gebhart/patrepeval huggingface dataset:
High-level eucaryotic in vivo expression of biologically active measles virus hemagglutinin by using an adenovirus type 5 helper-free vector system (1988)

The entire measles virus (MV) hemagglutinin (HA)-coding region was reconstructed from cloned cDNAs and used as part of a hybrid transcription unit to replace a region of the adenovirus type 5 genome corresponding to the entire E1a transcription unit and most of the E1b transcription unit. The resulting recombinant virus was stable and able to replicate to high titers in 293 cells (which constitutively express the complementary E1a-E1b functions) in the absence of helper virus. During infection of 293 cells, the hybrid virus expressed MV HA protein which was indistinguishable from that expressed in MV-infected cells in terms of immunoreactivity, gel mobility, glycosylation, subcellular localization, and biologic activity. Infection of 293 cells with the hybrid virus led to high-level synthesis of the MV HA protein (equivalent to 65 to 130% of the level seen in MV-infected cells). At late times after high-multiplicity hybrid virus infection of HeLa and Vero cells (which do not express E1 functions), the level of HA protein synthesis was at least 35% of that seen in 293 cells. This MV-adenovirus recombinant will be useful in the study of the biologic properties of the MV HA protein and in assessment of the potential usefulness of hybrid adenoviruses as live-virus vaccine vectors.
Adenosine Deaminase-deficient Mice Generated Using a Two-stage Genetic Engineering Strategy Exhibit a Combined Immunodeficiency (1998)

Adenosine deaminase (ADA) deficiency in humans leads to a combined immunodeficiency. The mechanisms involved in the lymphoid specificity of the disease are not fully understood due to the inaccessibility of human tissues for detailed analysis and the absence of an adequate animal model for the disease. We report the use of a two-stage genetic engineering strategy to generate ADA-deficient mice that retain many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T and B cell lymphopenia was accompanied by a pronounced accumulation of 2'-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in these organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathogenesis. These mice have provided in vivo information into the metabolic basis for the immune phenotype associated with ADA deficiency.
Strontium Ranelate in Osteoporosis (2002)

In the UK, there are around 200,000 osteoporotic fractures each year. National guidelines in the UK recommend preventative treatment in patients who are at high risk of fracture on the basis of age, fracture history, bone mineral density and other risk factors. For secondary prevention, an oral bisphosphonate, such as alendronate or risedronate, is the drug of choice but may not be tolerated, particularly because of unwanted upper gastrointestinal effects. Raloxifene provides a potential oral alternative in women. National guidelines also suggest subcutaneous teriparatide for women aged more than 65 years with severe osteoporosis who have failed to tolerate or respond to a bisphosphonate; however, we believe use of this drug is problematic. Strontium ranelate (Protelos-Servier) is a new oral treatment for women with postmenopausal osteoporosis that is promoted as "the first dual action bone agent" and "the only drug to simultaneously increase bone formation and decrease bone resorption". Here we review the evidence for strontium ranelate and consider whether it has a role in postmenopausal osteoporosis.
A ribozyme with DNA in the hybridising arms displays enhanced cleavage ability (1992)

Hammerhead ribozymes cleave RNA substrates containing the UX sequence, where X = U, C or A, embedded within sequences which are complementary to the hybridising “arms’ of the ribozyme. In this study we have replaced the RNA in the hybridising arms of the ribozyme with DNA, and the resulting ribozyme is many times more active than its precursor. In turnover-kinetics experiments with a 13-mer RNA substrate, the k cat /K m ratios are 10 and 150 µ M −1 min −1 for the RNA-and DNA-armed ribozymes, respectively. The effect is due mainly to differences in k cat . In independent experiments where the cleavage step is rate-limiting, the DNA-armed ribozyme cleaves the substrate with a rate constant more than 3 times greater than the all-RNA ribozyme. DNA substrates containing a ribocytidine at the cleavage site have been shown to be cleaved less efficiently than their all-RNA analogues; again however, the DNA-armed ribozyme is more effective than the all-RNA ribozyme against such DNA substrates. These results demonstrate that there are no 2′-hydroxyl groups in the arms of the ribozyme that are required for cleavage; and that the structure of the complex formed by the DNA-armed ribozyme with its substrate is more favourable for cleavage than that formed by the all-RNA ribozyme and its substrate.
Neuroprotective effects of the novel brain-penetrating pyrrolopyrimidine antioxidants U-101033E and U-104067F against post-ischemic degeneration of nigrostriatal neurons (1997)

A 10-min period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers a delayed retrograde degeneration of 35-40% of dopaminergic nigrostriatal (NS) neurons. The mechanism of the NS degeneration is believed to involve oxygen radical formation secondary to a postischemic increase in dopamine turnover (monoamine oxidase, MAO). If the oxygen radical increase is sufficiently severe, lipid peroxidative injury to the striatal NS terminals is followed by retrograde degeneration of the NS cell bodies. In the present study, we examined whether the novel brain-penetrating lipid antioxidant pyrrolopyrimidine, U-101033E, and its aromatized analog, U-104067F, could attenuate dopaminergic neurodegeneration in this model. Male Mongolian gerbils were dosed with U-101033E (1.5, 5, or 15 mg/kg, by mouth, twice daily) or U-104067F (5 or 15 mg/kg, by mouth, twice daily) for 27 days beginning on the day of the 10-min ischemic insult. Preservation of NS neurons was assessed by tyrosine hydroxylase immunohistochemistry at 28 days. In vehicle (40% hydroxypropyl-beta-cyclodextrin)-treated animals, there was a 42% loss of NS neurons. In contrast, gerbils that received 5 or 15 mg/kg U-101033E twice daily had only a 23% or 28% loss of NS neurons, respectively (P < 0.002 vs. vehicle). U-104067F showed little effect at sparing neurons at the 10 mg/kg dose, but did significantly attenuate neuronal loss to only 20% at the 30 mg/kg dose (P < 0.01 vs. vehicle). The results show that both the pyrrolopyrimidines (U-101033E and U-104067F) significantly attenuate the postischemic loss of NS dopaminergic neurons and further support the involvement of a dopamine metabolism-derived, oxygen radical-induced lipid peroxidative mechanism.
The philosophy of science in German‐speaking countries (1998)

(1998). The philosophy of science in German‐speaking countries. International Studies in the Philosophy of Science: Vol. 12, No. 1, pp. 45-86.
Reconstruction of cardiac-gated dynamic SPECT images (2005)

In this work, we propose an image reconstruction procedure which will unify gated SPECT and dynamic SPECT into a single imaging method. Traditionally, gated SPECT and dynamic SPECT are treated as two distinct directions in SPECT imaging: gated SPECT aims to reconstruct a periodic stationary sequence of the cardiac cycle, while dynamic SPECT aims to obtain a time-varying distribution of the radiolabeled tracer during the study. In the proposed reconstruction procedure, we divide the cardiac cycle into a number of gate intervals as in gated SPECT, but treat the tracer distribution for each gate as a time-varying signal. By using list-mode data, this procedure produces an image sequence that shows both cardiac motion and time-varying tracer distribution. To demonstrate the proposed method, we simulated gated cardiac perfusion imaging with Tc-99m labeled Teboroxime using the 4D gated mathematical cardiac-torso (gMCAT) phantom. Preliminary results are presented to demonstrate the feasibility of the proposed approach.
Sequentially Derived Mutants of the Constant Region of the Heavy Chain of Murine Immunoglobulins (1979)

Abstract In an effort to define the mechanism of the γ2b → γ2a subclass switch observed in cultured cells, a series of constant region mutants has been isolated in the cell line (45.6) derived from the MPC-11 tumor. The investigation was begun with 10-1, a spontaneous variant of 45.6 which synthesizes a 47,000 dalton heavy chain with a deletion in CH1. From 10-1, two types of secondary variant was synthesizing a 55,000 dalton heavy chain that was γ2a serologically. Five independent variants synthesizing 55,000 dalton γ2a heavy chain were isolated from 10-1. All five were of the same apparent m.w. and four, but not the fifth, had identical isoelectric focusing patterns. The second type of secondary variant isolated from 10-1 was synthesizing a heavy chain even smaller than the heavy chain of 10-1. Two different variants of this type, I17 and G251, synthesized heavy chains of approximately 35,000 and 40,000 daltons, respectively, which did not react with any subclass-specific antiserum. From I17 and G251 it was possible to isolate tertiary variants that synthesized γ2a heavy chains of either 47,000 daltons or 55,000 daltons m.w. The 55,000 dalton γ2a heavy chains exhibited many different isoelectric focusing patterns. Peptide map analysis of two 47,000 dalton and two 55,000 dalton γ2a tertiary variants showed no differences from the Fc of MOPC-173, a naturally occurring γ2a myeloma. However, a third 55,000 dalton γ2a variant synthesized a heavy chain with a Fc that was apparently not identical to that of MOPC-173. These experiments show that it is possible to isolate γ2b → γ2a subclass switch mutants from variants synthesizing short heavy chains. It is not possible to define unequivocally the mechanism of the subclass switch. However, it clearly does not result from the translocation of an intact V region to an intact constant region. The resulting data are, however, compatible with the γ2b → γ2a switch resulting from a recombination event between tandem genes on homologous chromosomes or chromatids.
Efficient and Expeditious Protocols for the Synthesis of Racemic and Enantiomerically Pure Endocyclic Enecarbamates from N-Acyl Lactams and N-Acyl Pyrrolidines (1999)

A mild, practical, and straightforward protocol for the construction of endocyclic enecarbamates starting from N-acyl lactams and N-acyl pyrrolidines is presented. Lactams were reduced to the corresponding alpha-hydroxycarbamates in good to excellent yields using DIBAL-H, SuperHydride, or NaBH(4) followed by beta-elimination (dehydration) promoted by trifluoroacetic anhydride in the presence of hindered nitrogenated bases such as 2,6-lutidine, diisopropylethylamine, or triethylamine. Small variations of this protocol permitted the preparation of several endocyclic enecarbamates (12 examples) in good to excellent overall yields (56-96%). The protocol was demonstrated to be applicable to several ring sizes, compatible with different protecting groups, and to be mild enough to prevent racemization of racemization-prone stereocenters. The efficacy of the procedure in the preparation of enantiomerically pure endocyclic enecarbamates was also demonstrated and compared to the commonly used Shono's protocol, which in our hands led to partial racemization of the endocyclic enecarbamate 18c.
Computational structure-based redesign of enzyme activity (2009)

We report a computational, structure-based redesign of the phenylalanine adenylation domain of the nonribosomal peptide synthetase enzyme gramicidin S synthetase A (GrsA-PheA) for a set of noncognate substrates for which the wild-type enzyme has little or virtually no specificity. Experimental validation of a set of top-ranked computationally predicted enzyme mutants shows significant improvement in the specificity for the target substrates. We further present enhancements to the methodology for computational enzyme redesign that are experimentally shown to result in significant additional improvements in the target substrate specificity. The mutant with the highest activity for a noncognate substrate exhibits 1/6 of the wild-type enzyme/wild-type substrate activity, further confirming the feasibility of our computational approach. Our results suggest that structure-based protein design can identify active mutants different from those selected by evolution.
Docosahexaenoic acid: A natural powerful adjuvant that improves efficacy for anticancer treatment with no adverse effects (2011)

Epidemiological studies have linked fish oil consumption to a decreased incidence of cancer. The anticancer effects of fish oil are mostly attributed to its content of omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, DHA, because of its unique effect of altering membrane composition, is often regarded as the major omega-3 fatty acid involved in anticancer activity. Although use of DHA as an anticancer drug to prevent or treat human cancer in clinical settings has not yet been well established, recent studies suggest that DHA can be very effective as an adjuvant with other anticancer agents. In this article, we present studies that show the role of DHA in improving anticancer drug efficacy. Several in vitro and animal studies suggest that combining DHA with other anticancer agents often improves efficacy of anticancer drugs and also reduces therapy-associated side effects. Incorporation of DHA in cellular membranes improves drug uptake, whereas increased lipid peroxidation is another mechanism for DHA-mediated enhanced efficacy of anticancer drugs. In addition, several intracellular targets including cyclooxygenase-2, nuclear factor kappa B, peroxisome proliferator-activated receptor gamma, mitogen-activated protein kinase, AKT, and BCL-2/BAX are found to play an important role in DHA-mediated additive or synergistic interaction with anticancer drugs. The data suggest that DHA is a safe, natural compound that can greatly improve the anticancer properties of anticancer drugs. Use of DHA with anticancer treatments provides an avenue to therapeutic improvement that involves less risk or side effects for patients and reduced regulatory burden for implementation.
Hybrid silicon evanescent lasers (2006)

Silicon photonic platforms have been of great interest for the integration of photonic and electronic circuits on a silicon substrate. However, efficient light generation inside a silicon crystal has been the major obstacle due to the indirect bandgap characteristics of silicon. To overcome this problem, recently we demonstrated optically pumped hybrid silicon evanescent lasers, in which III-V based quantum wells are bonded to silicon rib waveguides. This approach enables to build active silicon photonic devices by combining high optical gain of Ill-V materials with well developed silicon processing technology. The work presented here is a first step of the future development of the electrically driven silicon active photonic devices as well as the photonic integration with electrical circuitry on silicon-on-insulator (SOI) wafers.
BIOELECTRICAL IMPEDANCE METHOD FOR BODY COMPOSITION ASSESSMENT IN JAPANESE ADULT FEMALES AND ITS CROSS-VALIDITY (1992)

Several prediction equations for estimating body composition of Japanese men and women have recently been developed using a linear regression model with a combination of impedance and anthropometric measurements as independent variables. The purpose of this study was to determine the cross-validity of body density (Db) estimated from bioelectrical impedance (BI) and skinfold thickness (ST) methods in comparison with underwater weighing (UW) as a criterion reference method. Percentage body fat (%BF) was derived from Db according to the equation Brozek et al. Fifty-seven healthy Japanese women, aged 19 to 57 years, volunteered to participate in the study. Impedance was measured by use of a portable four-terminal impedance plethysmograph (Selco, SIF-891) . %BF derived from the BI method (r=0.860-0.875) was correlated with hydrodensitometrically determined %BF to a greater extent than %BF obtained using the ST method (r=0.7330.758) or ultrasound method (r=0.536-0.721) . Correlations of various anthropometric indices (r=0.655-0.691) with hydrodensitometrically determined %BF were even lower. It was noteworthy, however, that mean %BF derived from existing BI equations differed significantly from hydrodensitometrically determined mean %BF. Therefore, we attempted to develop a new equation that was applicable to Japanese adult women as follows: Db=1.1613-0.1038 (Wt⋅Z ) /Ht2, where Wt=weight in kg, Z=impedance in ohms, and Ht=height in cm. The prediction accuracy of this equation was r=0.866 or SEE=0.0077 g/ml. Cross-validation of this equation on a different sample (122 Japanese women, aged 18 to 59 years) revealed a correlation of r=0.869 in terms of %BF, SEE=3.2%, and no significant difference between estimated %BF and the criterion. We suggest that the BI method is one of the most convenient, valid means of assessing human body composition, and that the newly developed BI equation could be useful particularly when the subjects are Japanese adult women in their late teens to fifties.
Human Lymphoid and Myeloid Cell Development in NOD/LtSz- scid IL2R γ null Mice Engrafted with Mobilized Human Hemopoietic Stem Cells, (2005)

Ethical considerations constrain the in vivo study of human hemopoietic stem cells (HSC). To overcome this limitation, small animal models of human HSC engraftment have been used. We report the development and characterization of a new genetic stock of IL-2R common gamma-chain deficient NOD/LtSz-scid (NOD-scid IL2Rgamma(null)) mice and document their ability to support human mobilized blood HSC engraftment and multilineage differentiation. NOD-scid IL2Rgamma(null) mice are deficient in mature lymphocytes and NK cells, survive beyond 16 mo of age, and even after sublethal irradiation resist lymphoma development. Engraftment of NOD-scid IL2Rgamma(null) mice with human HSC generate 6-fold higher percentages of human CD45(+) cells in host bone marrow than with similarly treated NOD-scid mice. These human cells include B cells, NK cells, myeloid cells, plasmacytoid dendritic cells, and HSC. Spleens from engrafted NOD-scid IL2Rgamma(null) mice contain human Ig(+) B cells and lower numbers of human CD3(+) T cells. Coadministration of human Fc-IL7 fusion protein results in high percentages of human CD4(+)CD8(+) thymocytes as well human CD4(+)CD8(-) and CD4(-)CD8(+) peripheral blood and splenic T cells. De novo human T cell development in NOD-scid IL2Rgamma(null) mice was validated by 1) high levels of TCR excision circles, 2) complex TCRbeta repertoire diversity, and 3) proliferative responses to PHA and streptococcal superantigen, streptococcal pyrogenic exotoxin. Thus, NOD-scid IL2Rgamma(null) mice engrafted with human mobilized blood stem cells provide a new in vivo long-lived model of robust multilineage human HSC engraftment.
Synthetic analogues of nicotine VI1,2. Nicotine substituted in the 5-position. (1977)

&lt;p&gt;A comparison is made between tactile and vibrating microprobes regarding the measurement of typical high aspect ratio microfeatures. It is found that vibrating probes enable the use of styli with higher aspect ratios than tactile probes and are still capable of measuring with high sensitivity. In addition to the one dimensional sensitivity, the directional measurement sensitivity of a vibrating probe is investigated. A vibrating microprobe can perform measurements with high sensitivity in a space spanned by its mode shapes. If the natural frequencies that correspond to these mode shapes are different, the probe shows anisotropic and sub-optimal measurement sensitivity. It is shown that the closer the natural frequencies of the probe are, the better its performance is when regarding optimal and isotropic measurement sensitivity. A novel proof-of-principle setup of a vibrating probe with two nearly equal natural frequencies is realized. This system is able to perform measurements with high and isotropic sensitivity.&lt;/p&gt;
Micro contactor based on isotachophoretic sample transport (2009)

It is demonstrated how isotachophoresis (ITP) in a microfluidic device may be utilized to bring two small sample volumes into contact in a well-controlled manner. The ITP contactor serves a similar purpose as micromixers that are designed to mix two species rapidly in a microfluidic channel. In contrast to many micromixers, the ITP contactor does not require complex channel architectures and allows a sample processing in the spirit of "digital microfluidics", i.e. the samples always remain in a compact volume. It is shown that the ITP zone transport through microchannels proceeds in a reproducible and predictable manner, and that the sample trajectories follow simple relationships obtained from Ohm's law. Firstly, the micro contactor can be used to synchronize two ITP zones having reached a channel at different points in time. Secondly, fulfilling its actual purpose it is capable of bringing two samples in molecular contact via an interpenetration of ITP zones. It is demonstrated that the contacting time is proportional to the ITP zone extension. This opens up the possibility of using that type of device as a special type of micromixer with "mixing times" significantly below one second and an option to regulate the duration of contact through specific parameters such as the sample volume. Finally, it is shown how the micro contactor can be utilized to conduct a hybridization reaction between two ITP zones containing complementary DNA strands.
Surface Charge-Switching Polymeric Nanoparticles for Bacterial Cell Wall-Targeted Delivery of Antibiotics (2012)

Bacteria have shown a remarkable ability to overcome drug therapy if there is a failure to achieve sustained bactericidal concentration or if there is a reduction in activity in situ. The latter can be caused by localized acidity, a phenomenon that can occur as a result of the combined actions of bacterial metabolism and the host immune response. Nanoparticles (NP) have shown promise in treating bacterial infections, but a significant challenge has been to develop antibacterial NPs that may be suitable for systemic administration. Herein we develop drug-encapsulated, pH-responsive, surface charge-switching poly(D,L-lactic-co-glycolic acid)-b-poly(L-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for treating bacterial infections. These NP drug carriers are designed to shield nontarget interactions at pH 7.4 but bind avidly to bacteria in acidity, delivering drugs and mitigating in part the loss of drug activity with declining pH. The mechanism involves pH-sensitive NP surface charge switching, which is achieved by selective protonation of the imidazole groups of PLH at low pH. NP binding studies demonstrate pH-sensitive NP binding to bacteria with a 3.5 ± 0.2- to 5.8 ± 0.1-fold increase in binding to bacteria at pH 6.0 compared to 7.4. Further, PLGA-PLH-PEG-encapsulated vancomycin demonstrates reduced loss of efficacy at low pH, with an increase in minimum inhibitory concentration of 1.3-fold as compared to 2.0-fold and 2.3-fold for free and PLGA-PEG-encapsulated vancomycin, respectively. The PLGA-PLH-PEG NPs described herein are a first step toward developing systemically administered drug carriers that can target and potentially treat Gram-positive, Gram-negative, or polymicrobial infections associated with acidity.