gebhart/patrepeval huggingface dataset:
Structure of the DNA Repair Helicase Hel308 Reveals DNA Binding and Autoinhibitory Domains (2007)

Hel308 is a superfamily 2 helicase conserved in eukaryotes and archaea. It is thought to function in the early stages of recombination following replication fork arrest and has a specificity for removal of the lagging strand in model replication forks. A homologous helicase constitutes the N-terminal domain of human DNA polymerase Q. The Drosophila homologue mus301 is implicated in double strand break repair and meiotic recombination. We have solved the high resolution crystal structure of Hel308 from the crenarchaeon Sulfolobus solfataricus, revealing a five-domain structure with a central pore lined with essential DNA binding residues. The fifth domain is shown to act as an autoinhibitory domain or molecular brake, clamping the single-stranded DNA extruded through the central pore of the helicase structure to limit the helicase activity of the enzyme. This provides an elegant mechanism to tune the processivity of the enzyme to its functional role. Hel308 can displace streptavidin from a biotinylated DNA molecule, and this activity is only partially inhibited when the DNA is pre-bound with abundant DNA-binding proteins RPA or Alba1, whereas pre-binding with the recombinase RadA has no effect on activity. These data suggest that one function of the enzyme may be in the removal of bound proteins at stalled replication forks and recombination intermediates.
[Bacteria and their role in allergic diseases]. (2004)

From the beginning of life, human immune system is affected by interactions with different microorganisms. Immediately after the birth bacteria colonize mucous tissues and namely the gastrointestinal tract, which was antenatally sterile. Bacteria are involved in allergic inflammation by two different ways. They can either initiate the allergic response or they can diminish it. To the negative factors, which can trigger the allergic response belong superantigens, namely the bacterial enterotoxins. Positive factors include mycobacterial antigens, intestinal microflora, pathogen-associated molecular patterns and CpG motives that belong to components of the bacterial genome DNA. The effect of lipopolysaccharide from gram-negative bacteria on the development of allergic inflammation is two faced. Lipopolysaccharide has a protective role when the infection precedes the contact with allergen for a long time. Short period between the infection and allergen exposition leads in a sensitized person to the provocation of allergic disease. These and other factors are important in relation to the so-called hygiene hypothesis where the T regulatory lymphocytes seem to play the key role in the balance between Th1 and Th2 lymphocytes.
ADR Through a Cultural Lens: How Cultural Values Shape Our Disputing Processes (2005)

I arrived for my second Nepali language class on time, but the teacher kept chatting about inconsequential things. I was paying by the hour, and we had already spent 25 minutes talking about nothing! A week later, I received an invitation to an art exhibit. The location was "Royal Museum," so that is where I went, only to find an empty building and no people. What had I missed? In my first meeting with the Dean of the Law Campus, we talked about trekking, the upcoming religious holidays, his visit to Seattle two years ago, relatives in the United States, but never directly addressed the reason for my visit that day. I thought I was there to learn what and when I would be teaching. What was going on here? What was I supposed to read between the lines in each of these encounters?
Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs (2005)

Low oxygen tension is thought to be an integral component of the human mesenchymal stem cell (hMSC) native bone marrow microenvironment. HMSC were cultured under physiologically relevant oxygen environments (2% O2) in three-dimensional (3D) constructs for up to 1 month in order to investigate the combined effects of chronic hypoxia and 3D architecture on hMSC tissue-development patterns. Hypoxic hMSC exhibited an extended lag phase in order to acclimatize to culture conditions. However, they subsequently proliferated continuously throughout the culture period, while maintaining significantly higher colony-forming unit capabilities and expressing higher levels of stem cell genes than hMSC cultured at 20% O2 (normoxic) conditions. Upon induction, hypoxic hMSC also expressed higher levels of osteoblastic and adipocytic differentiation markers than normoxic controls. Hypoxia induced increased total protein levels in hMSC throughout the culture period, as well as significantly different fibronectin expression patterns suggesting that oxygen levels can significantly affect tissue-development patterns. Importantly, hMSC maintained the ability to thrive in prolonged hypoxic conditions suggesting that hypoxia may be an essential element of the in vivo hMSC niche. Further studies are required to determine how variations in cellular characteristics and ECM expression impact on the physiological properties of the engineered tissue, yet these results strongly indicate that oxygen tension is a key parameter that influences the in vitro characteristics of hMSC and their development into tissues.
Long-term effects of sevelamer hydrochloride on the calcium × phosphate product and lipid profile of haemodialysis patients* (1999)

Sevelamer is a safe and effective phosphate binder that leads to significant improvements in the calcium x phosphate product and lipid profile of haemodialysis patients.
Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial (1998)

The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.
Loss of ataxia telangiectasia mutated– and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival (2007)

The diverse responses of human cells to various forms of DNA damage are controlled by a complex network of signaling proteins. There has been considerable interest in the components of this signaling apparatus as potential targets for new forms of anticancer therapy. In this report, we examine the contributions of an upstream signaling molecule, the ataxia telangiectasia mutated- and Rad3-related (ATR) protein kinase, to the resistance of cancer cells to DNA-damaging agents that are commonly used as anticancer therapeutics. Loss of ATR function in knock-in cancer cells strikingly enhanced the effects of several of the most commonly used therapeutic compounds, impeding the progression of the cell cycle and reducing long-term cancer cell survival. Loss of ATR function potentiated the toxicity of alkylating agents most strikingly, antimetabolites moderately, and double-strand break-inducing agents to a lesser extent. These results suggest that specific inhibition of ATR activity will be a valid strategy to increase the effectiveness of currently used modes of therapy.
An Envelope-Modified Tetravalent Dengue Virus-Like-Particle Vaccine Has Implications for Flavivirus Vaccine Design (2017)

Dengue viruses (DENV) infect 50 to 100 million people each year. The spread of DENV-associated infections is one of the most serious public health problems worldwide, as there is no widely available vaccine or specific therapeutic for DENV infections. To address this, we developed a novel tetravalent dengue vaccine by utilizing virus-like particles (VLPs). We created recombinant DENV1 to -4 (DENV1-4) VLPs by coexpressing precursor membrane (prM) and envelope (E) proteins, with an F108A mutation in the fusion loop structure of E to increase the production of VLPs in mammalian cells. Immunization with DENV1-4 VLPs as individual, monovalent vaccines elicited strong neutralization activity against each DENV serotype in mice. For use as a tetravalent vaccine, DENV1-4 VLPs elicited high levels of neutralization activity against all four serotypes simultaneously. The neutralization antibody responses induced by the VLPs were significantly higher than those with DNA or recombinant E protein immunization. Moreover, antibody-dependent enhancement (ADE) was not observed against any serotype at a 1:10 serum dilution. We also demonstrated that the Zika virus (ZIKV) VLP production level was enhanced by introducing the same F108A mutation into the ZIKV envelope protein. Taken together, these results suggest that our strategy for DENV VLP production is applicable to other flavivirus VLP vaccine development, due to the similarity in viral structures, and they describe the promising development of an effective tetravalent vaccine against the prevalent flavivirus.<b>IMPORTANCE</b> Dengue virus poses one of the most serious public health problems worldwide, and the incidence of diseases caused by the virus has increased dramatically. Despite decades of effort, there is no effective treatment against dengue. A safe and potent vaccine against dengue is still needed. We developed a novel tetravalent dengue vaccine by using virus-like particles (VLPs), which are noninfectious because they lack the viral genome. Previous attempts of other groups to use dengue VLPs resulted in generally poor yields. We found that a critical amino acid mutation in the envelope protein enhances the production of VLPs. Our tetravalent vaccine elicited potent neutralizing antibody responses against all four DENV serotypes. Our findings can also be applied to vaccine development against other flaviviruses, such as Zika virus or West Nile virus.
Ductility of a Ti‐6Al‐4V alloy produced by selective laser melting of prealloyed powders (2010)

Purpose The aim of the paper is the study of the change in the mechanical properties (and in particular in ductility), with the microstructure, of a biomedical Ti‐6Al‐4V alloy produced by different variants of selective laser melting (SLM). Design/methodology/approach Ti‐6Al‐4V alloy produced by different variants of SLM has been mechanically characterized through tensile testing. Its microstructure has been investigated by optical observation after etching and by X‐ray diffraction analysis. Findings SLM applied to Ti‐6Al‐4V alloy produces a material with a martensitic microstructure. Some microcracks, due the effect of incomplete homologous wetting and residual stresses produced by the large solidification undercooling of the melt pool, are observable in the matrix. Owing to the microstructure, the tensile strength of the additive manufactured parts is higher than the strength of hot worked parts, whereas the ductility is lower. A pre‐heating of the powder bed is effective in assisting remelting and reducing residual stresses, but ductility does not increase significantly, since the microstructure remains martensitic. A post‐building heat treatment causes the transformation of the metastable martensite in a biphasic a‐b matrix, with a morphology that depends on the heat treatment. This results in an increase in ductility and a reduction in strength values. Originality/value The study evidenced how it is possible to obtain a fully dense material and make the martensite transform in Ti‐6Al‐4V alloy through the variation of the SLM process. The stabilization of the microstructure also results in an improvement of the ductility.
Atomic arrangement at the AlN/ZrB2 interface (2002)

Low-dislocation-density GaN films (∼108 cm−2) have been grown on closely lattice-matched ZrB2 substrates by metalorganic vapor phase epitaxy using low-temperature AlN as a buffer layer. High-resolution electron microscopy images of the AlN/ZrB2 interface region reveal that the AlN buffer layer does not grow directly on the ZrB2 substrate. Instead, the existence of an unintentional intermediate cubic-phase layer (approximately 2 nm thick) has been observed. Misfit dislocations are evident at both interfaces of the intermediate layer. Our analysis indicates that the intermediate layer has a lattice constant a=4.6 Å, and that it is a ternary alloy of ZrxByNz, which should result from a transformation from the hexagonal phase of ZrB2 due to interdiffusion of nitrogen and boron at the elevated temperature required for growth of GaN. This intermediate cubic-phase layer of ZrxByNz appears to have been so far unavoidable in the growth of high-quality GaN epilayers on ZrB2 substrates by our technique.
Fibroblast Growth Factor Receptors as Molecular Targets in Thyroid Carcinoma (2004)

Several molecular abnormalities of potential therapeutic target value have been described in thyroid neoplastic transition. We report the expression of the fibroblast growth factor receptor family (FGFR-1-4) in normal thyroid tissues, human thyroid cancers of various types and behaviors, and cell lines representative of the spectrum of differentiation of tumors derived from follicular epithelial cells. FGFR-2 was the only receptor consistently detected in normal human thyroid tissue, and its expression diminished in all thyroid cancers and carcinoma cell lines, suggesting that it may have a protective role. FGFR-1 and FGFR-3 were expressed in most well-differentiated tumor types. FGFR-4, however, was expressed predominantly in aggressive tumor types and the most rapidly proliferative cell lines, indicating that it may promote the progression of these tumors. To specifically determine the function of FGFR-4 in thyroid carcinoma, gain- or loss-of-function studies were performed in cell lines representative of the spectrum of thyroid cancer behavior. Introduction of FGFR-4 resulted in enhanced cell proliferation, an effect that was more pronounced in cell lines derived from aggressive tumors than in those derived from more indolent neoplasms. Moreover, transduction of a dominant-negative FGFR attenuated cell proliferation in the aggressive poorly differentiated cell lines with no appreciable effect in well-differentiated cells. Pharmacologic FGFR-4 tyrosine kinase inhibition resulted in significant proliferation arrest in an aggressive cell line endogenously expressing the receptor. Furthermore, systemic administration of the FGFR tyrosine kinase inhibitor PD173074 resulted in significant inhibition of follicular thyroid carcinoma-derived cell growth in xenografted severe combined immunodeficient mice. These data indicate a role for FGFR-4 in human thyroid cancer cell progression and provide a rationale for FGFR manipulation as a potentially novel therapeutic approach.
Mammalian lignan production from various foods (1991)

Mammalian lignans such as enterolactone and enterodiol, which are produced in the colon from precursors in foods, have been suggested as playing a role in the cancer-protective effect of vegetarian diets. Despite this, very little is known regarding the amount that is produced from different food products. Therefore, the objective of this study was to determine the production of mammalian lignans from 68 common plant foods by using the technique of in vitro fermentation with human fecal microbiota, which simulates colonic fermentation. Results showed a wide range (21-67,541 microgram(s)/100 g sample) in the amount of lignans produced. On the average as a group, the oilseeds produced the highest amounts (20,461 +/- 12,685), followed by the dried seaweeds (900 +/- 247), whole legumes (562 +/- 211), cereal brans (486 +/- 90), legume hulls (371 +/- 52), whole grain cereals (359 +/- 81), vegetables (144 +/- 23), and fruits (84 +/- 22). The vegetables produced the second highest concentration of lignans (1,546 +/- 280) when the data were expressed on a moisture-free basis. Flaxseed flour and its defatted meal were the highest producers of lignans (mean 60,110 +/- 7,431). Lignan production with the in vitro method related well to the urinary lignan excretion observed in rats and humans. The data should be useful in the estimation of lignan production from a given diet and in the formulation of high-lignan-producing diet for the purpose of reducing the cancer risk.
Disruption of the fucose pathway as a consequence of genetic adaptation to propanediol as a carbon source in Escherichia coli (1976)

In Escherichia coli, L-fucose is dissimilated via an inducible pathway mediated by L-fucose permease, L-fucose isomerase, L-fucose kinase, and L-fuculose 1-phosphate aldolase. The last enzyme cleaves the six-carbon substrate into dihydroxyacetone phosphate and L-lactaldehyde. Aerobically, lactaldehyde is oxidized to L-lactate by a nicotinamide adenine dinucleotide (NAD)-linked dehydrogenase. Anaerobically, lactaldehyde is reduced by an NADH-COUPLED REDUCTASE TO L-1,2-propanediol, which is lost into the medium irretrievably, even when oxygen is subsequently introduced. Propanediol excretion is thus the end result of a dismutation that permits further anaerobic metabolism of dihydroxy-acetone phosphate. A mutant selected for its ability to grow aerobically on propanediol as a carbon and energy source was reported to produce lactaldehyde reductase constitutively and at high levels, even aerobically. Under the new situation, this enzyme serves as a propanediol dehydrogenase. It was also reported that the mutant had lost the ability to grow on fucose. In the present study, it is shown that in wild-type cells the full synthesis of lactaldehyde dehydrogenase requires the presence of both molecular oxygen and a small molecule effector, and the full synthesis of lactaldehyde reductase requires anaerobiosis and the presence of a small molecule effector. The failure of mutant cells to grow on fucose reflects the impairment of a regulatory element in the fucose system that prevents the induction of the permease, the isomerase, and the kinase. The aldolase, on the other hand, is constitutively synthesized. Three independent fucose-utilizing revertants of the mutant all produce the permease, the isomerase, the kinase, as well as the aldolase, constitutively. These strains grow less well than the parental mutant on propanediol.
Attachment of an aminoglycoside, amikacin, to implantable collagen for local delivery in wounds (1993)

Cultured skin substitutes consisting of implantable collagen (COL) and cultured human skin cells often fail clinically from destruction by microbial contamination. Hypothetically, addition of selected antimicrobial drugs to the implant may control microbial contamination and increase healing of skin wounds with these materials. As a model for drug delivery, bovine skin COL (1 mg/ml) and amikacin (AM; 46 micrograms/ml) were modified by covalent addition of biotin (B-COL and B-AM, respectively) from B-N-hydroxysuccinimide and bound together noncovalently with avidin (A). B-COL was incubated with A and then with B-peroxidase (B-P) or by serial incubation with B-AM and B-P, before P-dependent chromogen formation. Colorimetric data (n = 12 per condition) from spot tests on nitrocellulose paper were collected by transmission spectrophotometry. Specificity of drug binding in spot tests was determined by (i) serial dilution of B-COL; (ii) reactions with COL, AM, or P that had no B; (iii) removal of A; or (iv) preincubation of B-COL-A with B before incubation with B-P. Binding of B-AM was (i) dependent on the concentration of B-COL; (ii) specific to B-COL, A, and B-P (P < 0.05); and (iii) not eluted by incubation in 0.15 or 1.0 M NaCl. B-AM was found to block binding of B-P to the B-COL-A complex and to retain bacteriocidal activity against 10 clinical isolates of wound bacteria in the wet disc assay. Antimicrobial activity of B-AM was removed from solution by treatment with magnetic A and a permanent magnet. These results suggest that selected antimicrobial drugs can be biotinylated for attachments to COL-cultured cell implants without loss of pharmacologic activity. Because this chemistry utilizes a common ligand, any molar ratio of agents may be administered simultaneously and localized to the site of implantation.
Structure‐Switching Signaling Aptamers: Transducing Molecular Recognition into Fluorescence Signaling (2004)

The development of aptamer technology considerably broadens the utility of nucleic acids as molecular recognition elements, because it allows the creation of DNA or RNA molecules for binding a wide variety of analytes (targets) with high affinity and specificity. Several recent studies have focused on developing rational design strategies for transducing aptamer-target recognition events into easily detectable signals, so that aptamers can be widely exploited for detection directed applications. We have devised a generalizable strategy for designing nonfluorescent aptamers that can be turned into fluorescence-signaling reporters. The resultant signaling probes are denoted "structure-switching signaling aptamers" as they report target binding by switching structures from DNA/DNA duplex to DNA/target complex. The duplex is formed between a fluorophore-labeled DNA aptamer and an antisense DNA oligonucleotide modified with a quencher (denoted QDNA). In the absence of the target, the aptamer hybridizes with QDNA, bringing the fluorophore into close proximity of the quencher for efficient fluorescence quenching. When this system is exposed to the target, the aptamer switches its binding partner from QDNA to the target. This structure-switching event is coupled to the generation of a fluorescent signal through the departure of QDNA, permitting the real-time monitoring of the aptamer-target recognition. In this article, we discuss the conceptual framework of the structure-switching approach, the essential features of structure-switching signaling aptamers as well as remaining challenges and possible solutions associated with this new methodology.
Three‐dimensional Arrangement of Short DNA Oligonucleotides at Surfaces via the Synthesis of DNA‐branched Polyacrylamide Brushes by SI‐ATRP (2011)

Short DNA oligonucleotide branches are incorporated into acrylamide brushes via surface initiated atom transfer radical polymerization in an attempt to increase DNA surface density by building three-dimensional molecular architectures. ATR-FTIR as well as hybridization studies followed by SPR confirm the incorporation of the DNA sequences into the polymer backbone. MALDI-TOF analysis further suggests that six acrylamide monomer units are typically separating DNA branches present on a single brushes approximately 26 units long. This new approach offers a promising alternative to SAM-based nucleic acid and aptamer sensors and could enable the realization of more complex soft materials of controlled architecture capable of both recognition and signaling by including additional optically or electrochemically active moieties.
High-level power modeling, estimation, and optimization (1998)

Silicon area, performance, and testability have been, so far, the major design constraints to be met during the development of digital very-large-scale-integration (VLSI) systems. In recent years, however, things have changed; increasingly, power has been given weight comparable to the other design parameters. This is primarily due to the remarkable success of personal computing devices and wireless communication systems, which demand high-speed computations with low power consumption. In addition, there exists a strong pressure for manufacturers of high-end products to keep power under control, due to the increased costs of packaging and cooling this type of device. Last, the need of ensuring high circuit reliability has turned out to be more stringent. The availability of tools for the automatic design of low-power VLSI systems has thus become necessary. More specifically, following a natural trend, the interests of the researchers have lately shifted to the investigation of power modeling, estimation, synthesis, and optimization techniques that account for power dissipation during the early stages of the design flow. This paper surveys representative contributions to this area that have appeared in the recent literature.