gebhart/patrepeval huggingface dataset:
MicroRNA-21 and MicroRNA-148a Contribute to DNA Hypomethylation in Lupus CD4+ T Cells by Directly and Indirectly Targeting DNA Methyltransferase 1 (2010)

Systemic lupus erythematosus is a complex autoimmune disease caused by genetic and epigenetic alterations. DNA methylation abnormalities play an important role in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. Whereas previous studies have shown miRNAs can regulate DNA methylation by targeting the DNA methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA hypomethylation of lupus is unclear. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, via promoter demethylation. Further experiments revealed that miR-21 indirectly downregulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1, which mediated the Ras-MAPK pathway upstream of DNMT1; miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in CD4+ T cells from patients with lupus could increase DNMT1 expression and attenuate DNA hypomethylation. Together, our data demonstrated a critical functional link between miRNAs and the aberrant DNA hypomethylation in lupus CD4+ T cells and could help to develop new therapeutic approaches.
Case of a mentally retarded child with non‐24 hour sleep–wake syndrome caused by deficiency of melatonin secretion (2000)

A case of a 5-year-old boy with non-24 hour sleep-wake syndrome and mental retardation is reported. His free-running sleep-wake rhythm was remarkably improved by the oral administration of melatonin. The circadian variation in melatonin secretion was extremely low, and circadian rhythm of cortisol secretion was noted. It was speculated that his non-24 hour sleep-wake syndrome was due to a congenital deficiency of melatonin secretion, and supplemental melatonin therapy proved effective for treating his condition.
Power estimation for cycle-accurate functional descriptions of hardware (2005)

Cycle-accurate functional descriptions (CAFD) are being widely adopted in integrated circuit (IC) design flows. Power estimation can potentially benefit from the inherent increase in simulation efficiency of cycle-based functional simulation. Currently, most approaches to hardware power estimation operate at the register-transfer level (RTL), or lower levels of design abstraction. Attempts at power estimation for functional descriptions have suffered from poor accuracy because the design decisions performed during their synthesis lead to an unavoidable, large uncertainty in any power estimate that is based solely on the functional description. We propose a methodology for CAFD power estimation that combines the accuracy achieved by power estimation at the structural RTL with the efficiency of cycle-accurate functional simulation. We achieve this goal by viewing a CAFD as an abstraction of a specific, known RTL implementation that is synthesized from it. We identify correlations between a CAFD and its RTL implementation, and "back-annotate" information into the CAFD solely for the purpose of power estimation. The resulting RTL-aware CAFD contains a layer of code that instantiates virtual placeholders for RTL components, and maps values of CAFD variables into the RTL components' inputs/outputs, thus enabling efficient and accurate power estimation. Power estimation is performed in our methodology by simply co-simulating the RTL-aware CAFD with a simulatable power model library that contains power macro-models for each RTL component. We present techniques to further improve the speed of CAFD power estimation, through the use of control state-based adaptive power sampling. We have implemented and evaluated the proposed techniques in the context of a commercial C-based hardware design flow. Experiments with a number of large industrial designs (up to 1 million gates) demonstrate that the proposed methodology achieves accuracy very close to RTL power estimation with two-to-three orders of magnitude speedup in estimation times.
Gene therapy for alpha-1 antitrypsin deficiency (2011)

Alpha-1 antitrypsin (AAT) deficiency is a common single-gene disorder among Northern Europeans and North Americans. The carrier frequency for the common missense mutation (Z-AAT) ranges from 4% in the US to nearly 25% in the Republic of Ireland. Severe AAT deficiency (plasma levels below 11 μm) is most commonly associated with an adult-onset lung disease, with pan-acinar emphysema and airway inflammation, which is thought to be primarily owing to the loss of function of AAT in neutralizing neutrophil elastase and other pro-inflammatory enzymes. In 5-10% of patients, severe liver disease may develop. This may occur at any time from infancy to adulthood, and is thought to be owing to toxicity from the Z-AAT mutant protein that folds poorly and forms insoluble polymers within the hepatocyte, which is the primary site for AAT production. Thus, gene therapy for AAT lung disease is conceived of as augmentation of serum levels (a prolonged form of protein replacement, which is currently in use), while gene therapy for liver disease presents the problem of also having to downregulate the production of Z-AAT protein. Over the years, numerous strategies have been employed for the gene therapy of both AAT-deficient lung disease and liver disease. These will be reviewed with an emphasis on modalities that have reached clinical trials recently.
Somatic BRAF-V600E Mutations in Familial Colorectal Cancer (2006)

The BRAF gene is mutated in 4% to 12% of unselected colorectal cancers, particularly those with high microsatellite instability and in premalignant lesions, such as serrated adenomas and hyperplastic polyps. However, it has been shown that activating BRAF mutations are almost never found in tumors from hereditary nonpolyposis colorectal cancer patients. To evaluate the role of oncogenic BRAF mutations in non-hereditary nonpolyposis colorectal cancer/non-familial adenomatous polyposis familial colorectal cancer, we did a mutation screening of the most common BRAF mutation, the V600E mutation, in 194 colorectal tumors from patients with a positive family history of the disease. The BRAF-V600E mutation was identified in 100% (8 of 8) of microsatellite-unstable tumors and in 9.7% (18 of 186) of microsatellite-stable tumors. Interestingly, families with extracolonic tumors showed a much higher mutation frequency (17.5%) compared with families with colonic cancer only (3.5%; P = 0.009). In addition, we studied colonoscopic results from 448 family members who had been under colonoscopic surveillance for several years. Subjects from families where the V600E mutation was identified had less adenomas compared with those from families where no BRAF mutation had been found (odds ratio, 8.5; 95% confidence interval, 1.1-64.6). These findings indicate that adenomas might be less important in the cancer development in the group of families with BRAF-V600E mutations and indirectly support a previous hypothesis that tumors might develop through the hyperplastic polyp-serrated adenoma pathway. In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal cancer families characterized by an increased risk of other common malignancies.
Application of Combinatorial Chemistry Science on Modern Drug Discovery (2008)

The science that established combinatorial chemistry as important new discipline in the 1980s and 1990s has re-emerged and infiltrated every sub-discipline within modern drug discovery and has profound impact. The application of combinatorial chemistry science has revolutioned high-throughput screening paradigms, chemical lead optimization, library purification, and post-purification sample handling, as well as in vitro and in vivo drug metabolism and pharmacokinetic assays. Although no longer in the spotlight and heralded as the savior of the drug industry, “combinatorial chemistry” is alive and well; in fact, combinatorial chemistry science is more prevalent and wide-spread than ever before.
Role of the carrier solution in cyclosporine pharmacokinetics in the baboon. (1987)

Although numerous investigational models have demonstrated the potent immunosuppressive properties of cyclosporine, the effectiveness of any given dosage may vary with the metabolism of the animal, the route of administration, and the carrier solution of the drug. We investigated the pharmacokinetics of intramuscular cyclosporine administration in the baboon using three carriers: polyoxethylated castor oil (Cremophor), a mixture of octanoic and decanoic acids (Miglyol), and olive oil. Cyclosporine prepared in Cremophor, Miglyol, or olive oil was injected intramuscularly into the hindlegs of baboons. Specimens for cyclosporine assay were obtained 2, 4, 6, 12, 18, and 24 hours after single intramuscular injection of 10 mg/kg or 15 mg/kg. In addition, weekly, then monthly, levels were obtained on animals receiving daily intramuscular injections following heterotopic heart xenografts. Attempts at oral administration proved unreliable and were discontinued. Cyclosporine assay was performed on stored serum using the RIA-KIT (Sandoz Pharmaceuticals Corporation, East Hanover, N.J.). Cremophor provides a more bioavailable form of cyclosporine than Miglyol when administered intramuscularly. (Area under curve = 7776 +/- 1437 for Cremophor 15 mg/kg vs 1837 +/- 726 for Miglyol 15 mg/kg; 2579 +/- 694 for Cremophor 10 vs 1123 +/- 393 for Miglyol 10.) Long-term daily intramuscular administration of Cremophor provides a sustained drug serum trough level with wide variability between individual animals (80 to 825 ng/ml). Toxicity was limited to injection site inflammation. There was no biochemical evidence of renal toxicity; however, some animals did demonstrate early histologic changes of cyclosporine effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Emulsions stabilised by whey protein microgel particles: towards food-grade Pickering emulsions (2014)

We have investigated a new class of food-grade particles, whey protein microgels, as stabilisers of triglyceride-water emulsions. The sub-micron particles stabilized oil-in-water emulsions at all pH with and without salt. All emulsions creamed but exhibited exceptional resistance to coalescence. Clear correlations exist between the properties of the microgels in aqueous dispersion and the resulting emulsion characteristics. For conditions in which the particles were uncharged, fluid emulsions with relatively large drops were stabilised, whereas emulsions stabilized by charged particles contained smaller flocculated drops. A combination of optical microscopy of the drops and spectrophotometry of the resolved aqueous phase allowed us to estimate the interfacial adsorption densities of the particles using the phenomenon of limited coalescence. We deduce two classes of particle arrangement. Complete adsorption of the particles was obtained when they were neutral or when their charges were screened by salt resulting in at least one particle monolayer at the interface. By contrast, only around 50% of the particles adsorbed when they were charged with emulsion drops being covered by less than half a monolayer. These findings were supported by direct visualization of drop interfaces using cryo-scanning electron microscopy. Uncharged particles were highly aggregated and formed a continuous 2-D network at the interface. Otherwise particles organized as individual aggregates separated by particle-free regions. In this case, we suggest that some particles spread at the interface leading to the formation of a continuous protein membrane. Charged particles displayed the ability to bridge opposing interfaces of neighbouring drops to form dense particle disks protecting drops against coalescence; this is the main reason for the flocculation and stability of emulsions containing sparsely covered drops.
Spontaneous Growth of Highly Conductive Two‐Dimensional Single‐Crystalline TiSi2 Nanonets (2008)

Net result: Two-dimensional nanonets form spontaneously in a chemical vapor deposition reaction. All beams in the nanonet are single-crystalline nanobelts that are connected by 90° joints. The nanonets are roughly 15 nm thick and a few micrometers long and wide (see pictures for three images at different tilting angles), and they assume a C49 TiSi2 structure.
Synthesis and self-assembly of triphenylene-containing conjugated macrocycles (2013)

Two imine-based shape-persistent macrocycles containing triphenylene building blocks, along with their noncyclic model compounds, have been synthesized. Their stable conformations are predicted by quantum mechanical calculations and confirmed by 2D NOESY NMR measurements. Compared to the noncyclic model compounds, the macrocycles (3 and 6) show a higher propensity for solution self-assembly due to their stronger π–π stacking interactions, and form micro-objects which exhibit an enhanced conductivity after doping. While both macrocycles have identical molecular geometries and very similar structures, their solution self-assembly leads to micro-objects with very different shapes. The two macrocycles also show different pH-dependent optical properties.
Functional domains of Bacillus thuringiensis insecticidal crystal proteins. Refinement of Heliothis virescens and Trichoplusia ni specificity domains on CryIA(c). (1991)

Insecticidal crystal proteins (delta-endotoxins), CryIA(a) and CryIA(c), from Bacillus thuringiensis are 82% homologous. Despite this homology, CryIA(c) was determined to have 10-fold more insecticidal activity toward Heliothis virescens and Trichoplusia ni than CryIA(a). Reciprocal recombinations between these two genes were performed by the homolog-scanning technique. The resultant mutants had different segments of their primary sequences exchanged. Bioassays with toxin proteins from these mutants revealed that amino acids 335-450 on CryIA(c) are associated with the activity against T. ni, whereas amino acids 335-615 on the same toxin are required to exchange full H. virescens specificity. One chimeric protein toxin, involving residues 450-612 from CryIA(c), demonstrated 30 times more activity against H. virescens than the native parental toxin, indicating that this region plays an important role in H. virescens specificity. The structural integrity of mutant toxin proteins was assessed by treatment with bovine trypsin. All actively toxic proteins formed a 65-kDA trypsin-resistant active toxic core, similar to the parental CryIA(c) toxin, indicating that toxin protein structure was not altered significantly. Contrarily, certain inactive mutant proteins were susceptible to complete protease hydrolysis, indicating that their lack of toxicity may have been due to structural alterations.
Cellulose Nanocrystal Inks for 3D Printing of Textured Cellular Architectures (2017)

3D printing of renewable building blocks like cellulose nanocrystals offers an attractive pathway for fabricating sustainable structures. Here, viscoelastic inks composed of anisotropic cellulose nanocrystals (CNC) that enable patterning of 3D objects by direct ink writing are designed and formulated. These concentrated inks are composed of CNC particles suspended in either water or a photopolymerizable monomer solution. The shear‐induced alignment of these anisotropic building blocks during printing is quantified by atomic force microscopy, polarized light microscopy, and 2D wide‐angle X‐ray scattering measurements. Akin to the microreinforcing effect in plant cell walls, the alignment of CNC particles during direct writing yields textured composites with enhanced stiffness along the printing direction. The observations serve as an important step forward toward the development of sustainable materials for 3D printing of cellular architectures with tailored mechanical properties.
Performance of fourier domain vs time domain optical coherence tomography (2003)

In this article we present a detailed discussion of noise sources in Fourier Domain Optical Coherence Tomography (FDOCT) setups. The performance of FDOCT with charge coupled device (CCD) cameras is compared to current standard time domain OCT systems. We describe how to measure sensitivity in the case of FDOCT and confirm the theoretically obtained values. It is shown that FDOCT systems have a large sensitivity advantage and allow for sensitivities well above 80dB, even in situations with low light levels and high speed detection.
New high temperature polymers. I. Wholly aromatic ordered copolyamides (1966)

Abstract Wholly aromatic ordered copolyamides of unusually high thermal stability were prepared by the condensation of aromatic diacid chlorides with symmetrical diamines containing preformed aromatic amide units in an ordered arrangement. The preservation of order in the condensation step was assured by using interfacial or solution polymerization techniques at temperatures below 50°C. Each polymer contains units derived from aminobenzoic acids, arylene diamines, and arylene diacids. By use of para ‐ and meta ‐ phenylene units, eight different polymers are possible; all were prepared. Differential thermal analyses and thermogravimetric analyses showed these polymers to have melting points or decomposition temperatures in a range from 410°C. for the all‐ meta polymer to 555°C. for the all‐ para one. Substitution of the internal N ‐hydrogens of the diamines with methyl groups or phenyl groups leads to additional ordered copolymers. Several were prepared, but their melting points were much lower than those of the parent polymers limiting their usefulness in high temperature applications. Tough pliable films were prepared from all eight unsubstituted polymers, and crystalline fibers with tenacities of ca. 6 g./den. were prepared from three of the polymers. The properties of the fibers were retained to a high degree even when determined at temperatures up to 400°C. Fibers aged at 300°C. for extended periods of time showed remarkable retention of fiber properties.
Mapping of sequences required for mouse neurovirulence of poliovirus type 2 Lansing (1986)

Intracerebral inoculation of mice with poliovirus type 2 Lansing induces a fatal paralysis, while most other poliovirus strains are unable to cause disease in the mouse. To determine the molecular basis for Lansing virus neurovirulence, we determined the complete nucleotide sequence of the Lansing viral genome from cloned cDNA. The deduced amino acid sequence was compared with that of two mouse-avirulent strains. There are 83 amino acid differences between the Lansing and Sabin type 2 strain and 179 differences between the Lansing and Mahoney type 1 strain scattered throughout the genome. To further localize Lansing sequences important for mouse neurovirulence, four intertypic recombinants were isolated by exchanging DNA restriction fragments between the Lansing 2 and Mahoney 1 infectious poliovirus cDNA clones. Plasmids were transfected into HeLa cells, and infectious recombinant viruses were recovered. All four recombinant viruses, which contained the Lansing capsid region and different amounts of the Mahoney genome, were neurovirulent for 18- to 21-day-old Swiss-Webster mice by the intracerebral route. The genome of neurovirulent recombinant PRV5.1 contained only nucleotides 631 to 3413 from Lansing, encoding primarily the viral capsid proteins. Therefore, the ability of Lansing virus to cause paralysis in mice is due to the viral capsid. The Lansing capsid sequence differs from that of the mouse avirulent Sabin 2 strain at 32 of 879 amino acid positions: 1 in VP4, 5 in VP2, 4 in VP3, and 22 in VP1.
Thrombin stimulation of synthesis and secretion of fibronectin by human A549 epithelial cells and mouse LB fibroblasts. (1991)

Thrombin, a serine protease generated at wound sites, takes part in multiple biological functions, including wound healing. The present report elucidates the effect of thrombin on fibronectin (FN) synthesis and secretion in fibroblasts and epithelial cells. Subconfluent cultures of mouse LB fibroblasts and human A549 epithelial cells were exposed to various concentrations of bovine plasma thrombin at 37 degrees C for 16 hr. After exposure, cells were processed for determination of cell-associated and secreted FN by metabolic labeling, immunoprecipitation, immunofluorescence, and peroxidase immunocytochemistry. The correlation of FN production with cell growth was studied by a combined procedure of peroxidase immunocytochemistry and light microscopic autoradiography. The amounts of cell-associated and secreted FN were significantly increased with dose increments of thrombin. The increases were most evident in secreted FN. The increase of cell-associated FN was also evidenced by results from immunofluorescence and immunocytochemical studies. Ultrastructurally, the intracellular FN was localized in rough endoplasmic reticulum, Golgi complexes, and secretory granules, whereas non-released extracellular FN was localized in the plasma membrane of cell-to-cell contacts and in the extracellular fibrils. More intense cytoplasmic FN staining was observed in cells that were not labeled with [3H]-thymidine, indicating that FN production may vary with different phases of cell growth. The results imply that thrombin may play an important role in the early phases of wound healing.
Risk of Developing Colorectal Cancer Following a Negative Colonoscopy Examination (2006)

The risk of developing colorectal cancer remains decreased for more than 10 years following the performance of a negative colonoscopy. There is a need to improve the early detection rate of right-sided colorectal neoplasia in usual clinical practice.
An HSVtk-mediated local and distant antitumor bystander effect in tumors of head and neck origin in athymic mice. (1997)

The "bystander effect," produced by ganciclovir-mediated killing of cells transduced with a herpes simplex virus thymidine kinase (HSVtk) gene, defines the cooperative killing of non-HSVtk-transduced cells. In vitro, a major contributor to this phenomenon is metabolic cooperation involving transfer of cytotoxic small molecules between cells via gap junctions. In this study, the bystander effect was assessed in vivo using cells of oral squamous cell carcinoma origin. Mixtures of HSVtk+ and HSVtk- tumor cells were implanted subcutaneously in the left flank of nude mice, and naive HSVtk- cells were implanted subcutaneously in the right flank. When tumors attained a size of 0.5 to 1 cm, the animals were treated with ganciclovir on a daily basis. The tumors comprised of mixed cells in the left flank resolved, consistent with a predicted bystander effect. The naive tumors in the right flank either resolved or became cytostatic showing little further growth compared to controls. Similar results were obtained when naive tumors were grown in both flanks and the tumor in the left flank received intratumoral injection of HSVtk retroviral producer cells or PA317 (HSVtk+) packaging cells, but not parental NIH 3T3 cells. Concomitant treatment with dexamethasone impaired the antitumor effect on the contralateral side. When these experiments were performed in SCID-Beige mice, there was a reduced antitumor effect on the ipsilateral flank and no antitumor response in the contralateral flank. Together with histology of regressing tumors, which showed an infiltration of lymphoid cells, these results are suggestive of an immune-related antitumor response that could account for the distant bystander effect.