gebhart/patrepeval huggingface dataset:
Evaluation of locked nucleic acid–modified small interfering RNAin vitroandin vivo (2007)

RNA interference has become widely used as an experimental tool to study gene function. In addition, small interfering RNA (siRNA) may have great potential for the treatment of diseases. Recently, it was shown that siRNA can be used to mediate gene silencing in mouse models. Locally administered siRNAs entered the first clinical trials, but strategies for successful systemic delivery of siRNA are still under development. Challenges still exist about the stability, delivery, and therapeutic efficacy of siRNA. In the present study, we compare the efficacy of two methods of systemic siRNA delivery and the effects of siRNA modifications using locked nucleic acids (LNA) in a xenograft cancer model. Low volume tail vein bolus injections and continuous s.c. delivery using osmotic minipumps yielded similar uptake levels of unmodified siRNA by tumor xenografts. Both routes of administration mediated sequence-specific inhibition of two unrelated targets inside tumor xenografts. Previous studies have shown that LNA can be incorporated into the sense strand of siRNA while the efficacy is retained. Modification of siRNA targeting green fluorescent protein with LNA results in a significant increase in serum stability and thus may be beneficial for clinical applications. We show that minimal 3' end LNA modifications of siRNA are effective in stabilization of siRNA. Multiple LNA modifications in the accompanying strand further increase the stability but negate the efficacy in vitro and in vivo. In vivo, LNA-modified siRNA reduced off-target gene regulation compared with nonmodified siRNA. End-modified siRNA targeting green fluorescent protein provides a good trade-off between stability and efficacy in vivo using the two methods of systemic delivery in the nude mouse model. Therefore, LNA-modified siRNA should be preferred over unmodified siRNA.
Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. (1994)

Like Taxol, this novel chemotherapeutic agent appears to possess promising activity in patients with refractory breast and ovarian neoplasms, with tolerable toxicities. Using this schedule, 100 mg/m2 per course is the recommended dose for future phase II trials.
Biochemical and functional analysis of mice deficient in expression of the CD45-associated phosphoprotein LPAP (1999)

The role of the CD45-associated phosphoprotein (LPAP / CD45-AP) during an immune response remains unclear. To understand better the function of LPAP we generated LPAP-deficient mice by disrupting exon 2 of the LPAP gene. LPAP-null mice were healthy and did not show gross abnormalities compared to their wild-type littermates. However, immunofluorescence analysis of T and B lymphocytes revealed a reduced expression of CD45, which did not affect a particular subpopulation. In contrast to a recent report (Matsuda et al., J. Exp. Med. 1998. 187: 1863 – 1870) we neither observed significant alterations of the assembly of the CD45 / lck-complex nor of polyclonal T-cell responses. However, lymphnodes from LPAP-null mice showed increased cellularity, which could indicate that expression of LPAP might be required to prevent expansion of lymphocytes in particular lymphatic organs rather than potentiating immune responses.
Simple liquid-liquid partition system for isolation of labeled oleic acid from mixtures with glycerides (1969)

Oleic acid has a partition coefficient, upper phase/lower phase, of 1.9 (22 degrees C) in the liquid-liquid partition system described herein. Tri-, di-, and monoolein are found almost exclusively in the lower (organic) phase. Oleic acid can be quantitatively removed from mixtures of triglyceride and partial glycerides by means of this partition system under conditions resembling those in a lipase assay.
Rationale for the Use of Histone Deacetylase Inhibitors as a Dual Therapeutic Modality in Multiple Sclerosis (2006)

Major recent advances in the field of chromatin remodeling have dramatically changed our understanding of the ways in which genes are regulated. Epigenetic regulators such as histone deacetylases (HDACs) and histone acetyltransferases (HATs) are increasingly being implicated as direct or indirect components in the regulation of expression of neuronal, immune and other tissue specific genes. HDACs and HATs have been shown to play important roles in cell growth, cell cycle control, development, differentiation and survival. Mutations in genes that encode HDAC-binding proteins cause neurological disorders, such as MeCP2 mutations in Rett's syndrome. Mutations of CBP, a gene with HAT function, cause the mental retardation-associated Rubinstein-Taybi syndrome. Recently, HDAC inhibitors have been found to ameliorate progression of the spinal muscular atrophy (SMA) motor neuron disease and the Huntington disease mouse models. The neuroprotective role of HDAC inhibitors seems to extend to other diseases that share mechanisms of oxidative stress, inflammation and neuronal cell apoptosis. HDAC inhibitors also have widespread modulatory effects on gene expression within the immune system and have been used successfully in the lupus and rheumatoid arthritis autoimmune disease models. Recently, we demonstrated the efficacy of the HDAC inhibitor Trichostatin A in ameliorating disease in the multiple sclerosis (MS) animal model, experimental autoimmune encephalomyelitis (EAE). In this review we describe the current literature surrounding these inhibitors and propose a rationale for harnessing both their neuroprotective and anti-inflammatory effects to treat MS, an autoimmune, demyelinating and degenerative disease of the human central nervous system (CNS).
Humanization of Antibodies Using Heavy Chain Complementarity-determining Region 3 Grafting Coupled with in Vitro Somatic Hypermutation (2013)

A method for simultaneous humanization and affinity maturation of monoclonal antibodies has been developed using heavy chain complementarity-determining region (CDR) 3 grafting combined with somatic hypermutation in vitro. To minimize the amount of murine antibody-derived antibody sequence used during humanization, only the CDR3 region from a murine antibody that recognizes the cytokine hβNGF was grafted into a nonhomologous human germ line V region. The resulting CDR3-grafted HC was paired with a CDR-grafted light chain, displayed on the surface of HEK293 cells, and matured using in vitro somatic hypermutation. A high affinity humanized antibody was derived that was considerably more potent than the parental antibody, possessed a low pm dissociation constant, and demonstrated potent inhibition of hβNGF activity in vitro. The resulting antibody contained half the heavy chain murine donor sequence compared with the same antibody humanized using traditional methods.
Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus (2003)

There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.
Molecular Cloning and Nucleotide Sequence of cDNAs Encoding the Precursors of Rat Long Chain Acyl-Coenzyme A, Short Chain Acyl-Coenzyme A, and Isovaleryl-Coenzyme A Dehydrogenases (1989)

cDNAs encoding the entire coding regions of the precursors (p) of rat long chain acyl-CoA (LCAD), short chain acyl-CoA (SCAD) and isovaleryl-CoA dehydrogenase (IVD) have been cloned and sequenced. Three cDNAs for rat liver LCAD together cover a 1440-base pair region. These cDNAs encode the entire 430-amino acid sequence of pLCAD, including the 30-amino acid leader peptide and the 400-amino acid mature LCAD. A single 1773 base pair cDNA for rat SCAD covers the entire coding region (414 amino acids), including the 26-amino acid leader peptide and the 388-amino acid mature peptide. Four identified IVD cDNAs, when combined, encompass a 2104 base region, and encode 424 amino acids including a 30-amino acid leader peptide and the 394-amino acid mature peptide. The identities of all cDNA clones have been confirmed by matching the amino acid sequences predicted from the respective cDNAs to the amino-terminal and tryptic peptide sequences derived from the corresponding purified rat enzyme. Comparison of the sequences of four rat acyl-CoA dehydrogenases, including LCAD, MCAD, SCAD, and IVD, and two of their human counterparts (MCAD and SCAD) reveals a high degree of homology (57 invariant and 92 near invariant residues: 30.6-35.4% of identical residues in pairwise comparisons), suggesting that these enzymes belong to a gene family and have evolved from a common ancestral gene.
Prolactin levels in antipsychotic treatment of patients with schizophrenia carrying the DRD2*A1 allele (2004)

Background Hyperprolactinaemia induced by D 2 dopamine receptor antagonist antipsychotic medication can result in significant health problems. Aims To examine the role of DRD2 polymorphism on prolactin levels in patients treated with antipsychotic medication. Method Antipsychotic drugs with different degrees of D 2 receptor binding were given to 144 patients with schizophrenia. Serum prolactin levels were obtained and Taq 1A DRD2 alleles were determined. Results Prolactin levels increased across medication groups reflecting increasingly tight D 2 receptor binding (clozapine, olanzapine, typical antipsychotics and risperidone). In the combined medication group, patients with the DRD2∗A1 allele had 40% higher prolactin levels than patients without this allele. In patients treated with clozapine (the loosest D 2 receptor binding agent), patients with the DRD2∗A1 allele had prolactin levels twice those of patients without this allele. Conclusions Patients with the DRD2A1 allele receiving antipsychotic medications had higher prolactin levels and were overrepresented among those with hyperprolactinaemia, suggesting greater functional D 2 receptor binding in this group.
Polymerase chain reaction for detection of the pMP6d-9/MspI RFLP, a marker closely linked to the cystic fibrosis mutation (1989)

SOURCE/DESCRIPTION: pMP6d-9 is a human genomic clone with a 2.6kb HindIll insert in pBR322(1). HindIII/Mspl subclones were sequenced in order to obtain oligonucleotides suitable for detection of the M8pI RFLP within pMP6d-9 by PCR. POLYMORPHISM: With Southern btotting the Mspt RFLP has alleles of 13kb(allele 1) and 8.5 + 4.5kb(allele 2). Allele 1 represents the absence
THE USE OF PHAGE DISPLAY IN THE STUDY OF RECEPTORS AND THEIR LIGANDS (2002)

Phage display technology presents a rapid means by which proteins and peptides that bind specifically to predefined molecular targets can be isolated from extremely complex combinatorial libraries. There are several important ways by which phage display can provide impetus to receptor-based research. Firstly, phage display can be applied, alongside transcriptome and proteome expression profiling techniques, to the identification and characterisation of receptors whose expression is specific to either a cell lineage, a tissue or a disease state. Secondly, specific monoclonal antibodies that enable researchers to identify, localize and quantify receptors can be produced very rapidly (weeks). Thirdly, it should be possible to apply phage display to the matching of orphan ligands and receptors. Finally, phage display can be used to identify proteins and peptides that modulate receptor activity. As well as being useful in the study of receptor function, biologically active proteins and peptides could also be used therapeutically, or as leads for drug design. Hence phage display is ready to play a central role in the study of receptors in the post-genome era. This review outlines the ways in which phage display has been applied to the study of receptor-ligand systems, and discusses how new developments in the technology may be of even greater utility to the field in the next decade.
Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. (1996)

The Src-family and Syk/ZAP-70 family of protein tyrosine kinases (PTK) are required for T cell receptor (TCR) functions. We provide evidence that the Src-family PTK Lck is responsible for regulating the constitutive tyrosine phosphorylation of the TCR zeta subunit in murine thymocytes. Moreover, ligation of the TCR expressed on thymocytes from Lck-deficient mice largely failed to induce the phosphorylation of TCR-zeta, CD3 epsilon, or ZAP-70. In contrast, we find that the TCR-zeta subunit is weakly constitutively tyrosine phosphorylated in peripheral T cells isolated from Lck-null mice. These data suggest that Lck has a functional role in regulation of TCR signal transduction in thymocytes. In peripheral T cells, other Src-family PTKs such as Fyn may partially compensate for the absence of Lck.
Humanization strategies for an anti-idiotypic antibody mimicking HIV-1 gp41 (2010)

Anti-idiotypic antibodies could represent an alternative vaccination approach in human therapy. The anti-idiotypic antibody Ab2/3H6 was generated in mouse and is directed against the human monoclonal antibody 2F5, which broadly and potently neutralizes primary HIV-1 isolates. Ab2/3H6 is able to mimic the antigen recognition site of 2F5 making it a putative candidate for HIV-1 vaccine purposes. In order to reduce immunogenicity of therapeutic proteins, humanization methods have been developed. The mouse variable regions of Ab2/3H6 were subjected to three different humanization approaches, namely resurfacing, complementarity determining region (CDR)-grafting and superhumanization. Four different humanized Ab2/3H6 variants were characterized for their binding affinity to 2F5 in comparison to the chimeric Ab2/3H6. The resurfaced and the 'conservative' CDR-grafted variants showed similar binding properties to 2F5 when compared to the chimeric version, while the 'aggressive' CDR-grafted antibody showed reduced affinity and the superhumanized type lost its binding ability. In this study, we developed humanized Ab2/3H6 variants that retained the same affinity as the parental antibody, and are therefore of potential interest for future clinical trails.
Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever. (1997)

The vaccinia virus (VV) strain Western Reserve B13R gene encodes a 38.5 kDa intracellular polypeptide that is non-essential for virus replication in vitro and does not affect virus virulence in a murine intranasal model. The protein has 92% amino acid identity with the cowpox virus cytokine response modifier A (crmA) protein which inhibits the interleukin (IL)-1beta converting enzyme (ICE). Here, we show that extracts from THP-1 cells infected with VV strains expressing B13R prevent the cleavage of in vitro transcribed and translated pro-IL-1beta into mature IL-1beta. Similarly, THP-1 cells infected with VVs expressing B13R process pro-IL-1beta into mature IL-1beta inefficiently in situ. Despite its inhibition of ICE, B13R does not prevent fever in infected mice, a systemic effect mediated by IL-1beta. Instead, fever is controlled by the VV IL-1beta receptor, encoded by gene B15R, and deletion of both the B13R and B15R genes did not increase the febrile response compared to deletion of B15R alone. The B13R protein does, however, block apoptosis mediated by anti-Fas antibodies or by tumour necrosis factor (TNF) and cycloheximide. Using DNA fragmentation, chromium release and microscopic analyses it was shown that cells infected with wild-type VV strain WR, or a revertant virus in which the B13R gene had been re-inserted into the B13R deletion mutant, are more resistant than uninfected cells or deletion mutant-infected cells to apoptosis mediated by anti-Fas and TNF.
Management and Application of Decision and Risk Analysis in Du Pont (1992)

Decision and risk analysis (D&amp;RA) enables Du Pont's business teams to develop creative strategy alternatives, evaluate them rigorously, select those with the greatest expected shareholder value, and design implementation plans the businesses can enthusiastically support. Du Pont organized internal and external resources to develop its D&amp;RA capability and incorporated D&amp;RA in several ongoing business processes. One Du Pont business utilized D&amp;RA techniques to develop a business strategy that enhances value by $175 million.
Fabry disease due to D313Y and novel GLA mutations (2017)

Four novel <i>GLA</i> pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb<sub>3</sub> concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.
Preparation of Supported Mesoporous Silica Layers in a Continuous Flow Cell (1997)

Mesoporous silica films have been synthesized on borosilicate glass substrates under static conditions and continuous flow of the precursor surfactant−silicate mixture. Evidence for flow-induced orientation is provided. When films are grown under a flow field and for short deposition times, the tubular mesostructures are elongated along the flow direction and acquire a tapelike morphology as shown in the FE-SEM top view micrograph. This texture is in contrast to the disklike morphology of films grown in contact with a quiescent mixture of the same composition.
The Depressor and Vasodilator Effects of Rutaecarpine are Mediated by Calcitonin Gene-Related Peptide (2003)

Previous studies have shown that rutaecarpine has depressor and vasodilator effects, and activates vanilloid receptors to evoke calcitonin gene-related peptide (CGRP) release. In the present study, we examined whether the depressor and vasodilator effects of rutaecarpine are related to the stimulation of endogenous CGRP release via activation of vanilloid receptors in rats. Rutaecarpine (30, 100, or 300 microg/kg, i. v.) caused a depressor effect concomitantly with an increase in the plasma concentrations of CGRP in a dose-dependent manner, and the effects of rutaecarpine were abolished by pretreatment with capsaicin (50 mg/kg, s. c.) which depletes neurotransmitters in sensory nerves. In aortic and superior mesenteric arterial rings, rutaecarpine (10 (-7)-10(-5) M) or capsaicin (3 x 10(-9)-3 x 10(-6) M) caused a concentration-dependent vasodilator response, which was significantly attenuated by capsazepine (10(-5) M), a competitive vanilloid receptor antagonist, or by CGRP-(8-37) (10(-6) M), a selective CGRP receptor antagonist. After pretreatment with capsaicin (10(-5) M) for 20 min, vasodilator responses to rutaecarpine were also markedly attenuated. Similarly, pretreatment with rutaecarpine (10(-5) M) for 20 min also attenuated vasodilator responses to capsaicin. These results suggest that the depressor and vasodilator effects of rutaecarpine are related to stimulation of endogenous CGRP release via activation of vanilloid receptors in rats.
11,12-Difluororhodopsin and Related Odd-Numbered Fluororhodopsins. The Use of JF,F for Following a Cis−trans Isomerization Process (1999)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXT11,12-Difluororhodopsin and Related Odd-Numbered Fluororhodopsins. The Use of JF,F for Following a Cis−trans Isomerization ProcessLeticia U. Colmenares, Xiang-long Zou, Jin Liu, Alfred E. Asato, Robert S. H. Liu, Angel R. de Lera, and Rosana AlvarezView Author Information Department of Chemistry, University of Hawaii 2545 The Mall, Honolulu, Hawaii 96822 Departamento de Quimica Fisica y Quimica Organica Facultad de Ciencias, Universidade de Vigo 36200 Vigo, Spain Cite this: J. Am. Chem. Soc. 1999, 121, 24, 5803–5804Publication Date (Web):June 3, 1999Publication History Received16 February 1999Revised8 April 1999Published online3 June 1999Published inissue 1 June 1999https://pubs.acs.org/doi/10.1021/ja990495whttps://doi.org/10.1021/ja990495wrapid-communicationACS PublicationsCopyright © 1999 American Chemical SocietyRequest reuse permissionsArticle Views138Altmetric-Citations17LEARN 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 SUBJECTS:Anions,Dyes and pigments,Molecular properties,Molecular structure,Peptides and proteins Get e-Alerts
Hardware-based synchronization support for shared accesses in multicore architectures (2008)

A new hardware-based design is presented to support shared accesses in multi-core processors. In the proposed design, instructions updating shared variables are issued by the processor cores but executed by the proposed hardware unit that is snooping on the bus. After issuing such an instruction, the processor core can proceed immediately with subsequent instructions. The proposed hardware unit assumes the responsibility of buffering and sequentializing the multiple access requests from the processor cores. The proposed hardware is shown to be sequentially consistent for accesses to shared variables. Comparison against lock-based synchronization shows that the proposed hardware design can significantly reduce synchronization overheads.