gebhart/patrepeval huggingface dataset:
In vivo selection of engineered homing endonucleases using double-strand break induced homologous recombination (2005)

Homing endonucleases, endonucleases capable of recognizing long DNA sequences, have been shown to be a tool of choice for precise and efficient genome engineering. Consequently, the possibility to engineer novel endonucleases with tailored specificities is under strong investigation. In this report, we present a simple and efficient method to select meganucleases from libraries of variants, based on their cleavage properties. The method has the advantage of directly selecting for the ability to induce double-strand break induced homologous recombination in a eukaryotic environment. Model selections demonstrated high levels of enrichments. Moreover, this method compared favorably with phage display for enrichment of active mutants from a mutant library. This approach makes possible the exploration of large sequence spaces and thereby represents a valuable tool for genome engineering.
Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease (2012)

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. (1996)

Tumor angiogenesis involves a combination of events including the production of inhibitors, proteases, and angiogenic factors that have a chemotactic and mitogenic effect on endothelial cells. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that promotes angiogenesis in solid tumors, including brain tumors such as astrocytomas. As an approach to the development of new strategies for gene therapy of brain tumors, we have interrupted the VEGF/VEGF receptor paracrine pathway in an attempt to inhibit angiogenesis and thereby control tumor growth. Rat C6 glioma cells were transfected with a eukaryotic expression vector bearing an antisense-VEGF cDNA. Stable transfectants were observed to express reduced levels of VEGF in culture under hypoxic conditions. When implanted s.c. into nude (nu/nu) mice, growth of the antisense-VEGF cell lines was observed to be greatly inhibited compared to control cells, despite the fact that they have a faster division time in vitro. Analysis of these tumors revealed that they have fewer blood vessels and a higher degree of necrosis, which is a plausible explanation for the reduced tumor size. We believe antisense-VEGF can be successfully used to control tumor growth and may provide the basis for the development of antiangiogenic gene therapy.
Efflux-Mediated Antifungal Drug Resistance (2009)

Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.
Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter Syndrome) (2013)

This study indicates that idursulfase beta generates clinically significant reduction of urinary GAG, improvements in endurance as measured by 6MWT, and it has an acceptable safety profile for the treatment of MPS II.
Mechanical behavior of the human lumbar spine. I. Creep analysis during static compressive loading (1987)

The in vitro viscoelastic "creep" behavior was examined in 18 cadaveric human lumbar motion segments subjected to static axial compressive loads. Axial deformation was followed for 30 min under constant applied load. Compressive material constants (moduli and viscosity coefficients) were then determined for each intervertebral disc using a linearization method based on a Taylor series expansion of experimental data for the "three parameter" viscoelastic creep model. The degree of disc degeneration and bone mineral content (BMC) were also assessed. Good correlation between the experimentally determined and model predicted strain values were found, with the average error less than 1%. We found that motion segments from older and more degenerated lumbar discs were less stable and had lower material constants than segments from younger and less degenerated discs. Material constants and BMC correlated closely, suggesting that an interdependency of disc and vertebral body properties exists. No correlation between the creep characteristics and disc height, disc area, segment level, or sex were noted.
Junction temperature in light-emitting diodes assessed by different methods (2005)

The junction temperature of red (AlGaInP), green (GaInN), blue (GaInN), and ultraviolet (GaInN) light-emitting diodes (LEDs) is measured using the temperature coefficients of the diode forward voltage and of the emission-peak energy. The junction temperature increases linearly with DC current as the current is increased from 10 mA to 100 mA. For comparison, the emission-peak-shift method is also used to measure the junction temperature. The emission-peak-shift method is in good agreement with the forward-voltage method. The carrier temperature is measured by the high-energy-slope method, which is found to be much higher than the lattice temperature at the junction. Analysis of the experimental methods reveals that the forward-voltage method is the most sensitive and its accuracy is estimated to be &plusmn; 3°C. The peak position of the spectra is influenced by alloy broadening, polarization, and quantum confined Stark effect thereby limiting the accuracy of the emission-peak-shift method to &plusmn;15°C. A detailed analysis of the temperature dependence of a tri-chromatic white LED source (consisting of three types of LEDs) is performed. The analysis reveals that the chromaticity point shifts towards the blue, the color-rendering index (CRI) decreases, the color temperature increases, and the luminous efficacy decreases as the junction temperature increases. A high CRI > 80 can be maintained, by adjusting the LED power so that the chromaticity point is conserved.
Neutrophil elastase up‐regulates interleukin‐8 via toll‐like receptor 4 (2003)

Cystic fibrosis is characterised in the lungs by high levels of neutrophil elastase (NE). NE induces interleukin-8 (IL-8) expression via an IL-1 receptor-associated kinase signalling pathway. Here, we show that these events involve the cell surface membrane bound toll-like receptor 4 (TLR4). We demonstrate that human embryonic kidney (HEK)293 cells transfected with a TLR4 cDNA (HEK-TLR4) express TLR4 mRNA and protein and induce IL-8 promoter activity in response to NE. Treatment of both HEK-TLR4 and human bronchial epithelial cells with NE decreases TLR4 protein expression. Furthermore, a TLR4 neutralising antibody abrogates NE-induced IL-8 production, and induces tolerance to a secondary lipopolysaccharide stimulus. These data implicate TLR4 in NE induced IL-8 expression in bronchial epithelium.
Dapper Homolog 1 Is a Novel Tumor Suppressor in Gastric Cancer through Inhibiting the Nuclear Factor-κB Signaling Pathway (2012)

Dapper homolog 1 (DACT1) is a disheveled partner in the planar cell polarity pathway. By using genome-wide promoter methylation screening, dapper homolog 1 (DACT1) was found to be frequently methylated in gastric cancer. We aim to clarify its epigenetic inactivation, biological function and clinical implication in gastric cancer. We demonstrated that DACT1 was silenced in 7 of 10 gastric cancer cell lines and in primary gastric cancers. Transcriptional gene silence of DACT1 was mainly regulated by promoter hypermethylation. Ectopic expression of DACT1 in silenced gastric cancer cell lines (AGS, BGC823 and MGC803) by stable transfection suppressed colony formation (P < 0.001), induced cell apoptosis (P < 0.01) and retarded tumorigenesis in nude mice (P < 0.001). The tumor suppressive effect of DACT1 was further confirmed by loss of DACT1 function experiment. The proapoptotic and antiproliferative effect by DACT1 was associated with inhibition of nuclear factor (NF)-κB activation and its downstream factors, including B-cell CLL/lymphoma-2, Bcl-X, interleukin-8 and tumor necrosis factor-α. Moreover, promoter methylation of DACT1 was detected in 29.3% (60/205) of primary gastric tumors. DACT1 methylation was significantly associated with tumor metastasis (P < 0.05), invasion (P < 0.05) and advanced tumor stage (P < 0.0005). These findings provided insight into the role of DACT1 as a novel functional tumor suppressor in gastric cancer through inhibiting NF-κB signaling pathway. Promoter methylation of DACT1 is associated with tumor aggressiveness.
Hydrophobic residues within the predicted N‐terminal amphiphilic α‐helix of a plant mitochondrial targeting presequence play a major role in in vivo import (2001)

A deletion and mutagenesis study was performed on the mitochondrial presequence of the beta-subunit of the F(1)-ATP synthase from Nicotiana plumbaginifolia linked to the green fluorescent protein (GFP). The various constructs were tested in vivo by transient expression in tobacco protoplasts. GFP distribution in transformed cells was analysed in situ by confocal microscopy, and in vitro in subcellular fractions by Western blotting. Despite its being highly conserved in different species, deletion of the C-terminal region (residues 48-54) of the presequence did not affect mitochondrial import. Deletion of the conserved residues 40-47 and the less conserved intermediate region (residues 18-39) resulted in 60% reduction in GFP import, whereas mutation of conserved residues within these regions had little effect. Further shortening of the presequence progressively reduced import, with the construct retaining the predicted N-terminal amphiphilic alpha-helix (residues 1-12) being unable to mediate mitochondrial import. However, point mutation showed that this last region plays an important role through its basic residues and amphiphilicity, but also through its hydrophobic residues. Replacing Arg4 and Arg5 by alanine residues and shifting the Arg5 and Leu6 (in order to disturb amphiphilicity) resulted in reduction of the presequence import efficiency. The most dramatic effects were seen with single or double mutations of the four Leu residues (positions 5, 6, 10 and 11), which resulted in marked reduction or abolition of GFP import, respectively. We conclude that the N-terminal helical structure of the presequence is necessary but not sufficient for efficient mitochondrial import, and that its hydrophobic residues play an essential role in in vivo mitochondrial targeting.
Bypass of Tumor Drug Resistance by Antivascular Therapy (2003)

Multidrug resistance (MDR) presents a major obstacle for the successful chemotherapy of cancer. Its emergence during chemotherapy is attributed to a selective process, which gives a growth advantage to MDR cells within the genetically unstable neoplastic cell population. The pleiotropic nature of clinical MDR poses a great difficulty for the development of treatment strategies that aim at blocking MDR at the tumor cell level. Targeting treatment to the nonmalignant vascular network-the lifeline of the tumor-is a promising alternative for the treatment of drug-resistant tumors. The present study demonstrates that MDR in cancer can be successfully circumvented by photodynamic therapy (PDT) using an antivascular treatment protocol. We show that, although P-glycoprotein-expressing human HT29/MDR colon carcinoma cells in culture are resistant to PDT with Pd-bacteriopheophorbide (TOOKAD), the same treatment induces tumor necrosis with equal efficacy (88% vs 82%) in HT29/MDR-derived xenografts and their wild type counterparts, respectively. These results are ascribed to the rapid antivascular effects of the treatment, supporting the hypothesis that MDR tumors can be successfully eradicated by indirect approaches that bypass their inherent drug resistance. We suggest that with progress in ongoing clinical trials, TOOKAD-PDT may offer a novel option for local treatment of MDR tumors.
Nonenzymatic glycosylation of human serum albumin alters its conformation and function. (1984)

Approximately 10% of the albumin in normal human serum is modified by nonenzymatic glycosylation, primarily at the epsilon-amino group of lysine residue 525. Incubation of albumin with glucose under physiological conditions in vitro resulted in glycosylation of the same residue. After separation of glycosylated human serum albumin from the nonglycosylated form by boronate affinity chromatography, the fluorescence emission characteristics of the sole tryptophan residue (Trp 214) were monitored. The quantum yield of tryptophan fluorescence for both in vivo and in vitro glycosylated albumin was reduced 30% relative to nonglycosylated albumin, and the maximal wavelength of the fluorescence emission band was shifted to shorter wavelengths. These observations show that nonenzymatic glycosylation induces a conformational change in human serum albumin. Ligand binding properties of glycosylated and unmodified albumin were compared. Hemin affinity was unaltered by glycosylation of albumin in vivo, whereas the affinity of bilirubin for glycosylated albumin was about 50% its value for the nonglycosylated form. The affinity of the long chain fatty acid cis-parinaric acid for albumin glycosylated in vivo and in vitro was reduced approximately 20-fold relative to nonglycosylated albumin. These differences in affinity suggest that lysine 525 plays a key role in the binding of physiologically important ligands to albumin.
In situ characterization of block copolymer ordering on chemically nanopatterned surfaces by time-resolved small angle x-ray scattering (2008)

The assembly of lamella-forming block copolymer blend thin films on chemically nanopatterned striped surfaces was monitored in real time with small angle x-ray scattering (SAXS) in transmission mode. The strongest diffraction from the assembled grating structure was detected after 4.5min of annealing as the temperature was ramped from 100to240°C at a rate of about 20°C∕min. Real-space images were also obtained from samples annealed for specific times using top-down scanning electron microscopy (SEM) and this identified structures formed during annealing that are unique to the block copolymer blends. The data are compared to previously reported SEM and molecular simulation studies with pure block copolymers. Because it can be used in real time and probes the entire film thickness, transmission SAXS proved to be a useful tool for better understanding the block copolymer annealing process.
Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides (2015)

Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.
Recombinant erythropoietin improves cognitive function in patients maintained on chronic ambulatory peritoneal dialysis (1995)

Psychometric performance was studied in 17 patients maintained on CAPD. Nine patients treated with rHuEpo performed a battery of psychometric tests before treatment (haemoglobin mean (SD) 6.8 (0.8) g/dl) and after partial correction of anaemia (haemoglobin 9.0 (1.0) g/dl). The same battery of psychometric tests was administered to eight patients (haemoglobin 7.7 (0.7) g/dl), matched with the treatment group for age, duration of dialysis and social class, who did not receive rHuEpo. The National Adult Reading Test was used in all patients to estimate the premorbid IQ (the peak cognitive level attained before any cognitive deterioration). In the rHuEpo-treated group current IQ, measured by a short form of the Wechsler Adult Intelligence Scale--Revised, improved by a mean of 7.2 points (P < 0.01) and approached estimated premorbid levels, while in the control group an improvement by 0.3 points was not significant. Concentration and speed of information processing were assessed by the Paced Auditory Serial Addition Task and also improved in the treatment group (P < 0.05). Memory, assessed by the Rey Auditory Verbal Learning Test, tended to improve in the treatment group with amelioration of anaemia, although only the improvement in delayed recall was significant. No overall change was seen in either group in the time taken to complete the Trail Making Test (part A). These results are consistent with our earlier findings in haemodialysis patients, indicating that anaemia makes a reversible contribution to uraemic cognitive dysfunction.
Expression of human α1‐antitrypsin using a recombinant adenovirus vector (1990)

In order to improve the in vivo delivery of human proteins destined for replacement therapy, a recombinant adenovirus containing the cDNA sequence encoding human α 1 ‐antitrypsin has been constructed and shown to direct expression of the protein in the supernatant of human cell lines.
Efficient Linear Re-rendering for Interactive Lighting Design (1997)

We present a framework for interactive lighting design based on linear re-rendering. The rendering operation is linear with respect to light sources, assuming a fixed scene and camera geometry. This linearity means that a scene may be interactively rerendered via linear combination of a set of basis images, each rendered under a particular basis light. We focus on choosing and designing a suitable set of basis lights. We provide examples of bases that allow 1) interactive adjustment of a spotlight direction, 2) interactive adjustment of the position of an area light, and 3) a combination in which light sources are adjusted in both position and direction. We discuss a method for reducing the size of the basis using principal components analysis in the image domain.