gebhart/patrepeval huggingface dataset:
E7080, an oral multitargeted tyrosine kinase inhibitor, has direct anti-tumor efficacy via inhibition of KIT signaling in small cell lung cancer (2004)

4636 Coexpression of the receptor tyrosine kinase KIT and its ligand SCF has been reported in up to 70% of small cell lung cancer (SCLC) cell lines and clinical SCLC samples. The coexpression of KIT and SCF in SCLC suggests that KIT signaling is accelerated or maintained by an autocrine activation loop. Several KIT inhibitors have been shown to inhibit SCF-stimulated SCLC proliferation in vitro and in vivo. E7080 is an oral multitargeted tyrosine kinase inhibitor of KDR (VEGFR-2), Flt-1 (VEGFR-1), FGFR1 and PDGFRbeta with IC50 values of 5 –50 nM in cell free kinase assay. E7080 also inhibits KIT with IC50 value of 270 nM. We evaluated the effect of E7080 on KIT activity in SCLC. Treatment of the KIT-expressing SCLC cell line, NCI-H526 with E7080 resulted in dose-dependent inhibition of SCF-stimulated cell proliferation, with IC50 value of 10 nM. E7080 inhibited SCF-stimulated KIT tyrosine phosphorylation of NCI-H526 in a dose-dependent manner, with IC50 value of 10 nM. E7080 also inhibited downstream events of KIT activation including ERK1/2 and Akt phosphorylation in a dose-dependent manner, with IC50 value consistent with that observed for the inhibition of KIT phosphorylation. E7080 was also evaluated in an NCI-H526 xenograft model. Oral administration of E7080 at doses from 10 to 100 mg/kg (BID, QDx14) resulted in dose-dependent inhibition of tumor growth that ranged from 61 to 71 %. E7080 at a dose of 100 mg/kg inhibited tumor growth, even if treatment was initiated following significant tumor growth. To investigate the status of KIT activation in vivo, NCI-H526 tumors were resected after 2 h treatment with E7080, then KIT phosphorylation was quantified. E7080 reduced phospho-KIT levels in NCI-H526 tumors, correlating with anti-tumor efficacy. Our results suggest that E7080 has therapeutic potential in SCLC, caused by direct anti-tumor efficacy via inhibition of KIT signaling as well as anti-angiogenesis efficacy via inhibition of KDR (VEGFR-2) signaling.
Activation of Peroxisome Proliferator–Activated Receptor δ Inhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice (2011)

These findings uncover a previously unrecognized mechanism for the renoprotective effects of PPARδ agonists and support the concept that PPARδ agonists may offer a novel therapeutic approach for the treatment of diabetic nephropathy.
Peripheral and central angiotensin II regulates expression of genes of the renin-angiotensin system (1992)

We investigated whether angiotensin (ANG) II has the potential to regulate expression of genes of the renin-angiotensin system (RAS) in peripheral and central tissues. ANG II (0.1 or 6.0 nmol/h) was infused by osmotic minipump into male Sprague-Dawley rats (225-250 g) for 5 days, either intravenously or intracerebroventricularly. We measured angiotensinogen mRNA in liver, adrenal glands, and brain (hypothalamus and lower brain stem), renin mRNA in the kidney, and angiotensin-converting enzyme (ACE) mRNA in the lung and testis by Northern blot analysis. We demonstrated that plasma ANG II increases the levels of liver angiotensinogen mRNA, decreases kidney renin mRNA, and decreases lung ACE mRNA. Intracerebroventricular administration of ANG II resulted in a different pattern of responses of the peripheral RAS components. Liver angiotensinogen mRNA was increased, and kidney renin mRNA was decreased by both doses of ANG II, whereas lung ACE mRNA remained unresponsive at either dose. Centrally mediated influences of ANG II are most likely indirect since plasma ANG II concentration was not changed. This study has revealed that ANG II has profound diverse effects that influence the regulation of its formation. Further, results indicate that genes of the RAS responded to exogenous ANG II in both tissue- and route-specific ways.
The 2004 International Electronics Manufacturing Initiative (iNEMI) Technology Roadmaps (2005)

The tenth anniversary edition of the biennial roadmap is the first edition under our new name: International Electronics Manufacturing Initiative (iNEMI). The nineteen technology roadmaps identify future research, development, and implementation needs to continue the growth of the worldwide electronics industry. During this roadmap cycle, we consciously targeted participation from key Asian and European firms/organizations in order to help insure that the technology projections truly represent a global view. With this roadmap we established an international collaborative agreement with the IEEE / CPMT (Institute of Electrical and Electronics Engineers / Components, Packaging and Manufacturing Technology), while continuing our strong linkages with other international roadmapping organizations - ITRS, IPC, IMAPS, INSIC, SCC, and OIDA- and with USDC. The 2004 iNEMI Roadmap consists of over 1200 pages, with more than 470 participants from over 220 companies, universities and associations from 11 countries. This paper highlights technology needs, paradigm shifts, strategic concerns, and key recommendations from the roadmap. Emphasis is placed on the advanced packaging, sensors, system in package, and organic and ceramic substrate roadmap chapters. This roadmap has increased the focus on forecasting potentially disruptive technology in the 2012-2015 time frame such as the use of nanotechnology to address the projected end of Moore's law and the scaling of CMOS devices. This roadmap balances the market needs against the future technology capabilities. The 2004 iNEMI Roadmap is a valuable snapshot of our industry in the third millennium. The challenge now shifts to leveraging these findings for the good of the electronics manufacturing supply chain
Maximum likelihood method for integer frequency offset estimation of OFDM systems (2004)

A novel method for integer frequency offset estimation of OFDM systems is derived, which is based on the maximum likelihood (ML) technique and exploits the differential information between two consecutive blocks of OFDM data symbols in the frequency domain. The reason why the proposed ML method has better performance than the conventional method is analysed.
Bivalirudin for Patients with Acute Coronary Syndromes (2006)

In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158 [ClinicalTrials.gov].).
Synthesis of Acyclonucleoside Phosphonates as Antiviral Agents Against Cytomegalovirus (1994)

Abstract Phosphonic acid analogs of ACV and DHPG that are isosteric with ACV phosphate and DHPG phosphate have been synthesized and evaluated for antiviral activity against human, murine, and guinea pig strains of cytomegalovirus. The phosphonates showed high activity against all of the strains. They were also evaluated against a DHPG resistant strain of human cytomegalovirus. Although the activity dropped considerably, significant antiviral activity was still evident.
关系性思维中的一些重要关联——对中国和澳大利亚6～7年级学生进行的调查研究 (2008)

近年来,关系性思维（relational thinking）的研究成为数学教育领域的一个热点问题.这一领域研究的主要目的之一就是促进学生从算术学习向代数学习的顺利过渡.利用带有一个未知数字和两个未知数字的数式,来探索学生在数式中运用关系性思维的能力与处理含有字母的式子的能力之间的重要关联.重点讨论学生对含有两个未知数字的数式和含有字母式子的不同类型的回答,以及学生在含有两个未知数字数式上的表现是如何影响他们在含有字母的式子上的表现.
Disease‐specific phenotypes in dopamine neurons from human iPS‐based models of genetic and sporadic Parkinson's disease (2012)

Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.
The human and African green monkey TRIM5α genes encode Ref1 and Lv1 retroviral restriction factor activities (2004)

The rhesus macaque tripartite motif containing protein TRIM5alpha specifically restricts HIV-1 infection at an early post-entry step before reverse transcription [Stremlau, M., Owens, C. M., Perron, M. J., Kiessling, M., Autissier, P. & Sodroski, J. (2004) Nature 427, 848-853]. Here, we show that the human and African green monkey (AGM) TRIM5alpha genes encode Ref1 and Lv1 antiretroviral activities, respectively. Expression of TRIM5alpha in permissive cat cells renders them resistant to restriction-sensitive murine leukemia virus but not closely related insensitive virus. Disruption of TRIM5alpha expression in human and AGM cells with small interfering RNA rescues infectivity of restricted virus without affecting unrestricted virus. We also demonstrate that the activity of the murine restriction factor Fv1 depends on TRIM5alpha expression when Fv1 is expressed in human cells. Furthermore, a drug that modifies the behavior of the related promyelocytic leukemia protein PML specifically rescues infection by viruses restricted by human TRIM5alpha. Alignment of the TRIM5alpha proteins from rhesus macaque and AGM indicates an 18-aa insertion. We speculate that this insertion may contribute to the broader specificity of the AGM TRIM5alpha restriction as compared with the human and rhesus macaque proteins.
Construction of a "mutagenesis cartridge" for poliovirus genome-linked viral protein: isolation and characterization of viable and nonviable mutants. (1988)

By following a strategy of genetic analysis of poliovirus, we have constructed a synthetic "mutagenesis cartridge" spanning the genome-linked viral protein coding region and flanking cleavage sites in an infectious cDNA clone of the type 1 (Mahoney) genome. The insertion of new restriction sites within the infectious clone has allowed us to replace the wild-type sequences with short complementary pairs of synthetic oligonucleotides containing various mutations. A set of mutations have been made that create methionine codons within the genome-linked viral protein region. The resulting viruses have growth characteristics similar to wild type. Experiments that led to an alteration of the tyrosine residue responsible for the linkage to RNA have resulted in nonviable virus. In one mutant, proteolytic processing assayed in vitro appeared unimpaired by the mutation. We suggest that the position of the tyrosine residue is important for genome-linked viral protein function(s).
Transcriptional Regulation of Neural Retina Leucine Zipper (Nrl), a Photoreceptor Cell Fate Determinant (2011)

The transcription factor neural retina leucine zipper (Nrl) is a critical determinant of rod photoreceptor cell fate and a key regulator of rod differentiation. Nrl(-/-) rod precursors fail to turn on rod genes and instead differentiate as cones. Furthermore, NRL mutations in humans cause retinitis pigmentosa. Despite the developmental and clinical significance of this gene, little is known about the transcriptional regulation of Nrl itself. In this study, we sought to define the cis- and trans-acting factors responsible for initiation and maintenance of Nrl transcription in the mouse retina. Utilizing a quantitative mouse retinal explant electroporation assay, we discovered a phylogenetically conserved, 30-base pair region immediately upstream of the transcription start site that is required for Nrl promoter activity. This region contains binding sites for the retinal transcription factors CRX, OTX2, and RORβ, and point mutations in these sites completely abolish promoter activity in living retinas. Gel-shift experiments show that CRX, OTX2, and RORβ can bind to the critical region in vitro, whereas ChIP experiments demonstrate binding of CRX and OTX2 to the critical region in vivo. Thus, our results indicate that CRX, OTX2, and RORβ directly regulate Nrl transcription by binding to critical sites within the Nrl promoter. We propose a model in which Nrl expression is primarily initiated by OTX2 and RORβ and later maintained at high levels by CRX and RORβ.
The lac Promoter (1980)

INTRODUCTION The lac promoter is a region of DNA required for the initiation of transcription of the lac operon (Jacob et al. 1964; Scaife and Beckwith 1967; Miller 1970; Reznikoff 1972; Dickson et al. 1975). The nucleotide sequence of the promoter contains the information necessary for the specific interaction of two proteins with the DNA. These proteins are RNA polymerase and a positive stimulatory protein, the catabolite gene activator protein, CAP (also termed CRP and CGA protein in other chapters of this volume). It is currently believed that transcription initiation occurs by the following general process. CAP in the presence of adenosine 3′,5′-monophosphate (cyclic [c]AMP) binds to a site in the promoter. The binding of the CAP–cAMP complex stimulates the productive interaction of RNA polymerase with the promoter such that, if the four ribonucleoside triphosphates are present, a lac mRNA transcript will be initiated (de Crombrugghe et al. 1971; Eron and Block 1971). This interaction of RNA polymerase with the promoter may be a complex process involving several steps such as the specific loose binding of RNA polymerase to the closed helix (formation of the “closed complex”), the generation of a region of localized denaturation (formation of the “open” or “rapid start complex”), and the initiation of the transcript (Chamberlin 1974). A complete understanding of the structure of the promoter and an analysis of how specific changes in the structure alter one or more of the reactions mentioned above may yield some insight as to how the various steps...
Long-term Vaccination with Multiple Peptides Derived from Cancer-Testis Antigens Can Maintain a Specific T-cell Response and Achieve Disease Stability in Advanced Biliary Tract Cancer (2013)

Four-peptide vaccination was well tolerated and seemed to provide some clinical benefit to some patients. These immunologic and clinical responses were maintained over the long term through continuous vaccinations.
Candida albicans Als1p: an adhesin that is a downstream effector of the EFG1 filamentation pathway (2002)

Filamentation and adherence to host cells are critical virulence factors of Candida albicans. Multiple filamentation regulatory pathways have been discovered in C. albicans using Saccharomyces cerevisiae as a model. In S. cerevisiae, these pathways converge on Flo11p, which functions as a downstream effector of filamentation and also mediates cell-cell adherence (flocculation). In C. albicans, such effector(s) have not yet been identified. Here, we demonstrate that the cell surface protein Als1p is an effector of filamentation in C. albicans. We show that Als1p expression is controlled by the transcription factor Efg1p, which is known to be a key regulator of filamentation in C. albicans. Further, disruption of ALS1 inhibited filamentation, and autonomous expression of Als1p restored filamentation in an efg1 homozygous null mutant. Thus, Als1p functions as a downstream effector of the EFG1 filamentation pathway. In addition, we found that Als1p mediates both flocculation and adherence of C. albicans to endothelial cells in vitro. As a cell surface glycoprotein that mediates filamentation and adherence, Als1p has both structural and functional similarity to S. cerevisiae Flo11p. Consistent with our in vitro results, Als1p was required for both normal filamentation and virulence in the mouse model of haematogenously disseminated candidiasis.
Synthesis and Properties of Second-Generation 2-5A-Antisense Chimeras with Enhanced Resistance to Exonucleases (1997)

In order to stabilize 2-5A-antisense chimeras to exonucleases, we have synthesized chimeric oligonucleotides in which the last phosphodiester bond at the 3'-terminus of the antisense domain was inverted from the usual 3',5'-linkage to a 3',3'-linkage. The preparation of such analogues was accomplished through standard phosphoramidite chemistry with the use of a controlled pore glass solid support with a nucleoside attached through its 5'-hydroxyl, thereby permitting elongation at the 3'-hydroxyl. The structures of such terminally inverted linkage chimeras of the general formula pA4-[pBu]2-(pdNn3'-3'dN) were corroborated by a combination of snake venom phosphodiesterase digestion in the presence or absence of bacterial alkaline phosphatase. Most characteristically, the presence of the 3'-terminal-inverted phosphodiester linkage produced an unnatural dinucleotide of general composition dN3'p3'dM. These structures could be confirmed by independent synthesis and fast atom bombardment mass spectroscopy (FAB). 2-5A-Antisense chimeras of this structural class, pA4-[pBu]2-(pdNn'3-3'dN), were 5-6-fold more stable than their unmodified congeners, pA4-[pBu]2-(pdN)n, to degradation by a representative phosphodiesterase from snake venom. In 10% human serum, the new 2-5A-antisense chimeras, pA4-[pBu]2-(pdNn3'-3'dN), possessed a half-life that was 28-fold longer than that of the unmodified chimeras. These results provide entry to a second generation of 2-5A-antisense chimeras.
Reductive acetogenesis in animal and human gut (1994)

chap. 7
Protein Extraction of Formalin-fixed, Paraffin-embedded Tissue Enables Robust Proteomic Profiles by Mass Spectrometry (2009)

Global mass spectrometry (MS) profiling and spectral count quantitation are used to identify unique or differentially expressed proteins and can help identify potential biomarkers. MS has rarely been conducted in retrospective studies, because historically, available samples for protein analyses were limited to formalin-fixed, paraffin-embedded (FFPE) archived tissue specimens. Reliable methods for obtaining proteomic profiles from FFPE samples are needed. Proteomic analysis of these samples has been confounded by formalin-induced protein cross-linking. The performance of extracted proteins in a liquid chromatography tandem MS format from FFPE samples and extracts from whole and laser capture microdissected (LCM) FFPE and frozen/optimal cutting temperature (OCT)-embedded matched control rat liver samples were compared. Extracts from FFPE and frozen/OCT-embedded livers from atorvastatin-treated rats were further compared to assess the performance of FFPE samples in identifying atorvastatin-regulated proteins. Comparable molecular mass representation was found in extracts from FFPE and OCT-frozen tissue sections, whereas protein yields were slightly less for the FFPE sample. The numbers of shared proteins identified indicated that robust proteomic representation from FFPE tissue and LCM did not negatively affect the number of identified proteins from either OCT-frozen or FFPE samples. Subcellular representation in FFPE samples was similar to OCT-frozen, with predominantly cytoplasmic proteins identified. Biologically relevant protein changes were detected in atorvastatin-treated FFPE liver samples, and selected atorvastatin-related proteins identified by MS were confirmed by Western blot analysis. These findings demonstrate that formalin fixation, paraffin processing, and LCM do not negatively impact protein quality and quantity as determined by MS and that FFPE samples are amenable to global proteomic analysis.
The EMT/ITK/TSK (EMT) tyrosine kinase is activated during TCR signaling: LCK is required for optimal activation of EMT (1996)

Functional T lymphocyte activation requires concurrent stimulation of the TCR complex and an accessory molecule, most frequently CD28. We have previously demonstrated that the TEC family tyrosine kinase EMT/ITK/TSK (EMT) is activated following cross-linking of CD28. We demonstrate herein that cross-linking of the CD3 component of the TCR complex also leads to EMT activation as indicated by a rapid and transient increase in EMT tyrosine phosphorylation and kinase activity in anti-EMT immunoprecipitates. However, although concurrent cross-linking of the TCR and CD28 results in a marked increase in production of the T cell growth factor IL-2, it does not result in a significant alteration in the magnitude or duration of EMT activation. Somatic cell mutants of the Jurkat T cell line, which lack the SRC family kinase LCK (JCaM1.6), fail to produce IL-2 when stimulated through the TCR complex. EMT activation, as evidenced by increased EMT tyrosine phosphorylation and EMT-associated kinase activity, was also greatly reduced following stimulation of the TCR in the JCaM1.6 Jurkat T cell mutants that lack LCK. In support of a role for LCK in EMT activation, reconstitution of the LCK-negative Jurkat T cell line by enforced expression of LCK restored TCR-mediated EMT activation. Taken together, the data indicate that the EMT tyrosine kinase is activated following cross-linking of the TCR, a process in which LCK likely plays an important role.
Atomic precision lithography on Si (2009)

Lithographic precision is as or more important than resolution. For decades, the semiconductor industry has been able to work with ±5% precision. However, for other applications such as micronanoelectromechanical systems, optical elements, and biointerface applications, higher precision is desirable. Lyding et al. [Appl. Phys. Lett. 64, 11 (1999)] have demonstrated that a scanning tunneling microscope can be used to remove hydrogen (H) atoms from a silicon (100) 2 × 1 H-passivated surface through an electron stimulated desorption process. This can be considered e-beam lithography with a thin, self-developing resist. Patterned hydrogen layers do not make a robust etch mask, but the depassivated areas are highly reactive since they are unsatisfied covalent bonds and have been used for selective deposition of metals, oxides, semiconductors, and dopants. The depassivation lithography has shown the ability to remove single H atoms, suggesting the possibility of precise atomic patterning. This patterning process is being developed as part of a project to develop atomically precise patterned atomic layer epitaxy of silicon. However, significant challenges in sample preparation, tip technology, subnanometer pattern placement, and patterning throughput must be overcome before an automated atomic precision lithographic technology evolves.