gebhart/patrepeval huggingface dataset:
A Lopinavir/Ritonavir-Based Once-Daily Regimen Results in Better Compliance and Is Non-inferior to a Twice-Daily Regimen Through 96 Weeks (2007)

We assessed the safety and efficacy and evaluated the adherence to lopinavir/ritonavir (LPV/r) dosed QD or BID in antiretroviral-naive, HIV-1-infected subjects through 96 weeks of treatment. A randomized, open-label, multicenter comparative study was conducted. A total of 190 antiretroviral-naive subjects with plasma HIV-1 RNA above 1000 copies/ml and any CD4(+) T cell count were enrolled. Subjects were randomized (3:2) to LPV/r 800/200 mg QD (n = 115) or 400/100 mg BID (n = 75). Subjects received TDF 300 mg and FTC 200 mg QD. Adherence to LPV/r through 96 weeks was measured using MEMS((R)) monitors. Median baseline VL and CD4(+) T cell count were 4.8 log(10) copies/ml and 216 cells/mm(3), respectively. Prior to week 96, 37% (QD) and 39% (BID) of subjects discontinued, primarily due either to adverse events (17% QD, 9% BID) or to loss to follow-up or nonadherence (12% QD, 17% BID). The proportion of subjects with VL <50 copies/ml [57% QD, 53% BID; p = 0.582 (ITT NC = F)], change in CD4 count (244 cells/mm(3) QD, 264 cells/mm(3) BID; p = 0.513), and evolution of resistance did not differ between groups through 96 weeks. Diarrhea (17% QD, 5% BID, p = 0.014) was the most common moderate or severe, study drug-related adverse event. Adherence to LPV/r was higher for the QD group than the BID group and declined over time in both groups. Time to loss of virologic response was significantly associated with adherence to LPV/r in both groups. LPV/r QD resulted in virologic response similar to LPV/r BID through 96 weeks in antiretroviral-naive subjects. Adherence was significantly higher in the QD group.
Alphavirus-Adjuvanted Norovirus-Like Particle Vaccines: Heterologous, Humoral, and Mucosal Immune Responses Protect against Murine Norovirus Challenge (2009)

The development of an effective norovirus vaccine likely requires the capacity to protect against infection with multiple norovirus strains. Advanced recombinant genetic systems and the recent discovery of a mouse-tropic norovirus strain (MNV) provide robust model systems for vaccine efficacy studies. We coadministered multivalent norovirus-like particle (VLP) vaccines with alphavirus adjuvant particles to mice and evaluated homotypic and heterotypic humoral and protective immunity to human and murine norovirus strains. Multivalent VLP vaccines induced robust receptor-blocking antibody responses to heterologous human strains not included in the vaccine composition. Inclusion of alphavirus adjuvants in the inoculum significantly augmented VLP-induced systemic and mucosal immunity compared to the responses induced by low-dose CpG DNA, validating the utility of such adjuvants with VLP antigens. Furthermore, multivalent vaccination, either including or excluding MNV VLP, resulted in significantly reduced viral loads following MNV challenge. Passive transfer of sera from mice monovalently vaccinated with MNV VLP to immunodeficient or immunocompetent mice protected against MNV infection; however, adoptive transfer of purified CD4(+) or CD8(+) cells did not influence viral loads in murine tissues. Together, these data suggest that humoral immunity induced by multivalent norovirus vaccines may protect against heterologous norovirus challenge.
Functionalization of Carbon Nanotubes with Polystyrene (2002)

Single-walled and multiple-walled carbon nanotubes were functionalized with a polystyrene copolymer, poly(styrene-co-p-(4-(4'-vinylphenyl)-3-oxabutanol)). The functionalization reaction conditions were designed for the esterification of the nanotube-bound carboxylic acids. The polymer-attached carbon nanotubes are soluble in common organic solvents, making it possible to characterize the samples using not only solid-state but also solution-based techniques. The solubility has also allowed an intimate mixing of the functionalized carbon nanotubes with polystyrene. Results from the characterization of the functionalized carbon nanotubes, including the chemical and thermal defunctionalizations of the soluble samples, and the fabrication of polystyrene−carbon nanotube composite thin films using a wet-casting method are presented and discussed.
Newcastle Disease Virus: A Promising Vector for Viral Therapy, Immune Therapy, and Gene Therapy of Cancer (2009)

This review deals with the avian paramyxovirus Newcastle disease virus (NDV) and describes properties that explain its oncolytic activity, its tumor-selective replication behavior, and its immune-stimulatory capacity with human cells. The strong interferon response of normal cells upon contact with NDV appears to be the basis for the good tolerability of the virus in cancer patients and for its immune stimulatory properties, whereas the weak interferon response of tumor cells explains the tumor selectivity of replication and oncolysis. Various concepts for the use of this virus for cancer treatment are pointed out and results from clinical studies are summarized. Reverse genetics technology has made it possible recently to clone the genome and to introduce new foreign genes thus generating new recombinant viruses. These can, in the future, be used to transfer new therapeutic genes into tumors and also to immunize against new emerging pathogens. The modular nature of gene transcription, the undetectable rate of recombination, and the lack of a DNA phase in the replication cycle make NDV a suitable candidate for the rational design of a safe and stable vaccine and gene therapy vector.
Molecular cloning of a second form of rac protein kinase. (1991)

A novel serine/threonine protein kinase (termed rac-PK) has recently been identified and cloned from cDNA libraries derived from the human cell lines MCF-7 and WI38. A second form of this protein kinase, termed rac protein kinase beta, has been identified from cDNAs derived from the same cell lines. These two closely related forms show 90% homology, although the beta form with a predicted Mr 60,200 has a carboxyl terminal extension of 40 amino acids in comparison to the alpha form. This extension has a high serine content with 11 serine residues in the last 30 amino acids. The beta form of the protein has been shown by both in vitro translation and bacterial expression to be approximately 5000 Da larger than the alpha form. rac protein kinase beta is encoded by a 3.4-kb transcript and the alpha form is encoded by a 3.2-kb mRNA. Using gene-specific probes both transcripts were detected in all cell types analyzed, although levels of expression were different for the two forms. The catalytic domain of rac protein kinase beta shows a high degree of homology to both the protein kinase C and cyclic AMP-dependent protein kinase families, and hence rac protein kinases appear to represent a new subfamily of the second messenger serine/threonine protein kinases.
The Effect of the CXCR1/2 Antagonist SCH257123 in a Mouse Model of Severe Asthma (2016)

Objective Severe asthma patient phenotypes are characterised as hard to control by low dose inhaled corticosteroids (ICS) and patients often require high doses of oral steroids for optimum symptom control. There is a high unmet medical need for novel therapies for the treatment of this disease. Neutrophilic airway inflammation has also been associated with corticosteroid insensitivity in the severe asthmatic population. In the current study, we have investigated the effect of a CXCR1/2 antagonist, SCH257123 (SCH), in a mouse severe asthma model known to be steroid insensitive. Methods BALB/c mice were sensitised subcutaneously (s.c.) with house dust mite (HDM) emulsified in Complete Freunds adjuvant (CFA) and 14 days later animals were administered HDM via the intranasal (i.n.) route. Animals were dosed with SCH (10 or 30 mg/kg, p.o., 1hr pre‐ and 5 hrs post‐HDM challenge), Dexamethasone (DEX) 1 mg/kg, p.o., 1hr pre‐HDM challenge), or the appropriate vehicle. The mice were killed 24hrs post‐HDM challenge, and a bronchoalveolar lavage (BAL) was performed to determine total and differential cell numbers. Additionally, levels of IFN γ , IL‐1β, IL‐2, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, KC/GRO and TNFα were measured in the BAL fluid. Results HDM‐challenge caused a significant increase in pulmonary inflammation, comprised of a mixed cell population of neutrophils and eosinophils. Pre‐treatment with 10 and 30mg/kg SCH only inhibited neutrophil cell numbers by a maximum of 30% in the BAL which was not significantly different when compared to the HDM‐vehicle treated group. As is consistent in this model, DEX did not significantly inhibit either the eosinophilic or neutrophilic inflammation. HDM‐challenge increased IFN γ , IL‐10 and TNFα levels in the BALF (p&lt;0.0001) which were decreased by DEX (p&lt;0.01) but not SCH. The levels of IL‐1β, IL‐4, IL‐6, and IL‐12p70 were also increased by HDM‐challenge, but were unaffected by both SCH and DEX. Of interest, BAL fluid levels of IL‐2, IL‐5 and KC/GRO were increased following HDM challenge, unaffected by DEX, but further increased by SCH (all p&lt;0.001). In summary, the CFA/HDM severe asthma model has a cellular infiltration insensitive to both steroids and a CXCR1/2 antagonist, at doses known to work in mouse models of neutrophilic inflammation (Chapman et al, JPET 2007 322(2):486–93). Of interest was the increase in the levels of several mediators associated with neutrophil recruitment in the HDM‐challenged mice following SCH administration, which may have limited its efficacy. In the clinic, SCH has been shown to reduce neutrophil numbers in the sputum of severe asthmatics by approximately 36%, which is of similar magnitude to that seen in this model (Nair et al Clin Exp Allergy, 2012 42(7):1097–103). Support or Funding Information Funded by Charles River
The history of Chagas disease (2014)

The ancestor of Trypanosome cruzi was probably introduced to South American via bats approximately 7-10 million years ago. When the first humans arrived in the New World, a sylvatic cycle of Chagas disease was then already well established. Paleoparasitological data suggests that human American trypanosomiasis originated in the Andean area when people founded the first settlements in the coastal region of the Atacama Desert. Identification of T. cruzi as the etiological agent and triatome bugs as the transmission vector of Chagas disease occurred within a few years at the beginning of the 20th century. History also teaches us that human activity leading to environmental changes, in particular deforestation, is the main cause for the spread of Chagas disease. Recently, migration of T. cruzi-infected patients has led to a distribution of Chagas disease from Latin America to non-endemic countries in Europe, North America and western Pacific region.
Design of a Genetic Algorithm for the Simulated Evolution of a Library of Asymmetric Transfer Hydrogenation Catalysts (2009)

A library of catalysts was designed for asymmetric-hydrogen transfer to acetophenone. At first, the whole library was submitted to evaluation using high-throughput experiments (HTE). The catalysts were listed in ascending order, with respect to their performance, and best catalysts were identified. In the second step, various simulated evolution experiments, based on a genetic algorithm, were applied to this library. A small part of the library, called the mother generation (G0), thus evolved from generation to generation. The goal was to use our collection of HTE data to adjust the parameters of the genetic algorithm, in order to obtain a maximum of the best catalysts within a minimal number of generations. It was namely found that simulated evolution's results depended on the selection of G0 and that a random G0 should be preferred. We also demonstrated that it was possible to get 5 to 6 of the ten best catalysts while investigating only 10 % of the library. Moreover, we developed a double algorithm making this result still achievable if the evolution started with one of the worst G0.
Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus (2002)

Since the idiotypic network is an important mechanism for controlling the immune repertoire, we tested anti-idiotypic modulation employing concentrated specific natural polyclonal anti-double-stranded (ds) DNA anti-idiotypic antibodies obtained from a commercial IVIG in the treatment of experimental systemic lupus erythematosus (SLE). Specific natural polyclonal anti-dsDNA anti-idiotypic antibodies (IVIG-ID) were affinity purified from IVIG on an anti-dsDNA-Sepharose column constructed from anti-dsDNA idiotypes (ID) affinity purified from 55 patients with active SLE. NZB/W F(1) mice were treated i.v. with 3 weekly injections of IVIG-ID (2 mg/kg/injection) or regular IVIG (400 mg/kg/injection) both before (age 8 weeks) and after developing anti-dsDNA antibodies at the age of 21-22 weeks. The IVIG-ID-treated mice showed a decline in the titer of anti-dsDNA antibodies during the treatment, reaching maximum suppression 1 week after the last injection. A significant difference in the proteinuria level in the IVIG-ID-treated group compared to the control group was observed. Immunohistology showed different patterns of IgG deposition, with mesangial and capillary wall deposits in controls and in the IVIG-treated group, but only mesangial deposits in the IVIG-ID-treated group. The survival time of the IVIG-ID-treated group was longer than the IVIG-treated group. Treatment with concentrated specific anti-dsDNA anti-ID prepared from commercial IVIG is more effective in suppressing the humoral reaction and clinical signs of SLE than native IVIG. These results point to the considerable regulatory role of anti-ID in the mechanism of action of IVIG in SLE.
Cyanovinylheteroaromatics for Organic Nonlinear Optics (1990)

Abstract Effects of various substituents including chromophores on the second harmonic generation (SHG) of Cyanovinylheteroaromatics were examined. The molecular polarizability was calculated by the PPP MO method to correlate SHG responsiveness with chemical structures. 3-[(2-cyano-2-ethoxycarbonyl)ethenyl]indole 8b exhibited good SHG efficiency (PE = 25 U). The X-ray analysis of 8b showed that the crystals belong to novel and the most favorable P1 space group.
Balthazar Computed Tomography Severity Index Is Superior to Ranson Criteria and APACHE II and III Scoring Systems in Predicting Acute Pancreatitis Outcome (2003)

In all outcome measures the APACHE scores generate small and of similar extent changes in probability. The Balthazar score is superior to other scoring systems in predicting acute pancreatitis severity and pancreatic necrosis. However the Ranson and APACHE scores perform slightly better with respect to organ failure prediction.
Generation of cohesive ends on PCR products by UDG-mediated excision of dU, and application for cloning into restriction digest-linearized vectors. (1993)

We have investigated the use of dU excision by uracil N-glycosylase (UDG) to create cohesive ends on PCR fragments "mimicking" those generated by restriction enzymes. The feasibility of this approach for directional and nondirectional cloning using cohesive ends mimicking SacI or PstI ends is demonstrated by the subcloning of a 383 to 388-bp fragment of bovine basic fibroblast growth factor into restriction enzyme-linearized pT7T318U. UDG-mediated cohesive ends imperfectly matched to PstI-generated vector ends gave reasonable cloning efficiency and accuracy, suggesting that the approach may be extended to mimicry of other restriction enzymes producing 3' overhangs. The rapid and specific excision of dU by UDG (within 30 min at 37 degrees C) has several potential advantages over the use of restriction site-modified primers, including the avoidance of restriction cleavage at internal sites within the PCR product. Also, following ligation, the approach described may be used to prevent subsequent cleavage of the joined DNA segments by the restriction enzyme, that is, by not recreating the restriction enzyme recognition sequence at the junction, which may find application in gene engineering. By adapting the approach to use dU-containing linkers or "vectorettes," the approach may be used for cloning unknown sequences (e.g., by cDNA or genomic library construction) or for mimicking 5' overhang cohesive ends on PCR fragments.
Highly Conserved Non-Coding Sequences Are Associated with Vertebrate Development (2004)

In addition to protein coding sequence, the human genome contains a significant amount of regulatory DNA, the identification of which is proving somewhat recalcitrant to both in silico and functional methods. An approach that has been used with some success is comparative sequence analysis, whereby equivalent genomic regions from different organisms are compared in order to identify both similarities and differences. In general, similarities in sequence between highly divergent organisms imply functional constraint. We have used a whole-genome comparison between humans and the pufferfish, Fugu rubripes, to identify nearly 1,400 highly conserved non-coding sequences. Given the evolutionary divergence between these species, it is likely that these sequences are found in, and furthermore are essential to, all vertebrates. Most, and possibly all, of these sequences are located in and around genes that act as developmental regulators. Some of these sequences are over 90% identical across more than 500 bases, being more highly conserved than coding sequence between these two species. Despite this, we cannot find any similar sequences in invertebrate genomes. In order to begin to functionally test this set of sequences, we have used a rapid in vivo assay system using zebrafish embryos that allows tissue-specific enhancer activity to be identified. Functional data is presented for highly conserved non-coding sequences associated with four unrelated developmental regulators (SOX21, PAX6, HLXB9, and SHH), in order to demonstrate the suitability of this screen to a wide range of genes and expression patterns. Of 25 sequence elements tested around these four genes, 23 show significant enhancer activity in one or more tissues. We have identified a set of non-coding sequences that are highly conserved throughout vertebrates. They are found in clusters across the human genome, principally around genes that are implicated in the regulation of development, including many transcription factors. These highly conserved non-coding sequences are likely to form part of the genomic circuitry that uniquely defines vertebrate development.
Cardiac markers: from enzymes to proteins, diagnosis to prognosis, laboratory to bedside. (1999)

For many years, serologic markers have been used to assist cardiologists in the diagnosis and management of patients with cardiovascular diseases. The use of laboratory markers has evolved and kept pace with the field of cardiology itself. The early markers involved testing for total enzyme activity such as aspartate aminotransferase, lactate dehydrogenase and creatine kinase. Shortly thereafter, the World Health Organization included serial enzyme markers as part of the triad for diagnosis of acute myocardial infarction (AMI). It was soon recognized that isoenzymes such as for CK-MB and LD-1 provided more specific organ specificity. The need for reporting rapid results led to the development of totally automated isoenzyme assays, which have evolved from immunoinhibition (INH) techniques to mass assays. The current emphasis for cardiac markers is use of protein markers such as cardiac troponin T (cTnT) and I (cTnI). These markers are more sensitive and specific than isoenzyme markers and enable risk stratification for non-AMI patients with unstable angina: patients with high troponin have a higher risk for AMI and cardiac death within the immediate future (4 to 6 weeks). Prospective management of cardiac patients requires more rapid testing and reporting of results. Point-of-care testing platforms on whole blood are now available for emergency testing at bedside.
Functional Expression of the Heteromeric “Olfactory” Cyclic Nucleotide-Gated Channel in the Hippocampus: A Potential Effector of Synaptic Plasticity in Brain Neurons (1997)

Cyclic nucleotide-gated (cng) channels are important components of signaling systems mediating sensory transduction. In vertebrate photoreceptors, light activates a signaling cascade that causes a decrease in intracellular cGMP concentrations, closing retinal cng channels. Signal transduction in olfactory receptor neurons is believed to proceed via G-protein-mediated elevation of intracellular cAMP in response to odorant binding by 7-helix receptors. cAMP opens the olfactory cng channel, which is highly permeable to Ca2+. Here we demonstrate by in situ hybridization and immunohistochemistry with subunit-specific antibodies that both subunits of the heteromeric rat olfactory cng channel are also widely expressed in the brain. Expression of the retinal rod cng channel, however, can be detected only in the eye. In the adult hippocampus, the olfactory cng channel is expressed on cell bodies and processes of CA1 and CA3 neurons. In cultured embryonic hippocampal neurons, the channel is localized to a subset of growth cones and processes. We recorded conductances with the electrophysiological characteristics of the heteromeric olfactory cng channel in excised inside-out patches from these cultured neurons. We also show that Ca2+ influx into hippocampal neurons in response to cyclic nucleotide elevation can be detected using fura-2 imaging. Cyclic nucleotide elevation has been implicated in several mechanisms of synaptic plasticity in the hippocampus, and these mechanisms also require elevation of intracellular Ca2+. Our results suggest that the "olfactory" cng channel could regulate synaptic efficacy in brain neurons by modulating Ca2+ levels in response to changes in cyclic nucleotide concentrations.
Divergence and Redundancy of 16S rRNA Sequences in Genomes with Multiple rrn Operons (2004)

The level of sequence heterogeneity among rrn operons within genomes determines the accuracy of diversity estimation by 16S rRNA-based methods. Furthermore, the occurrence of widespread horizontal gene transfer (HGT) between distantly related rrn operons casts doubt on reconstructions of phylogenetic relationships. For this study, patterns of distribution of rrn copy numbers, interoperonic divergence, and redundancy of 16S rRNA sequences were evaluated. Bacterial genomes display up to 15 operons and operon numbers up to 7 are commonly found, but approximately 40% of the organisms analyzed have either one or two operons. Among the Archaea, a single operon appears to dominate and the highest number of operons is five. About 40% of sequences among 380 operons in 76 bacterial genomes with multiple operons were identical to at least one other 16S rRNA sequence in the same genome, and in 38% of the genomes all 16S rRNAs were invariant. For Archaea, the number of identical operons was only 25%, but only five genomes with 21 operons are currently available. These considerations suggest an upper bound of roughly threefold overestimation of bacterial diversity resulting from cloning and sequencing of 16S rRNA genes from the environment; however, the inclusion of genomes with a single rrn operon may lower this correction factor to approximately 2.5. Divergence among operons appears to be small overall for both Bacteria and Archaea, with the vast majority of 16S rRNA sequences showing <1% nucleotide differences. Only five genomes with operons with a higher level of nucleotide divergence were detected, and Thermoanaerobacter tengcongensis exhibited the highest level of divergence (11.6%) noted to date. Overall, four of the five extreme cases of operon differences occurred among thermophilic bacteria, suggesting a much higher incidence of HGT in these bacteria than in other groups.