gebhart/patrepeval huggingface dataset:
Comparative analysis of KRAS codon 12, 13, 18, 61 and 117 mutations using human MCF10A isogenic cell lines (2015)

KRAS mutations occur in one third of human cancers and cluster in several hotspots, with codons 12 and 13 being most commonly affected. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. We used MCF10A human mammary epithelial cells to establish isogenic cell lines that express different cancer-associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological or elevated levels, and investigated the biochemical and functional consequences of the different variants. The overall effects of low-expressing mutants were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes, migratory abilities, or increased phosphorylation of ERK, PDK1, and AKT. KRAS-G12D, G12V, G13D, and K117N mediated EGF-independent proliferation, whereas anchorage-independent growth was primarily induced by K117N and Q61H. Both codon 13 mutations were associated with increased EGFR expression. Finally, global gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells.
Vitamin status in treated patients with cystic fibrosis. (1981)

The water-soluble (B1, B2, B6, C, folic acid) and fat-soluble vitamin (A, carotene, E, and D) status of 36 patients with cystic fibrosis was assessed and compared with a control group of 21 age-matched normal children. Twenty-seven of the patients were receiving vitamin supplements (except folic acid and vitamin E) at the time of investigation. Vitamin B1, B2, and B6 status was adequate in all patients, and there was little evidence of folic acid deficiency. Vitamin C stores might not have been adequate in some of these patients, despite daily supplements with 50 mg of the vitamin. Steatorrhoea, often severe, was present in most of them. Serum carotene and vitamin E concentrations were low in over 90% of patients and were related to the severity of steatorrhoea. Vitamin A was low in over 40% of the patients despite daily vitamin supplements of 4000 IU and correlated with the serum retinol-binding protein level. Serum 25-OH cholecalciferol was low in some patients whether or not they were receiving a daily supplement of 400 IU vitamin D. In a short-term supplementation trial with water-miscible preparations of vitamin A and E in 14 patients, the serum levels of both vitamins responded well to 2 weeks of treatment with 50 mg vitamin E and 4000 IU vitamin A. Except for serum vitamin A, which was lowest in patients with the poorest clinical grading, the other vitamins were not influenced by the clinical grade of the patients.
Prospects for Gene Therapy for Heart Failure (2000)

Heart failure represents an enormous clinical challenge in need of effective therapeutic approaches. The possibility of gene therapy for heart failure merits consideration at this time because of improvements in vector technology; cardiac gene delivery; and, most importantly, our understanding of the molecular pathogenesis of heart failure. We will first review recent advances in cardiac gene delivery in animal models and then examine several targets being considered for therapeutic intervention. In this context, gene transfer provides not only a potential therapeutic modality but also an important tool to help validate specific targets. Several interventions, particularly those enhancing sarcoplasmic calcium transport, show promise in animal models of heart failure and in myopathic cardiomyocytes derived from patients. However, bridging the gap between these basic investigative studies and clinical gene therapy remains a formidable task. Early experiments in rodents will need to be extended to large-animal models with clinical-grade vectors and delivery systems to assess both efficacy and safety. On the basis of a foundation of rigorous science and a growing understanding of heart failure pathogenesis, there is reason for cautious optimism for the future.
Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases (2014)

Brain stimulation, a therapy increasingly used for neurological and psychiatric disease, traditionally is divided into invasive approaches, such as deep brain stimulation (DBS), and noninvasive approaches, such as transcranial magnetic stimulation. The relationship between these approaches is unknown, therapeutic mechanisms remain unclear, and the ideal stimulation site for a given technique is often ambiguous, limiting optimization of the stimulation and its application in further disorders. In this article, we identify diseases treated with both types of stimulation, list the stimulation sites thought to be most effective in each disease, and test the hypothesis that these sites are different nodes within the same brain network as defined by resting-state functional-connectivity MRI. Sites where DBS was effective were functionally connected to sites where noninvasive brain stimulation was effective across diseases including depression, Parkinson's disease, obsessive-compulsive disorder, essential tremor, addiction, pain, minimally conscious states, and Alzheimer's disease. A lack of functional connectivity identified sites where stimulation was ineffective, and the sign of the correlation related to whether excitatory or inhibitory noninvasive stimulation was found clinically effective. These results suggest that resting-state functional connectivity may be useful for translating therapy between stimulation modalities, optimizing treatment, and identifying new stimulation targets. More broadly, this work supports a network perspective toward understanding and treating neuropsychiatric disease, highlighting the therapeutic potential of targeted brain network modulation.
The Chemistry That Formed Green River Formation Oil Shale (1983)

The Green River Formation with its energy-rich oil shales and its remarkable collection of huge amounts of novel minerals is the product of a gigantic chemical process system which established itself in ancient lakes surrounding Utah's Uinta Mountains. Once established the chemical process system stabilized and maintained itself, repeating the same chemical processes continuously for millions of years on the raw materials entering the lake. This chemistry produced uniform hydrogen-rich organic matter, a simple authigenic mineral suite, and massive deposits of sodium carbonate minerals like nahcolite (NaHCO3), dawsonite [NaAl(OH)2CO2], shortite (Na2CO3·2CaCO3), and trona (Na2CO3·NaHCO3·2H2O). The probable character of these chemical processes and their origin are reviewed.
Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome (2014)

Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.
Enhanced call: a paradigm for applications with dynamic client-membership and client-level binding in ATM networks (1996)

Sophisticated applications in asynchronous transfer mode (ATM) networks require high-level quality-of-service (QoS) guarantees in conjunction with ATM QoS guarantees. We focus on applications that involve varying client-membership and client-level binding (i.e., dependence between current and future clients). Such applications include certain types of conferences, computer-supported cooperative work (CSCW), and client-server based applications. In a traditional call, these applications are set up with a known set of clients and newer clients are admitted via individual connection admission procedures. While this approach guarantees ATM QoS for every client admitted to the application, it cannot guarantee the addition of new clients to an existing application. Consequently, carried clients that depend on a new client can perceive a degraded service when the new client cannot be added because of lack of bandwidth. We refer to this degradation as client-level degradation. To guarantee an upper bound on client-level degradation, we propose a paradigm called enhanced call that statistically reserves virtual channel links (VCLs) for potential new client arrivals. The enhanced call specification encapsulates client descriptors and client-level QoS measures. We propose simple, scaleable, and practical client descriptors. Where possible, the descriptors are chosen in the same spirit as ATM descriptors. Given these descriptors, we develop an analytical framework to determine whether or not to admit an enhanced call. We also present an operational conformance definition that is enforced globally as well as locally.
Current concepts on the theories of the mechanism of action of fluoride (1999)

The caries-preventive effect of fluoride is mainly attributed to the effects on demineralization/remineralization at the tooth oral fluids interface. Sub ppm levels of fluoride in saliva are effective in shifting the balance from demineralization, leading to caries, to remineralization. This is attributed to the fluoride-enhanced precipitation of calcium phosphates, and the formation of fluorhydroxyapatite in the dental tissues. Low fluoride levels are found in saliva after toothbrushing with fluoride containing dentifrices. Similar concentrations are ineffective in interfering with processes of growth and metabolism of bacteria, and also do not result in a significantly reduced dissolution of tooth mineral as a result of (firmly bound) fluoride incorporation. Comparative studies of fluoride efficacy have shown that higher concentrations in solution are needed in pH-cycling studies of dentine than in enamel to maintain the mineral balance or to induce remineralization. This is attributed to the greater solubility of the dentine and the smaller size of the dentine crystallites compared to enamel. Fluoride slow-release devices, in the form of fluoride-releasing restorative materials, may serve to increase the fluoride levels in saliva and plaque to levels at which caries can be prevented, also in high-risk patients. Research questions for the next millennium and future perspectives for fluoride applications should be found in the retention and slow release of fluoride after various combinations of fluoride treatment, the combination of fluoride and anti-microbial treatment, the individualization of caries prevention, and the combination of preventive schemes with new developments in caries diagnosis.
MM-141, an IGF-IR– and ErbB3-Directed Bispecific Antibody, Overcomes Network Adaptations That Limit Activity of IGF-IR Inhibitors (2013)

Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR-mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation.
The Nanopore Electrode (2004)

The fabrication and electrochemical characterization of truncated cone-shaped nanopore electrodes are reported. A nanopore electrode is a Pt disk electrode embedded at the bottom of a conical pore, the circular orifice of the pore having nanometer dimensions. The electrochemical properties of nanopore electrodes with orifice radii of 39 and 74 nm are presented. Both the steady-state and transient voltammetric behavior of the nanopore electrode are reported and compared to predictions obtained using finite-element simulations. The truncated cone-shaped pore electrode possesses a unique transport property-the steady-state flux of molecules into a deep pore is limited by the restriction near the pore orifice, and thus, the steady-state current is independent of the pore depth. This characteristic is potentially useful in studying transport through nanometer-scale orifices.
Salt-inducible kinase inhibition suppresses acute myeloid leukemia progression in vivo (2019)

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a salt-inducible kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF myocyte enhancer factor (MEF2C). In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. In this study, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitro and in vivo conditions. Similar phenotypes were obtained when cells were exposed to YKL-05-099, which caused cell-cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the antiproliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated 2 different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivo and extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing druglike inhibitors of SIK3 for definitive preclinical investigation and for studies in human patients.
Amphiphilic Dendritic Molecules:  Hyperbranched Polyesters with Alkyl-Terminated Branches (2003)

We report on the synthesis of a series of second-generation hyperbranched polyesters with a variable composition of alkyl-terminated groups. We observed that the chemical modification of the hyperbranched cores by substituting a controlled fraction of the terminal hydroxyl groups with hydrophobic alkyl chains is an effective method for a controlling amphiphilic balance of hyperbranched cores with a degree of branching of 50%. Even for imperfect cores, the chemical reaction of hydroxyl groups alkyl tails was very efficient. In fact, the number of attached alkyl tails was fairly close to the theoretical value based on the assumption that all targeted hydroxyl groups were available for the reaction despite their different interior/exterior location. Detailed microstructural analysis of the structure revealed that organized monolayers could be formed at the air−water interface if the number of alkyl tails was higher than two per core. Similar to regular dendrimers, the alkyl tails of hyperbranched molecules at high surface pressure form intramonolayer ordering of the quasi-hexagonal type. However, higher defectness and irregularities of the hyperbranched cores are responsible for poor intralayer ordering of alkyl tails in comparison with regular dendrimers. At high surface pressure, the alkyl tails became arranged in an up-right orientation. The highly water-swollen state of the hyperbranched cores of prolate shape and the partially submerged and standing-off alkyl tails is a characteristic of hyperbranched molecules with fewer alkyl chains in condensed monolayer state at the air−water interface. The core structure is transformed into the oblate, flattened state with preservation of standing-off orientation of the alkyl tails for hyperbranched molecules with crowded outer shells.
Creating a virtual classroom for interactive education on the Web (1995)

The World-Wide Web provides new opportunities for distance education over the Internet. The Web, when combined with other network tools, can be used to create a virtual classroom to bring together a community of learners for interactive education. The Cornell Theory Center, a national center for high performance computing, is investigating the use of emerging network technologies for training computational scientists and researchers in the concepts of parallel processing. This effort is being built on electronic educational materials already on the Web and will evaluate the effectiveness of various collaborative tools.
A fully integrated 22.6dBm mm-Wave PA in 40nm CMOS (2013)

A fully integrated 60GHz CMOS PA with a PSAT of 22.6dBm is presented. To our knowledge, this is the highest reported PSAT at mm-waves in standard CMOS. To achieve a high power level, 32 differential PAs are combined through a network of transmission lines, Wilkinson combiners, and a multi-port argyle transformer. This method of combining minimizes loss while implementing a low impedance load (~12Ω) at the drains of each of the last stage PAs. Electromigration and other reliability issues are discussed.
Single molecule measurements within individual membrane-bound ion channels using a polymer-based bilayer lipid membrane chip (2008)

The measurement of single poly(ethylene glycol) (PEG) molecules interacting with individual bilayer lipid membrane-bound ion channels is presented. Measurements were performed within a polymer microfluidic system including an open-well bilayer lipid membrane formation site, integrated Ag/AgCl reference electrodes for on-chip electrical measurements, and multiple microchannels for independent ion channel and analyte delivery. Details of chip fabrication, bilayer membrane formation, and alpha-hemolysin ion channel incorporation are discussed, and measurements of interactions between the membrane-bound ion channels and single PEG molecules are presented.
WNT-1 expression in basal cell carcinoma of head and neck. An immunohistochemical and confocal study with regard to the intracellular distribution of beta-catenin. (2002)

According to these data, the potential role of the WNT-1 gene in BCC seems to correlate with its ability to induce elevated cytoplasmic beta-catenin levels, suggesting that the WNT-1 gene can activate an intracellular signaling pathway involved in the process of cell transformation.
Reversal of sensory deficit through sacral neuromodulation in an animal model of fecal incontinence (2016)

Sacral neuromodulation augments anal representation in the sensory cortex and restores afferent pathways following injury. PSA-NCAM positive cell density is increased in stimulated cortices and positive cells are clustered in layers II, IV, and V.
Thymidylate Synthase Binds to c-mycRNA in Human Colon Cancer Cells and In Vitro (1995)

Using an immunoprecipitation-reverse transcription-PCR technique, we characterized a thymidylate synthase (TS) ribonucleoprotein complex in cultured human colon cancer cells that consists of TS protein and the mRNA of the nuclear oncogene c-myc. TS protein is complexed in intact cells with the C-terminal coding region of c-myc mRNA that includes nucleotide positions 1625 to 1790. RNA electrophoretic gel mobility shift assays confirm a specific interaction between TS protein and c-myc mRNA and provide additional evidence that the C-terminal coding region represents an important cis-acting regulatory element. Further evidence demonstrates that the in vitro translational efficiency of c-myc mRNA is inhibited as a result of its direct interaction with TS protein. In addition, the presence of exogenous c-myc mRNA specifically relieves the inhibitory effects of TS protein on TS mRNA translation.
Determination of Ergosterol in Yeast (1953)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDetermination of Ergosterol in YeastW Shaw and J JefferiesCite this: Anal. Chem. 1953, 25, 7, 1130Publication Date (Print):July 15, 1953Publication History Published online1 May 2002Published inissue 15 July 1953https://pubs.acs.org/doi/10.1021/ac60079a041https://doi.org/10.1021/ac60079a041research-articleACS PublicationsRequest reuse permissionsArticle Views63Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
From Stein's Unbiased Risk Estimates to the Method of Generalized Cross Validation (1985)

This paper concerns the method of generalized cross validation (GCV), a promising way of choosing between linear estimates. Based on Stein estimates and the associated unbiased risk estimates (Stein, 1981), a new approach to GCV is developed. Many consistency results are obtained for the cross-validated (Steinized) estimates in the contexts of nearest-neighbor nonparametric regression, model selection, ridge regression, and smoothing splines. Moreover, the associated Stein's unbiased risk estimate is shown to be uniformly consistent in assessing the true loss (not the risk). Consistency properties are examined as well when the sampling error is unknown. Finally, we propose a variant of GCV to handle the case that the dimension of the raw data is known to be greater than that of their expected values.