gebhart/patrepeval huggingface dataset:
Transgenic Expression of Human CD47 Markedly Increases Engraftment in a Murine Model of Pig-to-Human Hematopoietic Cell Transplantation (2014)

Mixed chimerism approaches for induction of tolerance of solid organ transplants have been applied successfully in animal models and in the clinic. However, in xenogeneic models (pig-to-primate), host macrophages participate in the rapid clearance of porcine hematopoietic progenitor cells, hindering the ability to achieve mixed chimerism. CD47 is a cell-surface molecule that interacts in a species-specific manner with SIRPα receptors on macrophages to inhibit phagocytosis and expression of human CD47 (hCD47) on porcine cells has been shown to inhibit phagocytosis by primate macrophages. We report here the generation of hCD47 transgenic GalT-KO miniature swine that express hCD47 in all blood cell lineages. The effect of hCD47 expression on xenogeneic hematopoietic engraftment was tested in an in vivo mouse model of human hematopoietic cell engraftment. High-level porcine chimerism was observed in the bone marrow of hCD47 progenitor cell recipients and smaller but readily measurable chimerism levels were observed in the peripheral blood of these recipients. In contrast, transplantation of WT progenitor cells resulted in little or no bone marrow engraftment and no detectable peripheral chimerism. These results demonstrate a substantial protective effect of hCD47 expression on engraftment and persistence of porcine cells in this model, presumably by modulation of macrophage phagocytosis.
Labelling of proteins by use of iodination and detection by ICP-MS (2008)

The labelling of three different proteins, bovine serum albumin (BSA), chicken egg white lysozyme and porcine gastric mucosa pepsin, with iodine using a commercially available reaction kit has been investigated for total protein amounts of 500 μg. The assay described here has already often been applied but with radioactive iodine isotopes and is extended in this work for the use of the stable isotope 127I and detection by ICP-MS. The reaction conditions are investigated and optimised for proteins separated by SDS-PAGE and electroblotted onto NC membranes. Detection has been performed by laser ablation ICP-MS on the membranes. Long reaction times result in degradation of proteins, whereas for short reaction times (4 min) integrated sensitivities of even 108 cps pmol−1 of protein have been realized. Total amounts of proteins have been investigated in the range from 0.015 (BSA) to 105 pmol (lysozyme). A calibration was performed for BSA from 0.015 to 15 pmol but the limit of detection was reached already at about 150 fmol due to high iodine blank values, only. The labelling procedure described here does not affect protein mobility in SDS-PAGE, because the change of the molecular weight is very moderate for the proteins investigated here. This is quite opposite to those procedures where chelating compounds are applied. ESI-FTICR-MS has been used to identify histidine and tyrosine as the target amino acids for iodination. Additionally, oxidation of methionine residues has been observed.
The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. (1997)

Lowering of the elevated plasma FFA concentration in 18- 24-h fasted rats with nicotinic acid (NA) caused complete ablation of subsequent glucose-stimulated insulin secretion (GSIS). Although the effect of NA was reversed when the fasting level of total FFA was maintained by coinfusion of soybean oil or lard oil (plus heparin), the more saturated animal fat proved to be far more potent in enhancing GSIS. We therefore examined the influence of individual fatty acids on insulin secretion in the perfused rat pancreas. When present in the perfusion fluid at 0.5 mM (in the context of 1% albumin), the fold stimulation of insulin release from the fasted pancreas in response to 12.5 mM glucose was as follows: octanoate (C8:0), 3.4; linoleate (C18:2 cis/cis), 5.3; oleate (C18:1 cis), 9.4; palmitate (C16:0), 16. 2; and stearate (C18:0), 21.0. The equivalent value for palmitoleate (C16:1 cis) was 3.1. A cis--> trans switch of the double bond in the C16:1 and C18:1 fatty acids had only a modest, if any, impact on their potency. A similar profile emerged with regard to basal insulin secretion (3 mM glucose). When a subset of these fatty acids was tested in pancreases from fed animals, the same rank order of effectiveness at both basal and stimulatory levels of glucose was seen. The findings reaffirm the essentiality of an elevated plasma FFA concentration for GSIS in the fasted rat. They also show, however, that the insulinotropic effect of individual fatty acids spans a remarkably broad range, increasing and decreasing dramatically with chain length and degree of unsaturation, respectively. Thus, for any given level of glucose, insulin secretion will be influenced greatly not only by the combined concentration of all circulating (unbound) FFA, but also by the makeup of this FFA pool. Both factors will likely be important considerations in understanding the complex interplay between the nature of dietary fat and whole body insulin, glucose, and lipid dynamics.
The design and bioactivation of presystemically stable prodrugs (1988)

(1988). The design and bioactivation of presystemically stable prodrugs. Drug Metabolism Reviews: Vol. 19, No. 2, pp. 165-194.
Simple nearest-neighbor two-body Hamiltonian system for which the ground state is a universal resource for quantum computation (2006)

We present a simple quantum many-body system---a two-dimensional lattice of qubits with a Hamiltonian composed of nearest-neighbor two-body interactions---such that the ground state is a universal resource for quantum computation using single-qubit measurements. This ground state approximates a cluster state that is encoded into a larger number of physical qubits. The Hamiltonian we use is motivated by the projected entangled pair states, which provide a transparent mechanism to produce such approximate encoded cluster states on square or other lattice structures (as well as a variety of other quantum states) as the ground state. We show that the error in this approximation takes the form of independent errors on bonds occurring with a fixed probability. The energy gap of such a system, which in part determines its usefulness for quantum computation, is shown to be independent of the size of the lattice. In addition, we show that the scaling of this energy gap in terms of the coupling constants of the Hamiltonian is directly determined by the lattice geometry. As a result, the approximate encoded cluster state obtained on a hexagonal lattice (a resource that is also universal for quantum computation) can be shown to have a larger energy gap than one on a square lattice with an equivalent Hamiltonian.
The Mechanism of Anti-CTLA-4 Activity and the Negative Regulation of T-Cell Activation (2008)

The survival rate of patients diagnosed with late-stage melanoma is poor--only 5%-10%. Enlisting the immune system in the fight against cancers such as melanoma could help improve the prognosis of these patients. Data have shown that melanocyte proteins make good targets for immune system-based therapy in this disease. However, self-tolerance, which develops to inhibit autoimmune attack, makes this strategy difficult. Two proteins on the surface of T cells--CD28 and cytotoxic T-lymphocyte antigen 4 (CTLA-4)--play important roles in the regulation of immune activation and tolerance. CD28 provides positive modulatory signals in the early stages of an immune response, while CTLA-4 signaling inhibits T-cell activation, particularly during strong T-cell responses. CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great appeal because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Both clinical and preclinical data indicate that CTLA-4 blockade results in direct activation of CD4+ and CD8+ effector cells, and anti-CTLA-4 monoclonal antibody therapy has shown promise in a number of cancers, particularly melanoma. Interestingly, the occurrence of adverse events among patients treated with CTLA-4 blockade helps shed light on the mechanism of action of anti-CTLA-4 monoclonal antibodies. Most adverse events involve immune-related toxicity to the skin and gastrointestinal tract. Major gastrointestinal toxicity develops in up to 21% of treated patients, and while an objective response occurs in approximately 36% of melanoma patients who develop enterocolitis with treatment, an objective response is found in only 11% of patients who do not experience this adverse reaction.
Use of parvovirus‐like particles for vaccination and induction of multiple immune responses (1999)

Expression of the VP2 gene of autonomous parvoviruses in insect cells with the use of the baculovirus system has led to the production of virus-like particles (VLPs) formed by the self-assembly of VP2. These VLPs are expressed at high levels and can easily be purified by salt fractionation. They are highly immunogenic in the corresponding host, being fully protective at doses as low as 1-2 microg of purified material per animal. No special adjuvants are required. An interesting property of these particles is their usefulness as a diagnostic reagent for ELISA kits, which have successfully replaced conventional methods for parvovirus diagnostics based on haemagglutination. Another application of the hybrid recombinant parvovirus-like particles of pig parvovirus (PPV) and canine parvovirus (CPV) is its use as an antigen delivery system. PPV:VLPs containing a CD8(+) epitope from the lymphocytic choriomeningitis virus (LCMV) nucleoprotein are able to evoke a potent cytolytic T-lymphocyte response and to protect mice against a lethal infection with LCMV. Also, PPV:VLPs containing the C3:T epitope from poliovirus elicited a T helper response in mice. These T-cell epitopes were inserted into the N-terminus of the VP2 protein. Unfortunately, the N-terminus is not adequate for antibody responses because it is inside the particle. Recent findings have shown that fine tailoring of the point of insertion around the tip of loop 2 of the surface of CPV allowed the elicitation of a potent antibody response. Thus mice immunized with chimaeric C3:B CPV:VLPs were able to elicit a strong neutralizing antibody response (>3 log10 units) against poliovirus. We now have the possibility of using these particles to elicit different immune responses against single or multiple pathogens in a simple and economic way.
Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty (1995)

Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. A heterozygous mutation encoding substitution of Asp578 with Gly in transmembrane helix 6 of the G protein-coupled receptor for luteinizing hormone (LHR) has been found in affected males from nine American FMPP families. Cells expressing the mutant LHR exhibit markedly increased cyclic adenosine monophosphate (cAMP) production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LHR. We have now analyzed genomic DNA from affected males from six additional FMPP families. PCR was used to amplify a fragment of the LHR gene encoding amino acid residues 441-594. None of the six new samples contained the Asp578-->Gly mutation, as indicated by absence of digestion with MspI. PCR products were then screened for heterozygous mutations using temperature-gradient gel electrophoresis. DNA fragments from two of the patients migrated abnormally. Direct sequencing of PCR product from one affected German male revealed a heterozygous mutation (ATG-->ATA) encoding Met571-->Ile at the cytoplasmic end of helix 6, the same mutation that has been reported in another European FMPP kindred. Affected males in the second family had a novel Thr577-->Ile mutation (ACC-->ATC). Mutations in different portions of the LHR or in a different gene may be responsible for disease in the other FMPP kindreds. Agonist binding and functional coupling of the mutant receptors to the cAMP and inositol phosphate pathways were studied by transiently expressing them in COS-7 cells. Agonist affinity was unaffected by the mutations.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies for Molecular Imaging of Cancer (2008)

Antibodies have attained a central role as targeted therapeutics, with several significant drugs on the market and many more in clinical development for oncological applications. Expansion of the role of antibodies in cancer imaging has been accelerated by a number of factors, including the recognition that antibodies can provide a powerful class of molecular imaging probes for interrogating cell surfaces in vivo. Identification of relevant cell surface biomarkers as imaging targets, coupled with advances in antibody technology, facilitate the generation of antibodies optimized for noninvasive imaging. Developments in imaging instrumentation and radionuclide availability have paved the way for broader evaluation and implementation of radioimmunoscintigraphy and immunoPET. Antibody imaging can provide a sensitive, noninvasive means for molecular characterization of cell surface phenotype in vivo, which can in turn guide diagnosis, prognosis, therapy selection, and monitoring of treatment in cancer.
High-pressure Food Processing (2008)

High pressure processing (HPP) of foods offers a commercially viable and practical alternative to heat processing by allowing food processors to pasteurize foods at or near room temperature. Pressure in combination with moderate temperature also seems to be a promising approach for producing shelf-stable foods. This paper outlines research needs for further advancement of high pressure processing technology. Kinetic models are needed for describing bacterial inactivation under combined pressure-thermal conditions and for microbial process evaluation. Further, identification of suitable surrogate organisms are needed for use as indicator organisms and for process validation studies. More research is needed to evaluate process uniformity at elevated pressure-thermal conditions to facilitate successful introduction of low-acid shelf-stable foods. Combinations of non-thermal technologies with high pressure could reduce the severity of the process pressure requirement. Likewise, processing equipment requires improvements in reliability and line-speed to compete with heat pasteurization lines. More studies are also needed to document the changes in animal and vegetable tissue and nutrient content during pressure processing, from types of packaging, and from storage.
Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis (2010)

Canonical animal microRNAs (miRNAs) are generated by sequential cleavage of precursor substrates by the Drosha and Dicer RNase III enzymes. Several variant pathways exploit other RNA metabolic activities to generate functional miRNAs. However, all of these pathways culminate in Dicer cleavage, suggesting that this is a unifying feature of miRNA biogenesis. Here, we show that maturation of miR-451, a functional miRNA that is perfectly conserved among vertebrates, is independent of Dicer. Instead, structure-function and knockdown studies indicate that Drosha generates a short pre-mir-451 hairpin that is directly cleaved by Ago2 and followed by resection of its 3' terminus. We provide stringent evidence for this model by showing that Dicer knockout cells can generate mature miR-451 but not other miRNAs, whereas Ago2 knockout cells reconstituted with wild-type Ago2, but not Slicer-deficient Ago2, can process miR-451. Finally, we show that the mir-451 backbone is amenable to reprogramming, permitting vector-driven expression of diverse functional miRNAs in the absence of Dicer. Beyond the demonstration of an alternative strategy to direct gene silencing, these observations open the way for transgenic rescue of Dicer conditional knockouts.
Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo. (2015)

Vitiligo is a common, disfiguring autoimmune disease caused by the destruction of epidermal melanocytes. It presents with patchy depigmentation of skin, which significantly affects patients’ self-esteem and quality of life. The mainstay of vitiligo treatment is topical steroids, calcineurin inhibitors, and/or narrow band UVB (nbUVB) phototherapy ( 1 ). These treatments utilize a non-targeted approach with moderate efficacy, but are used off-label, as they are not Food and Drug Administration (FDA)-approved for use in vitiligo. Currently, the only FDA-approved treatment for the disease is monobenzone cream (Benoquin ® ), which is actually used to permanently depigment, rather than repigment, the skin. This treatment results in an even skin tone, and can be appropriate for patients with extensive disease ( 2 , 3 ). However, it is one of a limited number of treatments used in medicine to intentionally make disease worse, and treatments focused on reversing vitiligo, with better efficacy, are greatly needed.
Drug Testing in Oral Fluid—Evaluation of Sample Collection Devices (2008)

Nine different oral fluid (OF) collection devices were studied to evaluate their suitability for collecting samples for drug analysis. The devices were Greiner Bio-One, Orasure Intercept, Immunalysis Quantisal, StatSure Saliva.Sampler, Cozart, Sarstedt Salivette, Malvern Medical OraCol, Acro Biotech Salicule, and Varian OraTube. For comparison, OF was also collected into plastic tubes. The volume of collected OF was quantified for samples collected both in vitro and from volunteers. Drug recovery was studied by collecting OF fortified at 1000 ng/mL with amphetamine, 3,4-methylenedioxymethamphetamine, cocaine, Delta(9)-tetrahydrocannabinol, morphine, codeine, diazepam, and alprazolam with the devices in vitro and analyzing the samples with gas chromatography-mass spectrometry. Recovery of ethanol was measured from 0.2% in OF by headspace gas chromatography-flame-ionization detection. The stability of drugs in the samples was studied by analyzing the samples after 0, 14, and 28 days storage. The study shows that there are substantial differences between the OF collection devices on the market. Some are well suited for collecting samples for toxicological analysis, but some give quite poor results.
Mitochondrial Depolarization in Glutamate-Stimulated Neurons: An Early Signal Specific to Excitotoxin Exposure (1996)

A brief exposure to high concentrations of glutamate kills cultured forebrain neurons by an excitotoxic process that is dependent on Ca2+ influx through the NMDA receptor. In this study, we have measured striking changes in mitochondrial function during and immediately after intense glutamate receptor activation. Using indo-1 microfluorometry and a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger, CGP-37157, we have demonstrated that mitochondria accumulate large quantities of Ca2+ during a toxic glutamate stimulus and further that Ca2+ efflux from mitochondria contributes to the prolonged [Ca2+]i elevation after glutamate removal. We then used JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine+ ++ iodide), a ratiometric indicator of mitochondrial membrane potential (delta psi), to show that Ca2+ accumulation within the organelle dissipates delta psi. The abrupt loss of delta psi after glutamate stimulation did not occur in the presence of MK801 or in the absence of extracellular Ca2+. The mitochondrial depolarization was also cyclosporin A-sensitive, indicating a probable role for the permeability transition pore. Hence mitochondrial Ca2+ accumulation and the subsequent permeability transition may be a critical early event specific to the NMDA receptor-mediated excitotoxic cascade.
Free-space quantum key distribution to a moving receiver (2015)

Technological realities limit terrestrial quantum key distribution (QKD) to single-link distances of a few hundred kilometers. One promising avenue for global-scale quantum communication networks is to use low-Earth-orbit satellites. Here we report the first demonstration of QKD from a stationary transmitter to a receiver platform traveling at an angular speed equivalent to a 600 km altitude satellite, located on a moving truck. We overcome the challenges of actively correcting beam pointing, photon polarization and time-of-flight. Our system generates an asymptotic secure key at 40 bits/s.
Micrometastases and Transplantation (1996)

The recent ISHAGE symposium on Minimal Residual Cancer contained a session on micrometastases and transplantation. This is an area of considerable interest and controversy. This review addresses these issues in the context of the meeting and in relation to the general difficulties encountered in this area of investigation.
A Region Rich in Aspartic Acid, Arginine, Tyrosine, and Glycine (DRYG) Mediates Eukaryotic Initiation Factor 4B (eIF4B) Self-Association and Interaction with eIF3 (1996)

The binding of mRNA to the ribosome is mediated by eukaryotic initiation factors eukaryotic initiation factor 4F (eIF4F), eIF4B, eIF4A, and eIF3, eIF4F binds to the mRNA cap structure and, in combination with eIF4B, is believed to unwind the secondary structure in the 5' untranslated region to facilitate ribosome binding. eIF3 associates with the 40S ribosomal subunit prior to mRNA binding. eIF4B copurifies with eIF3 and eIF4F through several purification steps, suggesting the involvement of a multisubunit complex during translation initiation. To understand the mechanism by which eIF4B promotes 40S ribosome binding to the mRNA, we studied its interactions with partner proteins by using a filter overlay (protein-protein [far Western]) assay and the two-hybrid system. In this report, we show that eIF4B self-associates and also interacts directly with the p170 subunit of eIF3. A region rich in aspartic acid, arginine, tyrosine, and glycine, termed the DRYG domain, is sufficient for self-association of eIF4B, both in vitro and in vivo, and for interaction with the p170 subunit of eIF3. These experiments suggest that eIF4B participates in mRNA-ribosome binding by acting as an intermediary between the mRNA and eIF3, via a direct interaction with the p170 subunit of eIF3.
Phase separation of signaling molecules promotes T cell receptor signal transduction (2016)

Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.