gebhart/patrepeval huggingface dataset:
Constitutive Activation of Extracellular Signal-Regulated Kinase in Human Acute Leukemias: Combined Role of Activation of MEK, Hyperexpression of Extracellular Signal-Regulated Kinase, and Downregulation of a Phosphatase, PAC1 (1999)

Extracellular signal-regulated kinase (ERK) is an important intermediate in signal transduction pathways that are initiated by many types of cell surface receptors. It is thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Constitutive activation of ERK in fibroblasts elicits oncogenic transformation, and recently, constitutive activation of ERK has been observed in some human malignancies, including acute leukemia. However, mechanisms underlying constitutive activation of ERK have not been well characterized. In this study, we examined the activation of ERK in 79 human acute leukemia samples and attempted to find factors contributing to constitutive ERK activation. First, we showed that ERK and MEK were constitutively activated in acute leukemias by in vitro kinase assay and immunoblot analysis. However, in only one half of the studied samples, the pattern of ERK activation was similar to that of MEK activation. Next, by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis, we showed hyperexpression of ERK in a majority of acute leukemias. In 17 of 26 cases (65.4%) analyzed by immunoblot, the pattern of ERK expression was similar to that of ERK activation. The fact of constitutive activation of ERK in acute leukemias suggested to us the possibility of an abnormal downregulation mechanism of ERK. Therefore, we examined PAC1, a specific ERK phosphatase predominantly expressed in hematopoietic tissue and known to be upregulated at the transcription level in response to ERK activation. Interestingly, in our study, PAC1 gene expression in acute leukemias showing constitutive ERK activation was significantly lower than that in unstimulated, normal bone marrow (BM) samples showing minimal or no ERK activation (P =.002). Also, a significant correlation was observed between PAC1 downregulation and phosphorylation of ERK in acute leukemias (P =.002). Finally, by further analysis of 26 cases, we showed that a complementary role of MEK activation, ERK hyperexpression, and PAC1 downregulation could contribute to determining the constitutive activation of ERK in acute leukemia. Our results suggest that ERK is constitutively activated in a majority of acute leukemias, and in addition to the activation of MEK, the hyperexpression of ERK and downregulation of PAC1 also contribute to constitutive ERK activation in acute leukemias.
Biological Properties of Antisense Oligonucleotides Conjugated to Different High-Molecular Mass Poly(Ethylen Glycols) (1999)

Abstract The effect of the different structures of high-molecular weight poly(ethylen glycol) chains on the biological properties of the conjugated antisense oligonucleotide has been investigated and compared.
Diels-Alder Polymerization between Bis(cyclopentadienones) and Acetylenes. A Versatile Route to New Highly Aromatic Polymers (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDiels-Alder Polymerization between Bis(cyclopentadienones) and Acetylenes. A Versatile Route to New Highly Aromatic PolymersUday Kumar and Thomas X. NeenanCite this: Macromolecules 1995, 28, 1, 124–130Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/ma00105a016https://doi.org/10.1021/ma00105a016research-articleACS PublicationsRequest reuse permissionsArticle Views779Altmetric-Citations46LEARN 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
Silencing of Hypoglossal Motoneurons Leads to Sleep Disordered Breathing in Lean Mice (2018)

Obstructive Sleep Apnea (OSA) is a prevalent condition and a major cause of morbidity and mortality in Western Society. The loss of motor input to the tongue and specifically to the genioglossus muscle during sleep is associated with pharyngeal collapsibility and the development of OSA. We applied a novel chemogenetic method to develop a mouse model of sleep disordered breathing Our goal was to reversibly silence neuromotor input to the genioglossal muscle using an adeno-associated viral vector carrying inhibitory designer receptors exclusively activated by designer drugs AAV5-hM4Di-mCherry (DREADD), which was delivered bilaterally to the hypoglossal nucleus in fifteen C57BL/6J mice. In the <i>in vivo</i> experiment, 4 weeks after the viral administration mice were injected with a DREADD ligand clozapine-N-oxide (CNO, i.p., 1mg/kg) or saline followed by a sleep study; a week later treatments were alternated and a second sleep study was performed. Inspiratory flow limitation was recognized by the presence of a plateau in mid-respiratory flow; oxyhemoglobin desaturations were defined as desaturations >4% from baseline. In the <i>in vitro</i> electrophysiology experiment, four males and three females of 5 days of age were used. Sixteen-nineteen days after DREADD injection brain slices of medulla were prepared and individual hypoglossal motoneurons were recorded before and after CNO application. Positive mCherry staining was detected in the hypoglossal nucleus in all mice confirming successful targeting. In sleep studies, CNO markedly increased the frequency of flow limitation n NREM sleep (from 1.9 ± 1.3% after vehicle injection to 14.2 ± 3.4% after CNO, <i>p</i> < 0.05) and REM sleep (from 22.3% ± 4.1% to 30.9 ± 4.6%, respectively, <i>p</i> < 0.05) compared to saline treatment, but there was no significant oxyhemoglobin desaturation or sleep fragmentation. Electrophysiology recording in brain slices showed that CNO inhibited firing frequency of DREADD-containing hypoglossal motoneurons. We conclude that chemogenetic approach allows to silence hypoglossal motoneurons in mice, which leads to sleep disordered breathing manifested by inspiratory flow limitation during NREM and REM sleep without oxyhemoglobin desaturation or sleep fragmentation. Other co-morbid factors, such as compromised upper airway anatomy, may be needed to achieve recurrent pharyngeal obstruction observed in OSA.
Simultaneous measurement of stress and temperature with a fiber Bragg grating based on a loop thin-wall section beam (2006)

We designed and demonstrated what we believe to be a novel sensor for simultaneous measurement of stress and temperature. A fiber Bragg grating is flatly adhered to the surface of a loop thin-wall section beam. The theoretical analyses and the experimental results show that both the central wavelength shift and the chirped bandwidth of the grating reflection spectrum have a linear relationship with the stress and the temperature, respectively, and the slopes of them are different. Therefore, the temperature and stress can be discriminated by interrogating the chirped fiber grating. Moreover, we also investigated the strain of the loop thin-wall section beam, and the results show that the strain is cosine proportional to the double positional angle.
Forgery and tamper-proof identification document (1993)

A novel technique for protecting identification documents (ID) against forgery and tampering is described. A security seal is printed beside the photograph on the face of the ID card. The security seal has the dimensions of a postage stamp and contains encrypted information derived from the photograph as well as alphanumeric information normally found on an ID card. It is used to verify the legitimacy of the ID card. The verification station consists of a scanner interfaced to a personal computer. During the verification process, the card is placed on the scanner, which transfers a digital representation of the card image to the computer. The information within the security seal is extracted and decoded using the public portion of the asymmetrical key and is then compared with the information derived from the face of the card including the photograph. A forgery is declared if the comparison fails. A fully functional prototype has been built and evaluated for variation of the hardware.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase (2000)

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation mechanisms of individual protein kinases can achieve both high affinity and high specificity.
FINRA 529 Plan Share Class Initiative encourages firms to self-report violations (2019)

Purpose To explain FINRA’s new 529 Plan Share Class Initiative, which encourages broker-dealers to self-report violations. Design/methodology/approach This article provides an overview of 529 plans, the various fee structures of the underlying investment funds, and guidance that broker-dealers should tailor their recommendations to the needs of the individual customer. The article discusses FINRA’s initiative for broker-dealers to self-report if they have violations in this area. It describes various supervisory failures brokerage firms may experience in connection with recommending 529 plans, eligibility for the self-reporting initiative and benefits of self-reporting. Findings This FINRA initiative provides an opportunity for firms to reflect on their supervisory systems and provide restitution to harmed customers. It also provides relevant fee-based investment information to customers. Practical implications 529 plans are valuable tax-advantaged tools to encourage saving for the future educational expenses of a designated beneficiary. If brokerage firms lack reasonable supervisory procedures to recommend appropriate investments based on the length of the investment horizon, this FINRA initiative provides a unique and limited opportunity for firms to assess their supervisory systems and procedures governing 529 Plan share-class recommendations, to identify and remediate any defects, and to compensate any investors harmed by supervisory failures, while possibly avoiding fines for such conduct. Originality/value Expert guidance from experienced financial services regulatory and public finance lawyers.
Specific T Regulatory Cells Display Broad Suppressive Functions against Experimental Allergic Encephalomyelitis upon Activation with Cognate Antigen (2005)

To date, very few Ag-based regimens have been defined that could expand T regulatory (Treg) cells to reverse autoimmunity. Additional understanding of Treg function with respect to specificity and broad suppression should help overcome these limitations. Ig-proteolipid protein (PLP)1, an Ig carrying a PLP1 peptide corresponding to amino acid residues 139-151 of PLP, displayed potent tolerogenic functions and proved effective against experimental allergic encephalomyelitis (EAE). In this study, we took advantage of the Ig-PLP1 system and the PLP1-specific TCR transgenic 5B6 mouse to define a regimen that could expand Ag-specific Treg cells in vivo and tested for effectiveness against autoimmunity involving diverse T cell specificities. The findings indicate that in vivo exposure to aggregated Ig-PLP1 drives PLP1-specific 5B6 TCR transgenic cells to evolve as Treg cells expressing CD25, CTLA-4, and Foxp3 and producing IL-10. These Treg cells were able to suppress PLP1 peptide-induced EAE in both SJL/J and F(1) (SJL/J x C57BL/6) mice. However, despite being effective against disease induced with a CNS homogenate, the Treg cells were unable to counter EAE induced by a myelin basic protein or a myelin oligodendrocyte glycoprotein peptide. Nevertheless, activation with Ag before transfer into the host mice supports suppression of both myelin oligodendrocyte glycoprotein- and myelin basic protein peptide-induced EAE. Thus, it is suggested that activation of Treg cells by the cognate autoantigen is necessary for operation of broad suppressive functions.
Total Synthesis of Vancomycin—Part 1: Design and Development of Methodology (1999)

A number of valuable new synthetic strategies, such as the triazene-driven biaryl ether synthesis, have been developed during the total synthesis of vancomycin (1). Modern catalytic asymmetric reactions were employed for the construction of the required amino acid building blocks, which were then assembled to the appropriate peptide fragments, whose cyclization in the order C-O-D→AB/C-O-D→AB/C-O-D-E led to framework of the vancomycin aglycon (2). Sequential attachment of the required sugar moieties onto a suitably protected aglycon derivative, followed by deprotection, allowed the stereoselective total synthesis of the glycopeptide antibiotic vancomycin (1).
Trifluoroacetic Acid-Promoted Synthesis of 3-Hydroxy, 3-Amino and Spirooxindoles from α-Keto-N-Anilides (2011)

Ketoanilides containing alkyl side chains were readily cyclized to 3-hydroxy-2-oxindoles or spirooxindoles by a single or double intramolecular Friedel-Crafts reaction in the presence of trifluoroacetic acid (TFA) at room temperature or at 45 °C. α-Iminocarboxamides, generated in situ from ketoamides, cyclized similarly to 3-aminooxindoles under identical conditions.
Analysis of receptor signaling pathways by mass spectrometry: Identification of Vav-2 as a substrate of the epidermal and platelet-derived growth factor receptors (2000)

Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (EGFR) by their cognate ligands leads to activation of the receptor. Transphosphorylation of the receptor subunits is followed by the recruitment of signaling molecules containing src homology 2 (SH2) or phosphotyrosine interaction domains (PID). Additionally, several cytoplasmic proteins that may or may not associate with the receptor undergo tyrosine phosphorylation. To identify several components of the EGFR signaling pathway in a single step, we have immunoprecipitated molecules that are tyrosine phosphorylated in response to EGF and analyzed them by one-dimensional gel electrophoresis followed by mass spectrometry. Combining matrix-assisted laser desorption/ionization (MALDI) and nanoelectrospray tandem mass spectrometry (MS/MS) led to the identification of nine signaling molecules, seven of which had previously been implicated in EGFR signaling. Several of these molecules were identified from low femtomole levels of protein loaded onto the gel. We identified Vav-2, a recently discovered guanosine nucleotide exchange factor that is expressed ubiquitously, as a substrate of the EGFR. We demonstrate that Vav-2 is phosphorylated on tyrosine residues in response to EGF and associates with the EGFR in vivo. Binding of Vav-2 to the EGFR is mediated by the SH2 domain of Vav-2. In keeping with its ubiquitous expression, Vav-2 seems to be a general signaling molecule, since it also associates with the platelet-derived growth factor (PDGF) receptor and undergoes tyrosine phosphorylation in fibroblasts upon PDGF stimulation. The strategy suggested here can be used for routine identification of downstream components of cell surface receptors in mammalian cells.
Molecular mechanisms of cell death and regeneration in acute ischemic renal injury (1999)

Acute renal failure continues to have an unacceptably high mortality rate. Ischemic renal injury is the most common cause of acute renal failure. Understanding the molecular mechanisms of cell death and regeneration is important for designing future therapeutic strategies. Recent interest in our laboratory has focused on molecular response after ischemic renal injury and, in particular, genes that are important in cell death and repair after ischemia. The identification of genes that are differentially expressed after ischemia has led to new information regarding the identity of possible mediators of cell death and regeneration in renal tubular epithelial cells.
An archaeal CRISPR type III-B system exhibiting distinctive RNA targeting features and mediating dual RNA and DNA interference (2014)

CRISPR-Cas systems provide a small RNA-based mechanism to defend against invasive genetic elements in archaea and bacteria. To investigate the in vivo mechanism of RNA interference by two type III-B systems (Cmr-α and Cmr-β) in Sulfolobus islandicus, a genetic assay was developed using plasmids carrying an artificial mini-CRISPR (AC) locus with a single spacer. After pAC plasmids were introduced into different strains, Northern analyses confirmed that mature crRNAs were produced from the plasmid-borne CRISPR loci, which then guided gene silencing to target gene expression. Spacer mutagenesis identified a trinucleotide sequence in the 3'-region of crRNA that was crucial for RNA interference. Studying mutants lacking Cmr-α or Cmr-β system showed that each Cmr complex exhibited RNA interference. Strikingly, these analyses further revealed that the two Cmr systems displayed distinctive interference features. Whereas Cmr-β complexes targeted transcripts and could be recycled in RNA cleavage, Cmr-α complexes probably targeted nascent RNA transcripts and remained associated with the substrate. Moreover, Cmr-β exhibited much stronger RNA cleavage activity than Cmr-α. Since we previously showed that S. islandicus Cmr-α mediated transcription-dependent DNA interference, the Cmr-α constitutes the first CRISPR system exhibiting dual targeting of RNA and DNA.
Cross-national prevalence and risk factors for suicidal ideation, plans and attempts (2008)

There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours. These findings have significant implications for the prediction and prevention of suicidal behaviours.
Essential Amino Acid Residues in the Single-stranded DNA-binding Protein of Bacteriophage T7 (2002)

Gene 2.5 of bacteriophage T7 is an essential gene that encodes a single-stranded DNA-binding protein. T7 phage with gene 2.5 deleted can grow only on Escherichia coli cells that express gene 2.5 from a plasmid. This complementation assay was used to screen for lethal mutations in gene 2.5. By screening a library of randomly mutated plasmids encoding gene 2.5, we identified 20 different single amino acid alterations in gene 2.5 protein that are lethal in vivo. The location of these essential residues within the three-dimensional structure of gene 2.5 protein assists in the identification of motifs in the protein. In this study we show that a subset of these alterations defines the dimer interface of gene 2.5 protein predicted by the crystal structure. Recombinantly expressed and purified gene 2.5 protein-P22L, gene 2.5 protein-F31S, and gene 2.5 protein-G36S do not form dimers at salt concentrations where the wild-type gene 2.5 protein exists as a dimer. The basis of the lethality of these mutations in vivo is not known because altered proteins retain the ability to bind single-stranded DNA, anneal complementary strands of DNA, and interact with T7 DNA polymerase.
Islet Amyloid and Type 2 Diabetes Mellitus (2000)

Almost a century ago, in 1901, Eugene L. Opie described “hyaline degeneration of the islands of Langerhans” in the pancreas of patients with hyperglycemia (Figure 1).1 A relation with diabetes mellitus was suggested, although at that time insulin had not yet been identified as an islet protein. The chief component of the proteinaceous deposits described by Opie — later referred to as islet amyloid — was identified in 1986 as a protein of beta-cell origin named islet amyloid polypeptide.2 Islet amyloid is a characteristic pathological finding in patients with type 2 diabetes mellitus, being present in more than 90 percent. . . .
Overexpression and Preferential Nuclear Translocation of the Transcription Factor Yin Yang 1 (YY1) in Human Bone Marrow-Derived Multiple Myeloma. (2005)

Abstract Yin Yang 1 (YY1) is a ubiquitously expressed zinc-finger transcriptional regulator that can function as an activator, a repressor, or an initiator binding protein. YY1 has been implicated in the control of cell growth, development, differentiation and tumor suppression. We have recently reported that YY1 regulates the transcription of death receptors in carcinoma and lymphoma and thus, YY1 regulates tumor sensitivity to immune-mediated apoptosis (Huerta-Yepez, et al., 2004, Oncogene23: 4993–5003; Vega, M., et al., 2005, Journal of Immunology175: 2174–2183). In addition, we have also reported that human prostate tumor tissues overexpress YY1 (Seligson, et al., 2005, International Journal of Oncology 27:131). This study investigated the expression of YY1 in multiple myeloma (MM) with the objective of determining whether YY1 plays a role in the progression and drug- resistance of MM. We have initiated these studies by examining nine bone marrow (BM) samples derived from patients with MM. Immunohistochemical studies were performed for the detection and cytoplasmic or nuclear localization of YY1 in the MM cells and also in adjacent normal mature and immature cells. The intensity of staining by the anti-YY1 antibody was scored and the relative intensity was calculated. Two slides from each patient were analyzed and 200 cells per slide were scored. Mean intensities of all samples were calculated and the data were subjected to statistical analysis. YY1 expression in normal BM was low and primarily of cytoplasmic origin. In contrast, YY1 was significantly overexpressed in MM cells. The mean intensity in the MM was approximately three-four fold higher than that of the normal cells and was primarily of nuclear origin (p-value &amp;lt; 0.05). The signals that control shuttling YY1 are undefined. The expression of YY1 in normal mature and immature cells was low and there was comparable staining in the cytoplasm and the nucleus. Analysis of the cell distribution expressing YY1 by flow cytometry revealed that greater than 50% of the cells in the CD38+ subset expressed YY1. In addition, the MM tumor cells also expressed high level of pleiotrophin (PTN) and the patients had high levels of circulating PTN. PTN is a growth factor for MM and PTN transcription is regulated by an initiator element and could thus be a target of YY1-mediated transcriptional control. These findings suggest that YY1 overexpression may be involved in the pathogenesis of MM and is a potential target for therapeutic intervention. Current studies are aimed at examining the prognostic and diagnostic roles of YY1 and PTN in MM and molecular mechanisms that underlie their overexpression in MM.