gebhart/patrepeval huggingface dataset:
Fast formation of high‐purity methyl esters from vegetable oils (1998)

Abstract Experiments have confirmed that the base‐catalyzed methanolysis of vegetable oils occurs much slower than butanolysis because of the two liquid phases initially present in the former reaction. For the same reason, second‐order kinetics are not followed. The use of a cosolvent such as tetrahydrofuran or methyl tertiary butyl ether speeds up methanolysis considerably. However, like one‐phase butanolysis, one‐phase methanolysis initially exhibits a rapid formation of ester, but then slows drastically. Experiments show that the half‐life of the hydroxide catalyst is too long to explain the sudden slowing of the reaction. Similarly, lower rate constants for the methylation of the mono‐ and diglycerides are not a reasonable explanation. Instead the cause has been identified as the fall in polarity which results from the mixing of the nonpolar oil with the methanol. This lowers the effectiveness of both hydroxide and alkoxide catalysts. Increasing the methanol/oil molar ratio to 27 in the one‐phase system raises the polarity such that the methyl ester content of the ester product exceeds 99.4 wt% in 7 min. This has obvious implications for the size of new methyl ester plants as well as the capacity of existing facilities.
Preclinical Pharmacokinetics and Tissue Distribution of Long-Acting Nanoformulated Antiretroviral Therapy (2013)

Long-acting injectable nanoformulated antiretroviral therapy (nanoART) was developed with the explicit goal of improving medicine compliance and for drug targeting of viral tissue reservoirs. Prior nanoART studies completed in humanized virus-infected mice demonstrated sustained antiretroviral responses. However, the pharmacokinetics (PK) and tissue distribution of nanoART were not characterized. To this end, the PK and tissue distribution of nanoformulated atazanavir (ATV) and ritonavir (RTV) injected subcutaneously or intramuscularly in mice and monkeys were evaluated. Fourteen days after injection, ATV and RTV levels were up to 13-, 41-, and 4,500-fold higher than those resulting from native-drug administration in plasma, tissues, and at the site of injection, respectively. At nanoART doses of 10, 50, 100, and 250 mg/kg of body weight, relationships of more- and less-than-proportional increases in plasma and tissue levels with dose increases were demonstrated with ATV and RTV. Multiple-dose regimens showed serum and tissue concentrations up to 270-fold higher than native-drug concentrations throughout 8 weeks of study. Importantly, nanoART was localized in nonlysosomal compartments in tissue macrophages, creating intracellular depot sites. Reflective data were obtained in representative rhesus macaque studies. We conclude that nanoART demonstrates blood and tissue antiretroviral drug levels that are enhanced compared to those of native drugs. The sustained and enhanced PK profile of nanoART is, at least in part, the result of the sustained release of ATV and RTV from tissue macrophases and at the site of injection.
A 2-mm$^{2}$ 0.1–5 GHz Software-Defined Radio Receiver in 45-nm Digital CMOS (2009)

A software-defined radio (SDR) should theoretically receive any modulated frequency channel in the (un)licensed spectrum, and guarantee top performance with energy savings, while still being integrated in a digital CMOS technology. This paper demonstrates a practical 0.1-5 GHz front-end implementation for such an SDR concept, including receiver and local oscillator (LO), with only 2-mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> core area occupation in a 45-nm CMOS process. This scalable radio uses shunt-shunt feedback LNAs, a passive mixer with enhanced out-of-band IIP3, and a fifth order low-area 0.5-20 MHz baseband filter. LO quadrature signals are generated from a dual-VCO 4-10 GHz fractional-N PLL. With noise figure between 2.3 dB and 6.5 dB, out-of-band IIP3 between -3 dBm and -10 dBm, and total power consumption between 59 and 115 mW from a 1.1-V supply voltage, the presented prototype favorably compares with state-of-the-art dedicated radios while enabling, for the first time, wideband reconfigurable performance and energy scalability.
Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. (1996)

The gene for the bacterial enzyme carboxypeptidase G2 (CPG2) was expressed internally in mammalian cells. Mammalian-expressed CPG2 had kinetic properties indistinguishable from bacterially expressed CPG2. Human tumor cell lines A2780, SK-OV-3 (ovarian adenocarcinomas), LS174T, and WiDr (colon carcinomas) were engineered to express constitutively either CPG2 or bacterial beta-galactosidase. These cell lines were subjected to a gene-directed enzyme prodrug therapy regime, using the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-L-glutamic acid (CMDA). The lines which expressed CPG2 had enhanced sensitivity to CMDA. Comparing IC50S, WiDr-CPG2 and SK-OV-3-CPG2 were 11-16-fold more sensitive, whereas A2780-CPG2 and LS174T-CPG2 were approximately 95-fold more sensitive than the corresponding control lines. CPG2-expressing cells and control cells were mixed in differing proportions and then treated with prodrug. Total kill occurred when only approximately 12% of cells expressed CPG2 with the WiDr and SK-OV-3 lines and when only 4-5% of cells expressed CPG2 with the LS174T and A2780 lines, indicating a substantial bystander effect. These results establish this CPG2 enzyme/CMDA prodrug system as an effective combination for the gene-directed enzyme prodrug therapy approach.
Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds (2012)

SMAD4 is an essential mediator of canonical TGFβ/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme. While this Smad4 inactivation did not alter the early Sox9 distribution, prefiguring the chondrogenic primordia of the stylopod and zeugopod, it disrupted formation of all Sox9-positive digit ray primordia. Specific inactivation of Smad4 during handplate development pointed to its differential requirement for posterior and anterior digit ray primordia. At the cellular level, Smad4 deficiency blocked the aggregation of Sox9-positive progenitors, thereby preventing chondrogenic differentiation as revealed by absence of collagen type II. The progressive loss of SOX9 due to disrupting digit ray primordia and chondrogenesis was paralleled by alterations in genes marking other lineages. This pointed to a general loss of tissue organization and diversion of mutant cells toward non-specific connective tissue. Conditional inactivation of Bmp2 and Bmp4 indicated that the loss of digit ray primordia and increase in connective tissue were predominantly a consequence of disrupting SMAD4-mediated BMP signal transduction. In summary, our analysis reveals that SMAD4 is required to initiate: (1) formation of the Sox9-positive digit ray primordia; and (2) aggregation and chondrogenic differentiation of all limb skeletal elements.
Increased Production of Specific Antibodies by Presentation of the Antigen Determinants with Covalently Coupled Lipopetide Mitogens (1985)

A new concept for the production of antibodies consists in preparing a conjugate from the “lipid membrane anchor” N ‐palmitoyl‐ S [2,3‐bis(palmitoyl‐oxy) propyl]cysteiny1 serine and the antigen—for example, a tetradecapeptide. These conjugates are potent immunogens, which, within a few days, induce the production of high titers of antigen‐specific antibodies (IgG and IgM), both in vivo and in vitro, with only one application and without either carrier proteins or Freund 's adjuvant. It has already been possible to produce monoclonal antibodies with these new low‐molecular‐weight, chemically defined conjugates, which are obtainable via Merrifield synthesis.
Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles – opportunities & challenges (2010)

One of the big challenges of medicine today is to deliver drugs specifically to defected cells. Nanoparticulate drug carriers have the potential to answer to this call, as nanoparticles can cross physiological barriers and access different tissues, and also be provided in a targetable form aimed at enhancing cell specificity of the carrier. Recent developments within material science and strong collaborative efforts crossing disciplinary borders have highlighted the potential of mesoporous silica nanoparticles (MSNs) for such targeted drug delivery. Here we outline recent advances which in this sense push MSNs to the forefront of drug delivery development. Relatively straightforward inside-out tuning of the vehicles, high flexibility, and potential for sophisticated release mechanisms make these nanostructures promising candidates for targeted drug delivery such as 'smart' cancer therapies. Moreover, due to the large surface area and the controllable surface functionality of MSNs, they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting, simultaneously carrying traceable (fluorescent or magnetically active) modalities, also making them highly interesting as theragnostic agents. However, the increased relative surface area and small size, and flexible surface functionalization which is beneficially exploited in nanomedicine, consequently also includes potential risks in their interactions with biological systems. Therefore, we also discuss some safety issues regarding MSNs and highlight how different features of the drug delivery platform influence their behaviour in a biological setting. Addressing these burning questions will facilitate the application of MSNs in nanomedicine.
Acute effects of angiotensin II on fibrinolysis in healthy volunteers (1999)

Recent studies have suggested that angiotensin II may inhibit fibrinolysis. In order to further test this hypothesis, we investigated the acute effects of angiotensin II (intravenous infusion of 10 ng/kg per min over 15-20 min) on fibrinolytic function in 18 healthy men. Time-controls (n=11) and control experiments with a placebo infusion (n = 13) were also performed. The activities of plasmin activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA), as well as t-PA antigen levels, were determined in plasma before, during and 60 min after the infusion of angiotensin II. Angiotensin II caused a clear-cut elevation in blood pressure; heart rate and plasma noradrenaline levels tended to decrease during the infusion but increased afterwards, indicating reflexogenic adjustments. Plasma t-PA activity and antigen levels increased by 81+/-11 and 14+/-3%, respectively, during angiotensin II infusion (both P < 0.001), whereas t-PA activity was unchanged and t-PA antigen decreased (P < 0.05) in placebo experiments. PAI-1 activity decreased similarly in time-controls and during angiotensin infusion (P < 0.001). Thus, short-term infusion of angiotensin II enhances fibrinolysis by elevating plasma t-PA. It is not clear whether this is a direct angiotensin-receptor-mediated effect or if it is related to the hemodynamic effects of the infusion.
Generation of α‐1,3‐Galactosyltransferase‐Deficient Porcine Embryonic Fibroblasts by CRISPR/Cas9‐Mediated Knock‐in of a Small Mutated Sequence and a Targeted Toxin‐Based Selection System (2015)

The CRISPR/Cas9 system has enabled the editing of mammalian genomes; however, its applicability and efficiency in the pig genome has not been studied in depth. The α-gal epitope synthesized by α-1,3-galactosyltransferase gene (GGTA1) is known as a xenoantigen obtained upon pig-to-human xenotransplantation. We here employed the CRISPR/Cas9 system-mediated knock-in of endogenous GGTA1 via targeted homologous recombination (HR). Linearized donors with ~800-bp homology flanking the CRISPR/Cas9 target site [exon 4 (containing ATG) of GGTA1] served as a template for gene targeting by HR. Using a targeted toxin strategy to select clones lacking α-gal epitope expression, we successfully obtained several knock-in clones within 3 weeks of initial transfection. These results suggest that the use of CRISPR/Cas9-mediated HR to knock-in a mutated fragment at defined loci represents an efficient strategy to achieve the rapid modulation of genes of interest in swine cells and is a promising tool for the creation of KO piglets.
Functional Blockade of Tyrosine Kinase A in the Rat Basal Forebrain by a Novel Antagonistic Anti-Receptor Monoclonal Antibody (1999)

We have exploited a new monoclonal antibody against the tyrosine kinase A (TrkA) nerve growth factor (NGF) receptor to block the NGF-TrkA interaction in the rat basal forebrain. The monoclonal antibody MNAC13 is a potent antagonist that prevents the binding of NGF to TrkA in a variety of systems. This antibody was used to study the maintenance of the cholinergic phenotype in the rat basal forebrain in vivo, by the implant of antibody-secreting cells. Basal forebrain cholinergic neurons (BFCNs) are greatly affected by the antibody treatment, both in terms of cell number and of cell soma size. When antibody-secreting cells are implanted at postnatal day 2 (P2), the effects observed at P8 are as severe as those obtained with anti-NGF antibodies and, interestingly, are observed also if anti-TrkA cells are implanted at P8, when anti-NGF antibodies, delivered by the same route, are no longer effective (). The effects induced by anti-TrkA, as those induced by anti-NGF, are reversible, but the time required for recovery and the critical period in the sensitivity of BFCNs to the functional inactivation of TrkA is twice as long than that observed when NGF is intercepted. These results demonstrate that BFCNs are more sensitive to the block of TrkA activation than they are to the block of NGF. The cloning of MNAC13 variable regions and their assembly into a functional polypeptide of reduced size (single chain Fv fragment) will allow its use in gene transfer applications.
Automated Single‐Kernel Sorting to Select for Quality Traits in Wheat Breeding Lines (2009)

ABSTRACT An automated single kernel near‐infrared system was used to select kernels to enhance the end‐use quality of hard red wheat breeder samples. Twenty breeding populations and advanced lines were sorted for hardness index, protein content, and kernel color. To determine whether the phenotypic sorting was based upon genetic or environmental differences, the progeny of the unsorted control and sorted samples were planted at two locations two years later to determine whether differences in the sorted samples were transmitted to the progeny (e.g., based on genetic differences). The average hardness index of the harvested wheat samples for segregating populations improved significantly by seven hardness units. For the advanced lines, hardness index was not affected by sorting, indicating little genetic variation within these lines. When sorting by protein content, a significant increase from 12.1 to 12.6% was observed at one location. Purity of the red samples was improved from ≈78% (unsorted control) to ≈92% (sorted samples), while the purity of the white samples improved from 22% (control) to ≈62% (sorted samples). Similar positive results were found for sorting red and blue kernel samples. Sorting for kernel hardness, color, and protein content is effective and based upon genetic variation.
Anti‐IL‐6 neutralizing antibody modulates blood‐brain barrier function in the ovine fetus (2015)

Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.
Analysis of Sequence Upstream of the Endogenous H19 Gene Reveals Elements Both Essential and Dispensable for Imprinting (2002)

Imprinting of the linked and oppositely expressed mouse H19 and Igf2 genes requires a 2-kb differentially methylated domain (DMD) that is located 2 kb upstream of H19. This element is postulated to function as a methylation-sensitive insulator. Here we test whether an additional sequence 5' of H19 is required for H19 and Igf2 imprinting. Because repetitive elements have been suggested to be important for genomic imprinting, the requirement of a G-rich repetitive element that is located immediately 3' to the DMD was first tested in two targeted deletions: a 2.9-kb deletion (Delta D MD Delta G) that removes the DMD and G-rich repeat and a 1.3-kb deletion (Delta G) removing only the latter. There are also four 21-bp GC-rich repetitive elements within the DMD that bind the insulator-associated CTCF (CCCTC-binding factor) protein and are implicated in mediating methylation-sensitive insulator activity. As three of the four repeats of the 2-kb DMD were deleted in the initial 1.6-kb Delta DMD allele, we analyzed a 3.8-kb targeted allele (Delta 3.8kb-5'H19), which deletes the entire DMD, to test the function of the fourth repeat. Comparative analysis of the 5' deletion alleles reveals that (i) the G-rich repeat element is dispensable for imprinting, (ii) the Delta DMD and Delta DMD Delta G alleles exhibit slightly more methylation upon paternal transmission, (iii) removal of the 5' CTCF site does not further perturb H19 and Igf2 imprinting, suggesting that one CTCF-binding site is insufficient to generate insulator activity in vivo, (iv) the DMD sequence is required for full activation of H19 and Igf2, and (v) deletion of the DMD disrupts H19 and Igf2 expression in a tissue-specific manner.
Development of an Oligonucleotide-Based SNP Detection Method on Lateral Flow Strips Using Hexapet Tags (2005)

Detection of point mutations or single nucleotide polymorphisms (SNPs) is important in relation to disease susceptibility or detection in pathogens of mutations determining drug resistance or host range. There is an emergent need for rapid detection methods amenable to point-of-care applications. The purpose of this study was to reduce to practice a novel method for SNP detection and to demonstrate that this technology can be used downstream of nucleic acid amplification. The authors used a model system to develop an oligonucleotide-based SNP detection system on nitrocellulose lateral flow strips. To optimize the assay they used cloned sequences of the herpes simplex virus-1 (HSV-1) DNA polymerase gene into which they introduced a point mutation. The assay system uses chimeric polymerase chain reaction (PCR) primers that incorporate hexameric repeat tags (“hexapet tags”). The chimeric sequences allow capture of amplified products to predefined positions on a lateral flow strip. These “hexapet” sequences have minimal cross-reactivity and allow specific hybridization-based capture of the PCR products at room temperature onto lateral flow strips that have been striped with complementary hexapet tags. The allele-specific amplification was carried out with both mutant and wild-type primer sets present in the PCR mix (“competitive” format). The resulting PCR products carried a hexapet tag that corresponded with either a wild-type or mutant sequence. The lateral flow strips are dropped into the PCR reaction tube, and mutant sequence and wild-type sequences diffuse along the strip and are captured at the corresponding position on the strip. A red line indicative of a positive reaction is visible after 1 minute. Unlike other systems that require separate reactions and strips for each target sequence, this system allows multiplex PCR reactions and multiplex detection on a single strip or other suitable substrates. Unambiguous visual discrimination of a point mutation under room temperature hybridization conditions was achieved with this model system in 10 minutes after PCR. The authors have developed a capture-based hybridization method for the detection and discrimination of HSV-1 DNA polymerase genes that contain a single nucleotide change. It has been demonstrated that the hexapet oligonucleotides can be adapted for hybridization on the lateral flow strip platform for discrimination of SNPs. This is the first step in demonstrating SNP detection on lateral flow using the hexapet oligonucleotide capture system. It is anticipated that this novel system can be widely used in point-of-care settings.
Image completion using planar structure guidance (2014)

We propose a method for automatically guiding patch-based image completion using mid-level structural cues. Our method first estimates planar projection parameters, softly segments the known region into planes, and discovers translational regularity within these planes. This information is then converted into soft constraints for the low-level completion algorithm by defining prior probabilities for patch offsets and transformations. Our method handles multiple planes, and in the absence of any detected planes falls back to a baseline fronto-parallel image completion algorithm. We validate our technique through extensive comparisons with state-of-the-art algorithms on a variety of scenes.
Effect of human parathyroid hormone (PTH(1-34)) on experimental osteopenia of rats induced by ovariectomy. (1988)

The effect of human PTH(1-34) on the development of osteopenia induced by ovariectomy was investigated in immature female Sprague-Dawley rats. After the surgery, human PTH(1-34) was injected subcutaneously three times a week for 25 weeks. A reduction of serum calcium level and a tendency to increased serum alkaline phosphatase activity were seen in ovariectomized rats. The ovariectomized rat bones were characterized by reduction of dry weight, ash weight, calcium content and phosphorus content, but there was no change in length, volume and ash content in these bones. Human PTH(1-34) prevented the reduction of dry weight, ash weight, calcium content and phosphorus content dose dependently (1.5-6.0 micrograms/kg) in ovariectomized rats. It was concluded that pulsatile administration of human PTH(1-34) prevented the development of osteopenia induced by ovariectomy.