gebhart/patrepeval huggingface dataset:
Small But Increasingly Mighty: Latest Advances in AAV Vector Research, Design, and Evolution (2017)

Recombinant gene delivery vectors derived from naturally occurring or genetically engineered adeno-associated viruses (AAV) have taken center stage in human gene therapy, fueled by rapidly accumulating and highly encouraging clinical data. Nonetheless, it has also become evident that the current generation of AAV vectors will require improvements in transduction potency, antibody evasion, and cell specificity in order to realize their full potential and to widen applicability in larger patient cohorts. Fortunately, in the recent past, the field has seen a flurry of exciting new developments that enhance our understanding of AAV vector biology, including virus-host interactions, and/or that expand our arsenal of technologies for AAV capsid design and evolution. This review highlights a collection of latest advances in these areas, which, in the authors' opinion, hold particular promise to propel the AAV vector field forward in the near future, especially when applied in combination. These include fundamental novel insights into the AAV life cycle, from an unexpected role of autophagy and interactions with other viruses to the (re-)discovery of a universal AAV receptor and the function of AAV-AAP for capsid assembly. Concurrently, recent successes in the rational design of next-generation synthetic AAV capsids are pointed out, exemplified by the structure-guided derivation of AAV mutants displaying robust in vivo immune evasion. Finally, a variety of new and innovative strategies for high-throughput generation and screening of AAV capsid libraries are briefly reviewed, including Cre recombinase-based selection, ancestral AAV capsid reconstruction, and DNA barcoding of AAV genomes. All of these examples showcase the present momentum in the AAV field and, together with work by many other academic or industrial entities, raise substantial optimism that the remaining hurdles for human gene therapy with AAV vectors will (soon) be overcome.
The fibrillar collagens, collagen VIII, collagen X and the C1q complement proteins share a similar domain in their C&#x2010;terminal non&#x2010;collagenous regions (1992)

A sequence comparison of the C-termini of collagens X, VIII, the collagen-like complement factor C1q, and the fibrillar collagens showed a conserved cluster of aromatic residues. This conserved cluster was in a domain of approximately 130 amino acids that exhibited marked similarities in hydrophilicity profiles between the different collagens, despite a low level of sequence similarity. These data suggest that the 'collagen X-like family' and the fibrillar collagens contain a domain within their C-termini that adopts a common tertiary structure, and that a conserved cluster of aromatic residues in this domain may be involved in C-terminal trimerization.
Simulation throughout the life of a reservoir (1996)

In the family of tools designed to help oil companies make effective use of expensive data, simulators play a key role in making sense of information acquired at different spatial scales and from numerous physical experiments. Simulation is one of the few tools available for modeling changes in a reservoir over various stages of production. Combined with other measurements, it promotes a higher degree of confidence in our understanding of reservoirs. 20 figs., 20 refs.
Monoclonal antibody therapies for solid tumors (2009)

Anti-tumor responses have been modest. However, the advent of novel antibody engineering and combination therapy strategies has generated much optimism for current and future antibody-based therapeutics in solid tumors.
Ligninolytic enzymes of the white-rot fungus Phlebia radiata (1988)

One oxidase (EC 1.10.3.2) and three lignin peroxidases (EC 1.11.1.-) were purified from the culture liquid of the white-rot fungus Phlebia radiata Fr. All the enzymes were glycoproteins. The oxidase had Mr 64,000 and the lignin peroxidases I, II and III had Mr values 42,000, 45,000 and 44,000 respectively. The lignin peroxidases were found to share common antigenic determinants: lignin peroxidases II and III were serologically indistinguishable and lignin peroxidase I was related but distinguishable. The oxidase did not share any immunological properties with the lignin peroxidases. Lignin peroxidases of Phlebia contain protoporphyrin IX as a prosthetic group. In the presence of H2O2 and an electron donor, veratryl alcohol, lignin peroxidases exhibit spectral shifts analogous to those of animal catalase (EC 1.11.1.6). Phlebia enzymes show optimal activity at pH 3-4.5 at 40 degrees C and are stable in the pH range 5-6. They modify Kraft lignin and phenolic compounds containing hydroxy and methoxy groups.
Sexual dimorphism of arrestment and gregariousness in the bed bug ( Cimex lectularius ) in response to cuticular extracts from nymphal exuviae (2010)

Releaser pheromones have direct behavioural effects to arrest, attract or disperse insects, whereas interactions within groups of social insects are often influenced by primer pheromones. The behaviour of insects displaying intermediate levels of sociality is largely unexplored in this context. In the present study, both the gregariousness and arrestment (settling near the odour source) of bed bugs Cimex lectularius L. (Hemiptera: Cimicidae) in response to conspecific exuvial extracts are described. Adult males are arrested on filter papers with extracts derived from exuviae of fifth‐instar nymphs. Adult females and nymphs display no significant evidence for such behaviour. Adults of both sexes show no preference for extracts of male versus female fifth‐instar exuviae. Arrestment of adult males does not occur on papers treated with fourth‐instar exuvial extracts. Because the insects are assayed behaviourally in groups, an index is calculated describing how far bugs are away from being located independently of one another, as a measure of gregariousness. Adult males have lower values for this index (i.e. locations are closer to independence). Adult females, nymph cohorts and mixed age groups all have higher values for this index, which tend to increase over time. Females exhibit a clear increasing dose‐dependent relationship for this index. It is concluded that the extracts of fifth‐instar nymphal exuvia arrest males on refuges that possess the odour source. However, gregariousness is induced in females, without evidence of a tendency to assemble near the odour source.
Gasolines for Low-Emission Vehicles (1973)

&lt;div class="htmlview paragraph"&gt;International concern over air quality and the recognition that the internal combustion engine-powered passenger car is a contributor of atmospheric pollutants has imposed restrictive design criteria upon both the automobile manufacturer and the petroleum refiner. For the passenger car engine builder serving the American market, these criteria have been specified by the emission standards required by the Clean Air Amendments of 1970. On the other hand, gasolines for these low-emitting passenger cars have only recently been specified and their required quality and performance characteristics have not yet been completely spelled out. This paper discusses the influence of emission control requirements on future gasoline quality. Lead antiknocks, hydrocarbon composition, and gross physical properties are among the factors considered and an effort is made to quantify the effects of changes in these characteristics on emissions and to estimate their impact on the industry. It is concluded that future automotive fuels, that is, fuels that will be produced for low-emission vehicles, will be a blend of liquid hydrocarbons, free of lead alkyl antiknocks and other materials deleterious to catalysts. Hydrocarbon composition and volatility will be adjusted to provide optimum emissions control at lowest overall system cost.&lt;/div&gt;
Rep*: a Viral Element That Can Partially Replace the Origin of Plasmid DNA Synthesis of Epstein-Barr Virus (1998)

Replication of the Epstein-Barr viral (EBV) genome occurs once per cell cycle during latent infection. Similarly, plasmids containing EBV's plasmid origin of replication, oriP, are replicated once per cell cycle. Replication from oriP requires EBV nuclear antigen 1 (EBNA-1) in trans; however, its contributions to this replication are unknown. oriP contains 24 EBNA-1 binding sites; 20 are located within the family of repeats, and 4 are found within the dyad symmetry element. The site of initiation of DNA replication within oriP is at or near the dyad symmetry element. We have identified a plasmid that contains the family of repeats but lacks the dyad symmetry element whose replication can be detected for a limited number of cell cycles. The detection of short-term replication of this plasmid requires EBNA-1 and can be inhibited by a dominant-negative inhibitor of EBNA-1. We have identified two regions within this plasmid which can independently contribute to this replication in the absence of the dyad symmetry element of oriP. One region contains native EBV sequences within the BamHI C fragment of the B95-8 genome of EBV; the other contains sequences within the simian virus 40 genome. We have mapped the region contributing to replication within the EBV sequences to a 298-bp fragment, Rep*. Plasmids which contain three copies of Rep* plus the family of repeats support replication more efficiently than those with one copy, consistent with a stochastic model for the initiation of DNA synthesis. Plasmids with three copies of Rep* also support long-term replication in the presence of EBNA-1. These observations together indicate that the latent origin of replication of EBV is more complex than formerly appreciated; it is a multicomponent origin of which the dyad symmetry element is one efficient component. The experimental approach described here could be used to identify eukaryotic sequences which mediate DNA synthesis, albeit inefficiently.
Biochemical Analysis of Human T Lymphocyte Differentiation Antigens T4 and T5 (1980)

Two major functionally distinct T cell subsets in man have been defined with heteroantiserums and monoclonal antibodies directed against stable cell surface antigens that appear during thymic ontogeny. A monoclonal antibody to T4 antigen (anti-T4) is reactive with the peripheral inducer T cell population while a monoclonal antibody to T5 antigen (anti-T5) is reactive with the cytotoxic and suppressor population. Immunoprecipitation and electrophoresis on sodium dodecyl sulfate polyacrylamide gel were used to show that on human thymocytes or peripheral T cells the T4 antigen is a single 62,000-dalton glycoprotein while the T5 antigen is a complex of two glycoproteins, one being 30,000 daltons and the other 32,000 daltons. Similar glycoproteins have been isolated with antibodies to murine Lyt 1 and Lyt 2,3 antigens. Both the antigens defining the phenotypes of inducer and suppressor populations in man and mouse are structurally homologous.
Mechanisms of Rhodopsin Inactivation in Vivo as Revealed by a COOH-Terminal Truncation Mutant (1995)

Although biochemical experiments suggest that rhodopsin and other receptors coupled to heterotrimeric guanosine triphosphate-binding proteins (G proteins) are inactivated by phosphorylation near the carboxyl (COOH)-terminus and the subsequent binding of a capping protein, little is known about the quenching process in vivo. Flash responses were recorded from rods of transgenic mice in which a fraction of the rhodopsin molecules lacked the COOH-terminal phosphorylation sites. In the single photon regime, abnormally prolonged responses, attributed to activation of individual truncated rhodopsins, occurred interspersed with normal responses. The occurrence of the prolonged responses suggests that phosphorylation is required for normal shutoff. Comparison of normal and prolonged single photon responses indicated that rhodopsin begins to be quenched before the peak of the electrical response and that quenching limits the response amplitude.
Infliximab som “rescue terapi” vid steroidrefraktärt skov av ulcerös kolit : en retrospektiv uppföljningsstudie (2011)

Infliximab som “rescue terapi” vid steroidrefraktart skov av ulceros kolit : en retrospektiv uppfoljningsstudie
Evidence That Nonsteroidal Anti-inflammatory Drugs Decrease Amyloid β42 Production by Direct Modulation of γ-Secretase Activity (2003)

Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of developing Alzheimer's disease. Recent evidence indicates that some NSAIDs specifically inhibit secretion of the amyloidogenic A beta 42 peptide in cultured cells and mouse models of Alzheimer's disease. The reduction of A beta 42 peptides is not mediated by inhibition of cyclooxygenases (COX) but the molecular mechanism underlying this novel activity of NSAIDs has not been further defined. We now demonstrate that NSAIDs efficiently reduce the intracellular pool of A beta 42 in cell-based studies and selectively decrease A beta 42 production in a cell-free assay of gamma-secretase activity. Moreover, we find that presenilin-1 (PS1) mutations, which affect gamma-secretase activity, differentially modulate the cellular A beta 42 response to NSAID treatment. Overexpression of the PS1-M146L mutation enhances the cellular drug response to A beta 42 lowering NSAIDs as compared with cells expressing wild-type PS1. In contrast, expression of the PS1-Delta Exon9 mutation strongly diminishes the A beta 42 response, showing that PS1 mutations can modulate the cellular drug response to NSAID treatment both positively and negatively. Enhancement of the NSAID drug response was also observed with overexpression of the APP V717F mutation but not with Swedish mutant APP, which affects beta-secretase cleavage. In sum, these results strongly suggest that NSAIDs represent a founding group of compounds that lower A beta 42 production by direct modulation of gamma-secretase activity or its substrate.
Accumulation of magnetic iron oxide nanoparticles coated with variably sized polyethylene glycol in murine tumors (2012)

Iron oxide nanoparticles have found widespread applications in different areas including cell separation, drug delivery and as contrast agents. Due to water insolubility and stability issues, nanoparticles utilized for biological applications require coatings such as the commonly employed polyethylene glycol (PEG). Despite its frequent use, the influence of PEG coatings on the physicochemical and biological properties of iron nanoparticles has hitherto not been studied in detail. To address this, we studied the effect of 333-20,000 Da PEG coatings that resulted in larger hydrodynamic size, lower surface charge, longer circulation half-life, and lower uptake in macrophage cells when the particles were coated with high molecular weight (M(w)) PEG molecules. By use of magnetic resonance imaging, we show coating-dependent in vivo uptake in murine tumors with an optimal coating M(w) of 10,000 Da.
Vinyl polymerization. 217. Vinyl compounds of nucleic acid basis. I. Synthesis of N‐vinylthymine, and N‐vinyladenine (1968)

Abstract The synthesis of N‐vinyluracil, N‐vinylthymine, and N‐vinyladenine is described. The general procedure consists of the conversion of the corresponding nucleric acid bases to their N‐hydroxyethyl compounds, followed by chlorination to the N‐chloroethyl compounds and dehydrochlorination to the N‐vinyl derivaties.
Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. (2002)

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I(2) (PGI(2), prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.
Involvement of 5-HT2C receptors in the m-CPP-induced antinociception in mice. (1995)

Effects of the non-selective 5-hydroxytryptamine (5-HT) receptor agonist m-chlorophenylpiperazine (m-CPP) on the nociceptive responsiveness in a hot plate and tail flick tests were examined in mice. Intraperitoneal administration of m-CPP (1-10 mg/kg) produced a dose-dependent antinociception in both those tests; the effect of m-CPP in the hot plate test was stronger. The antinociceptive effect of m-CPP in either test was abolished by pretreatment with mesulergine (2 mg/kg), ritanserin (1-2 mg/kg), 5-HT2A/5-HT2C receptor antagonists, and metergoline (0.5-2 mg/kg), a non-selective 5-HT receptor antagonist. On the other hand, spiperone (0.25-0.5 mg/kg), a dopamine, 5-HT1A and 5-HT2A receptor antagonist; pindolol (4-8 mg/kg), a beta-adrenoceptor, 5-HT1A and 5-HT1B receptor antagonist and zacopride (0.1-1 mg/kg) a 5-HT3 receptor antagonist, did not affect the analgesia induced by m-CPP. Neither of the drugs used as putative receptor antagonists changed the nociceptive responsiveness in mice. The obtained results suggest that the analgesia induced by m-CPP is mediated by 5-HT2C receptors.
Functional Mapping of Cre Recombinase by Pentapeptide Insertional Mutagenesis (2004)

Cre is a site-specific recombinase from bacteriophage P1. It is a member of the tyrosine integrase family and catalyzes reciprocal recombination between specific 34-bp sites called loxP. To analyze the structure-function relationships of this enzyme, we performed large scale pentapeptide insertional mutagenesis to generate insertions of five amino acids at random positions in the protein. The high density of insertion mutations into Cre allowed us to identify an unexpected degree of functional tolerance to insertions into the 4-5 beta-hairpin and into the loop between helices J and K (both of which contact the DNA in the minor groove) and also into helix A. The phenotypes of the majority of inserts allowed us to confirm a variety of predictions made on the basis of sequence conservation, known three-dimensional structure, and proposed catalytic mechanism. In particular, most insertions into conserved regions or secondary structure elements inactivated Cre, and most insertions located in nonconserved, unstructured regions preserved Cre activity. Less expectedly, the non-conserved and poorly structured loops and linkers between helices A-B, E-F, and M-N did not tolerate insertions, thus identifying these as critical regions for recombinase activity. We purified and characterized in vitro several representatives of these "unexpected" Cre insertion mutants. The role of those regions in the recombination process is discussed.
A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5'-flanking sequence of the chicken c-myc gene. (1990)

The chicken c-myc 5'-flanking sequence has previously been shown to bind multiple proteins present in undifferentiated and differentiated red blood cells. In this report the protein binding to one specific region within a hypersensitive site approximately 200 base pairs upstream of the start of transcription has been analysed in detail. Using a combination of a modified agarose gel retardation assay with O-phenanthroline-copper footprinting in situ, missing contact point and methylation interference techniques, two proteins were found to bind to overlapping sequences within 180-230 bp upstream of the start of transcription. One protein resembles the transcription factor Sp1, the other is a protein which binds to three regularly spaced repeats of the core sequence CCCTC. This CCCTC-binding factor was termed CTCF. It requires additional sequences outside the three recognition motifs for tight binding. CTCF was purified to near homogeneity by sequence-specific DNA chromatography. The approximate molecular weight of the CTCF was estimated to be 130,000. Removal of 110 bp sequence binding both CTCF and Sp1-like proteins leads to a 4 to 8-fold increase in transcription of stably transfected c-myc fusion constructs in chicken embryonic fibroblasts, suggesting that the CTCF is likely to be one of multiple nuclear factors involved in the transcriptional regulation of the chicken c-myc gene.
Efficacy of daratumumab‐based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials (2017)

Outside of clinical trials, experience with daratumumab-based combination therapies (DCTs) using bortezomib (V)/lenalidomide (R)/pomalidomide (P), and dexamethasone (d) in relapsed/refractory multiple myeloma (RRMM) is limited. We reviewed the outcomes of 126 patients who received ≥ 1 cycle of any DCT. Median age at DCT initiation was 67 (range, 43-93) years. High-risk cytogenetics was present in 33% patients. Median number of prior therapies was 4 (range, 1-14) and time to first DCT from diagnosis was 4.3 years (range, 0.4-13.0). Seventeen (13%) patients were refractory to single agent daratumumab. Fifty-two (41%), 34 (27%), 23 (18%), and 17 (14%) received DPd, DRd, DVd and "other" DCTs, respectively. Overall response rate was 47%. Median follow-up was 5.5 months (95% CI, 4.2-6.1). Median progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.8). Median overall survival was not reached (NR) with any regimen. Median PFS (months) was worst for penta-refractory MM (n = 8) vs quadruple refractory MM (n = 18) and others (n = 100) (2.2 [95% CI, 1-2.4] vs 3.1 [95% CI, 2.1-NR] vs 5.9 [95% CI, 5.0-NR]; P < .001); those who were refractory to ≥1 agents used in the DCT vs others (4.9 [95% CI, 3.1-6.0] vs 8.2 [95% CI, 4.6-NR]; P = .02); and those who received >2 prior therapies vs others (5.0 months [95% CI, 3.7-5.9] vs NR [95% CI, NR-NR]; P = .002). Non-hematologic toxicities included infections (38%), fatigue (32%), and infusion reactions (18%). Grade 3 or higher hematological toxicities were seen in 41% of patients. DCTs are effective in RRMM. ORR and PFS in heavily pretreated patients are lower than those reported in clinical trials.
Regional citrate anticoagulation in cardiac surgery patients at high risk of bleeding: a continuous veno-venous hemofiltration protocol with a low concentration citrate solution (2012)

RCA safely prolonged filter life while decreasing CRRT downtime, transfusion rates and supplementation needs for antithrombin III and platelets. In cardiac surgery patients with severe multiple organ dysfunction syndrome, the adoption of a 12 mmol/l citrate solution may provide a suboptimal buffers supply, easily overwhelmed by bicarbonate supplementation.