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential (2012)

Fusion protein AML1-ETO, resulting from t(8;21) translocation, is highly related to leukemia development. It has been reported that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. We have previously shown that the expression of AE9a, a splice isoform of AML1-ETO, can rapidly cause leukemia in mice. To understand how AML1-ETO is involved in leukemia development, we took advantage of our AE9a leukemia model and sought to identify its interacting proteins from primary leukemic cells. Here, we report the discovery of a novel AE9a binding partner PRMT1 (protein arginine methyltransferase 1). PRMT1 not only interacts with but also weakly methylates arginine 142 of AE9a. Knockdown of PRMT1 affects expression of a specific group of AE9a-activated genes. We also show that AE9a recruits PRMT1 to promoters of AE9a-activated genes, resulting in enrichment of H4 arginine 3 methylation, H3 Lys9/14 acetylation, and transcription activation. More importantly, knockdown of PRMT1 suppresses the self-renewal capability of AE9a, suggesting a potential role of PRMT1 in regulating leukemia development.
Rapid discovery and optimization of therapeutic antibodies against emerging infectious diseases (2008)

Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5-4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.