gebhart/patrepeval huggingface dataset:
Monovalent immunotoxin containing truncated form of Pseudomonas exotoxin as potent antitumor agent. (1992)

Recombinant truncated forms of Pseudomonas exotoxin A that lack the cell binding domain of Pseudomonas exotoxin A were coupled to an F(ab') fragment of a monoclonal antibody HB21 directed against the human transferrin receptor. One of these was NlysPE40. The other, NlysPE38QQR, has two amino groups on residues near the NH2-terminus and has no amino groups near the COOH-terminus. The proteins were linked by a stable thioether bond that connected the sulfhydryl group present in the hinge region of the antibody fragment to an amino group on the toxin. The F(ab')-PE40 immunotoxin, containing NlysPE40, exhibited potent cytotoxic activity on human carcinoma cell lines with a concentration of immunotoxin at which isotope incorporation falls by 50% when compared to nontreated cells (ID50) of 5.3 pM (0.5 ng/ml) on both the epidermoid carcinoma A431 and on the colon carcinoma Colo205. Immunotoxins made with whole antibody were considerably less active, with an ID50 of 15.9 pM (3.1 ng/ml) on these cell lines. F(ab')-PE38QQR, the immunotoxin containing NlysPE38QQR, was found to be the most active agent with an ID50 of 1.05 pM (0.1 ng/ml) on A431 cells. The greater cytotoxicity of immunotoxins containing fragmented antibody was probably due to the higher binding affinity of F(ab') conjugates in comparison to whole antibody conjugates to the transferrin receptor. The increase in cytotoxic activity of the immunotoxin made with NlysPE38QQR than that with NlysPE40 may reflect selective coupling of the toxin through NH2-terminal amino groups. The monovalent and divalent immunotoxins had dose-dependent antitumor effects on human epidermoid carcinoma xenografts in nude mice. A431 tumors completely regressed in all animals at a total dose of 105 pmol (10 micrograms) of F(ab')-PE38QQR and of 154 pmol (30 micrograms) of IgG-PE38QQR. Furthermore, the F(ab') immunotoxin was less toxic to mice than the conjugate containing IgG (840 pmol or 80 micrograms of total dose causing measurable adverse effects versus 208 pmol or 40 micrograms, respectively). Thus, a truncated Pseudomonas exotoxin A molecule coupled to the F(ab') fragment of an antibody is more active and less toxic in mice than an immunotoxin made with a whole antibody. Therefore, the therapeutic index for the monovalent immunotoxin is about four times better than that for the divalent immunotoxin.
Penile vascular surgery for treating erectile dysfunction: Current role and future direction (2013)

Penile vascular surgery for treating erectile dysfunction (ED) is still regarded cautiously. Thus we reviewed relevant publications from the last decade, summarising evidence-based reports consistent with the pessimistic consensus and, by contrast, the optimistically viable options for vascular reconstruction for ED published after 2003. Recent studies support a revised model of the tunica albuginea of the corpora cavernosa as a bi-layered structure with a 360° complete inner circular layer and a 300° incomplete outer longitudinal coat. Additional studies show a more sophisticated venous drainage system than previously understood, and most significantly, that the emissary veins can be easily occluded by the shearing action elicited by the inner and outer layers of the tunica albuginea. Pascal's law has been shown to be a significant, if not the major, factor in erectile mechanics, with recent haemodynamic studies on fresh and defrosted human cadavers showing rigid erections despite the lack of endothelial activity. Reports on revascularisation surgery support its utility in treating arterial trauma in young males, and with localised arterial occlusive disease in the older man. Penile venous stripping surgery has been shown to be beneficial in correcting veno-occlusive dysfunction, with outstanding results. The traditional complications of irreversible penile numbness and deformity have been virtually eliminated, with the venous ligation technique superseding venous cautery. Penile vascular reconstructive surgery is viable if, and only if, the surgical handling is appropriate using a sound method. It should be a promising option in the near future.
Synthesis and Evaluation of Hydroxylated Polyamine Analogues as Antiproliferatives (1999)

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.
Revisiting IP multicast (2006)

This paper revisits a much explored topic in networking - the search for a simple yet fully-general multicast design. The many years of research into multicast routing have led to a generally pessimistic view that the complexity of multicast routing-and inter-domain multicast routing in particular - can only be overcome by restricting the service model (as in single-source) multicast. This paper proposes a new approach to implementing IP multicast that we hope leads to a reevaluation of this commonly held view.
A Recoverable Enzymatic Microgel Based on Biomolecular Recognition (2003)

The enzyme beta-galactosidase has been immobilized through incorporation into a selectively soluble microgel, prepared from DNA, biotinylated peptide nucleic acid (PNA), and the protein avidin. The enzyme was conjugated to avidin, allowing it to be integrated directly into the microgel network. Efficient hydrolysis of a small-molecule substrate occurred at 37 degrees , but cooling and centrifuging led to precipitation of the microgels and product separation. The microgels were then reconstituted by adding fresh buffer and shaking. The enzymatic activity was completely recovered through repeated cycles. This method should be generalizable to a wide variety of other enzymes and substrates.
Cannabinoid Receptors: A brief history and "what's hot". (2009)

Our understanding of the complexity of the endocannabinoid system has evolved considerably since the cloning of the receptors in the early 1990s. Since then several endogenous ligands have been identified and their respective biosynthetic pathways unravelled. This research has revealed the involvement of the cannabinoid system in a number of important physiological processes including the regulation of neurotransmitter release, pain and analgesia, energy homeostasis, and control of immune cell function. All of these events are mediated by two similar receptors, CB1 and CB2, which were initially thought to possess mutually exclusive expression profiles. Recent advances have begun to dissolve such absolutes with the discovery of CB2 in brain tissue and identification of a range of functions for CB1 in peripheral tissues. With improved understanding of the cannabinoid system comes the illumination of various roles in disease pathologies and identification of potential therapeutic targets. This review provides an overview of the current understanding of the endocannabinoid system, and then focuses on recent discoveries that we believe are likely to shape the future directions of the field.
Elemental carbon cages (1988)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTElemental carbon cagesT. G. Schmalz, W. A. Seitz, D. J. Klein, and G. E. HiteCite this: J. Am. Chem. Soc. 1988, 110, 4, 1113–1127Publication Date (Print):February 17, 1988Publication History Published online1 May 2002Published inissue 17 February 1988https://pubs.acs.org/doi/10.1021/ja00212a020https://doi.org/10.1021/ja00212a020research-articleACS PublicationsRequest reuse permissionsArticle Views1172Altmetric-Citations651LEARN 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
Clonal analysis of a human antibody response. II. Sequences of the VH genes of human IgM, IgG, and IgA to rabies virus reveal preferential utilization of VHIII segments and somatic hypermutation (1993)

The construction of mAb-producing cell lines has been instrumental in dissecting the fine specificities and genetic makeup of murine antibodies to exogenous and self Ag. The analysis of the genetic composition of human antibody responses has been hampered by the difficulty in generating human mAb of predetermined class and specificity. Using B lymphocytes from three healthy subjects vaccinated with inactivated rabies virus vaccine, we generated nine human mAb binding to rabies virus and analyzed the genes encoding their VH regions. Six mAb (five IgG1 and one IgA1) were monoreactive and displayed high affinities for rabies virus Ag. The remaining three mAb (IgM) were polyreactive and displayed lower affinities for rabies virus Ag. Seven mAb (3 IgG1, the IgA1, and the three IgM) utilized VH gene segments of the VHIII family. The remaining two IgG1 mAb utilized gene segments of the VHI and VHIV families. Of the seven expressed VHIII family genes, three were similar to the germline VH26c gene, two to the germline 22-2B gene, one to the germline H11 gene, and one to the germline 8-1B gene. The expressed VHI and VHIV genes displayed sequences similar to those of the germline hv1263 and V71-4 genes, respectively. The VH genes of all but one mAb (mAb55) resembled those that are predominantly expressed by C mu + clones in human fetal liver libraries. When compared with known germline sequences, the VH genes of the rabies virus-binding mAb displayed variable numbers of nucleotide differences. That such differences resulted from a process of somatic hypermutation was formally demonstrated (by analyzing DNA from polymorphonuclear neutrophil of the same subject whose B lymphocytes were used for the mAb generation) in the case of the VH gene of the high affinity (anti-rabies virus glycoprotein) IgG1 mAb57 that has been shown to efficiently neutralize the virus in vitro and in vivo. The distribution, mainly within the complementarity determining regions, and the high replacement-to-silent ratio of the mutations, were consistent with the hypothesis that the mAb57-producing cell clone underwent a process of Ag-driven affinity maturation through clonal selection. The D gene segments of the rabies virus-selected mAb were heterogeneous and, in most cases, flanked by significant N segment additions. The JH segment utilization was unbalanced and reminiscent of those of the adult and fetus. Four mAb utilized JH4, two JH6, two JH3, and one JH5; no mAb utilized JH1 or JH2 genes.(ABSTRACT TRUNCATED AT 400 WORDS)
494. Topical Delivery of mRNA to the Murine Lung and Nasal Epithelium (2004)

One of the significant barriers to non-viral gene transfer in vivo is penetration of the nuclear membrane. mRNA, which is translated in the cytoplasm and therefore does not need to negotiate nuclear transport, is being evaluated for gene transfer in vivo. A plasmid expressing firefly luciferase (pSP64-lux-Poly(A)) was constructed and linearised to serve as a template for in vitro transcription (yield was 2.0mg RNA per 1ml reaction). HEK293T cells were transfected with 2g mRNA (encoding luciferase) complexed with 4g cationic lipid (DOTAP) and luciferase expression was observed 9 hours after transfection, confirming the integrity of the luciferase mRNA. For in vivo delivery, luciferase-expressing mRNA was complexed with Genzyme lipid GL67 (80g RNA/60nmol GL67) and dosed to the lungs of female BALB/c mice (6–8 weeks) via intranasal instillation. Lungs were harvested at 3, 6, 12, and 24 hours after delivery (n = 5–6 per group). At 3 hours, mean luciferase expression was five-fold greater than that of naive animals (mRNA: 0.236 0.089 RLU/mg protein, naive: 0.047 0.019 RLU/mg protein) (ANOVA with Fisher's PLSD, p = 0.0001). mRNA dependent reporter gene expression decreased with time and was lower than expression from luciferase expressing plasmid DNA. In vivo delivery was also demonstrated following perfusion to the mouse nose. Naked mRNA (150g), mRNA/DOTAP (100g) or mRNA/DOTAP-Chol (25g) was delivered to female BALB/c mice (n=7). The reagents were delivered in a total volume of 100l and perfused over 15 minutes. Nasal tissue was harvested and measured for luciferase activity after 4 hours. Naked mRNA generated a mean luciferase activity approximately 500 fold over values of mRNA/DOTAP, mRNA/DOTAP-Chol and naive groups (ANOVA, p = 0.0001). The lack of expression seen with the mRNA/lipid complexes in the nasal epithelium could be due to the route of entry for these complexes via endocytosis and/or the release of the mRNA into the cytoplasm may take longer than 4 hours. This study demonstrates that mRNA can be used to deliver and express transgenes in the mouse lung and nose. Gene replacement therapy is being considered as a potential treatment for Cystic Fibrosis, where absence of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein from the respiratory epithelium results in fatal lung disease. As only a small amount of CFTR expression may be needed per cell to achieve normal levels (Trapnell et al, 1991, PNAS 88:6565–6569), the use of mRNA might offer advantages over other gene transfer agents, depending on the number of cells transfected in vivo. Time course and dose response studies of mRNA expression in the mouse nose are underway. Further studies using GFP mRNA will investigate the number and type of cells transfected.
Sequence comparison by exponentially-damped alignment (1984)

We describe a new method of comparing sequences, based on the Needleman-Wunsch sequence alignment algorithm, which can detect similarities that are interrupted by insertions or deletions in either sequence. The sequences are compared by calculating for each pair of residues a score which represents the best local alignment bringing those residues into correspondence; smooth localisation is achieved by reducing the contribution of distant parts of the alignment path by a factor which decreases exponentially with their distance from the point in question. The calculated values are used to draw a line graph in which regions of local similarity are shown by diagonal lines. Examples are shown of the application of the method to nucleic acid and amino acid sequences.
Translocation Properties of Novel Cell Penetrating Transportan and Penetratin Analogues (2000)

Novel analogues of the cell-penetrating peptides penetratin and transportan were synthesized. The distribution of the biotin-labeled peptides in Bowes melanoma cell line has been investigated by indirect fluorescence with fluorescein-streptavidin detection. The time course of uptake of (125)I-labeled transportan analogues has been characterized in the same cell line. Molecular modeling was used to analyze the penetration and the orientation of molecules in a simulated biological membrane. The results, both from molecular modeling and fluorescence studies, imply that penetratin and transportan do not enter the cells by related mechanisms and that they do not belong to the same family of translocating peptides.
Differential αv integrin–mediated Ras-ERK signaling during two pathways of angiogenesis (2003)

Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.
Blue-shifted third-harmonic generation and correlated self-guiding during ultrafast barrier suppression ionization of subatmospheric density noble gases (1996)

The generation of frequency upshifted, pressure-tunable third-harmonic pulses during ultrafast ionization of subatmospheric noble gases at peak intensity 1016 W/cm2 is reported. Pressure tuning of the power spectrum centroid over the range 10−5 ≲ Δω/ω ≲ 10−1, corresponding to a pressure range of 0.1 ≲ p ≲ 700 Torr, is demonstrated. We also demonstrate that the blue-shifted portions of both the 3ω and the ω pulses are preferentially self-guided in a limited pressure range (10 ≲ p ≲ 500 Torr), which is key to separating the pressure-tunable component of the harmonic from nontunable harmonic generated by means of atomic nonlinearities.
Variability in Structure (1996)

In the utilisation of timber, perhaps the single most important factor detracting from its outstanding performance as a material is its variability. In all applications of timber, whether it is in furniture manufacture or housing construction, large quantities are rejected on the grounds that they are different in appearance or behave differently in machining. It is most unlikely that two pieces of timber are identical in both appearance and performance: within a batch of timber pieces, there will be a wide spectrum in what we could loosely call quality. At some arbitrary point, a line is drawn above which the pieces though variable are acceptable, and below which the pieces are unacceptable for a particular use.KeywordsRing WidthCompression WoodTension WoodBuilding ResearchNormal WoodThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Kit regulatory elements required for expression in developing hematopoietic and germ cell lineages (2003)

The Kit (White) gene encodes the transmembrane receptor of stem cell factor/Kit ligand (KL) and is essential for the normal development/maintenance of pluripotent primordial germ cells (PGCs), hematopoietic stem cells (HSCs), melanoblasts, and some of their descendants. The molecular basis for the transcriptional regulation of Kit during development of these important cell types is unknown. We investigated Kit regulation in hematopoietic cells and PGCs. We identified 6 DNase I hypersensitive sites (HS1-HS6) within the promoter and first intron of the mouse Kit gene and developed mouse lines expressing transgenic green fluorescent protein (GFP) under the control of these regulatory elements. A construct driven by the Kit promoter and including all 6 HS sites is highly expressed during mouse development in Kit+ cells including PGCs and hematopoietic progenitors (erythroid blast-forming units and mixed colony-forming units). In contrast, the Kit promoter alone (comprising HS1) is sufficient to drive low-level GFP expression in PGCs, but unable to function in hematopoietic cells. Hematopoietic expression further requires the addition of the intronproximal HS2 fragment; HS2 also greatly potentiates the activity in PGCs. Thus, HS2 acts as an enhancer integrating transcriptional signals common to 2 developmentally unrelated stem cell/progenitor lineages. Optimal hematopoietic expression further requires HS3-HS6.
A Novel L-ficolin/Mannose-binding Lectin Chimeric Molecule with Enhanced Activity against Ebola Virus (2010)

Ebola viruses constitute a newly emerging public threat because they cause rapidly fatal hemorrhagic fevers for which no treatment exists, and they can be manipulated as bioweapons. We targeted conserved N-glycosylated carbohydrate ligands on viral envelope surfaces using novel immune therapies. Mannose-binding lectin (MBL) and L-ficolin (L-FCN) were selected because they function as opsonins and activate complement. Given that MBL has a complex quaternary structure unsuitable for large scale cost-effective production, we sought to develop a less complex chimeric fusion protein with similar ligand recognition and enhanced effector functions. We tested recombinant human MBL and three L-FCN/MBL variants that contained the MBL carbohydrate recognition domain and varying lengths of the L-FCN collagenous domain. Non-reduced chimeric proteins formed predominantly nona- and dodecameric oligomers, whereas recombinant human MBL formed octadecameric and larger oligomers. Surface plasmon resonance revealed that L-FCN/MBL76 had the highest binding affinities for N-acetylglucosamine-bovine serum albumin and mannan. The same chimeric protein displayed superior complement C4 cleavage and binding to calreticulin (cC1qR), a putative receptor for MBL. L-FCN/MBL76 reduced infection by wild type Ebola virus Zaire significantly greater than the other molecules. Tapping mode atomic force microscopy revealed that L-FCN/MBL76 was significantly less tall than the other molecules despite similar polypeptide lengths. We propose that alterations in the quaternary structure of L-FCN/MBL76 resulted in greater flexibility in the collagenous or neck region. Similarly, a more pliable molecule might enhance cooperativity between the carbohydrate recognition domains and their cognate ligands, complement activation, and calreticulin binding dynamics. L-FCN/MBL chimeric proteins should be considered as potential novel therapeutics.