gebhart/patrepeval huggingface dataset:
Transposon Mutagenesis To Improve the Growth of Recombinant <i>Saccharomyces cerevisiae</i> on <scp>d</scp> -Xylose (2007)

Saccharomyces cerevisiae L2612 transformed with genes for xylose reductase and xylitol dehydrogenase (XYL1 and XYL2) grows well on glucose but very poorly on d-xylose. When a gene for d-xylulokinase (XYL3 or XKS1) is overexpressed, growth on glucose is unaffected, but growth on xylose is blocked. Spontaneous or chemically induced mutants of this engineered yeast that would grow on xylose could, however, be obtained. We therefore used insertional transposon mutagenesis to identify two loci that can relieve this xylose-specific growth inhibition. One is within the open reading frame (ORF) of PHO13, and the other is approximately 500 bp upstream from the TAL1 ORF. Deletion of PHO13 or overexpression of TAL1 resulted in a phenotype similar to the insertional mutation events. Quantitative PCR showed that deletion of PHO13 increased transcripts for TAL1, indicating that the growth inhibition imposed by the overexpression of XYL3 on xylose can be relieved by an overexpression of transcripts for downstream enzymes. These results may be useful in constructing better xylose-fermenting S. cerevisiae strains.
The Management of Restless Legs Syndrome: An Updated Algorithm (2021)

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha<sub>2</sub>-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.
Exploring the potential of phosphotriazole 5′ mRNA cap analogues as efficient translation initiators (2018)

Augmenting the mRNA translation efficiency and stability by replacing the standard 7-methylguanosine 5'-cap with properly designed analogues is a viable strategy for increasing the in vivo expression of proteins from exogenously delivered mRNA. However, the development of novel cap analogues with superior biological properties is hampered by the challenges associated with the synthesis of such highly modified nucleotides. To provide a simpler alternative to traditional methods for cap analogue preparation, we have recently proposed a click-chemistry-based strategy for the synthesis of dinucleotide cap analogues and identified several triazole-containing compounds with promising biochemical properties. Here, we further explored the concept of CuAAC-mediated cap synthesis by designing and studying 'second generation' triazole-modified caps, which were derived from the most promising 'first generation' compounds by modifying the oligophosphate chain length, altering the position of the triazole moiety, or replacing chemically labile P-N bonds with P-O bonds. The biochemical properties of the new analogues were evaluated by determining their affinity for eIF4E, susceptibility to hDcp2-catalysed decapping, and translation efficiencies in vitro and in cultured cells. The results led to identification of cap analogues that have superior translational properties compared to standard caps and the parent triazole-modified compounds as well as provided directions for future improvements.
The structure of the RCAN1:CN complex explains the inhibition of and substrate recruitment by calcineurin (2020)

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the Ser/Thr phosphatase calcineurin (CN). It has been shown that excessive inhibition of CN is a critical factor for Down syndrome and Alzheimer's disease. Here, we determined RCAN1's mode of action. Using a combination of structural, biophysical, and biochemical studies, we show that RCAN1 inhibits CN via multiple routes: first, by blocking essential substrate recruitment sites and, second, by blocking the CN active site using two distinct mechanisms. We also show that phosphorylation either inhibits RCAN1-CN assembly or converts RCAN1 into a weak inhibitor, which can be reversed by CN via dephosphorylation. This highlights the interplay between posttranslational modifications in regulating CN activity. Last, this work advances our understanding of how active site inhibition of CN can be achieved in a highly specific manner. Together, these data provide the necessary road map for targeting multiple neurological disorders.
Automated Integration of Multimodal MRI for the Probabilistic Detection of the Central Vein Sign in White Matter Lesions (2018)

The current study presents the first fully automated method for detecting the central vein sign in white matter lesions and demonstrates promising performance in a sample of patients with and without MS.
A structure-activity-relationship (SAR) study of somatostatin receptor-binding peptides radiolabeled with Tc-99m (1994)

Somatostatin receptor (SSTR)-expressing tumors can be detected with high accuracy using In-111-[DTPA]octreotide. We sought a high-affinity SSTR-binding peptide labeled with the preferred radioisotope Tc-99m. We have prepared over 120 SSTR-binding peptides each containing a (N{sub 3}S or N{sub 2}S{sub 2}) chelator for Tc-99m in a SAR study in which peptide structure was systematically altered to optimize SSTR-binding affinity, in vivo rumor uptake and favorable biodistribution and pharmacokinetics. The HPLC-purified (>90% purity), chelator-containing peptides were characterized by FAB/ESMS and assayed in vitro for SSTR binding affinity by a competition assay (I-125 somatostatin-14 tracer and AR42J rat pancreatic tumor cell membranes). The oxo-rhenium complexes of the peptides were prepared by ligand exchange, characterized by FAB or ESMS and assayed for SSTR binding affinity as surrogates for the Tc-99m complexes. The Tc-99m complexes of peptides giving high-affinity oxo-rhenium complexes were also prepared by ligand exchange with specific activities of approx 300 mCi/mmol and examined in vivo for biodistribution and tumor uptake characteristics in CA20948 tumor-bearing rats.
Feasibility analysis of an epidermal glucose sensor based on time-resolved fluorescence (2007)

The goal of this study is to test the feasibility of using an embedded time-resolved fluorescence sensor for monitoring glucose concentration. Skin is modeled as a multilayer medium with each layer having its own optical properties and fluorophore absorption coefficients, lifetimes, and quantum yields obtained from the literature. It is assumed that the two main fluorophores contributing to the fluorescence at these excitation and emission wavelengths are nicotinamide adenine dinucleotide (NAD)H and collagen. The intensity distributions of excitation and fluorescent light in skin are determined by solving the transient radiative transfer equation by using the modified method of characteristics. The fluorophore lifetimes are then recovered from the simulated fluorescence decays and compared with the actual lifetimes used in the simulations. Furthermore, the effect of adding Poissonian noise to the simulated decays on recovering the lifetimes was studied. For all cases, it was found that the fluorescence lifetime of NADH could not be recovered because of its negligible contribution to the overall fluorescence signal. The other lifetimes could be recovered to within 1.3% of input values. Finally, the glucose concentrations within the skin were recovered to within 13.5% of their actual values, indicating a possibility of measuring glucose concentrations by using a time-resolved fluorescence sensor.
Method oil shale pollutant sorption/NO.sub.x reburning multi-pollutant control (2008)

A method of decreasing pollutants produced in a combustion process. The method comprises combusting coal in a combustion chamber to produce at least one pollutant selected from the group consisting of a nitrogen-containing pollutant, sulfuric acid, sulfur trioxide, carbonyl sulfide, carbon disulfide, chlorine, hydroiodic acid, iodine, hydrofluoric acid, fluorine, hydrobromic acid, bromine, phosphoric acid, phosphorous pentaoxide, elemental mercury, and mercuric chloride. Oil shale particles are introduced into the combustion chamber and are combusted to produce sorbent particulates and a reductant. The at least one pollutant is contacted with at least one of the sorbent particulates and the reductant to decrease an amount of the at least one pollutant in the combustion chamber. The reductant may chemically reduce the at least one pollutant to a benign species. The sorbent particulates may adsorb or absorb the at least one pollutant. A combustion chamber that produces decreased pollutants in a combustion process is also disclosed.
A self-adaptive boundary search genetic algorithm and its application to water distribution systems (2002)

The success of the application of genetic algorithms (GA) or evolutionary optimization methods to the design and rehabilitation of water distribution systems has been shown to be an innovative approach for the water industry. The optimal design and rehabilitation of water distribution systems is a constrained non-linear optimization problem. Constraints (for example, the minimum pressure requirements) are generally handled within genetic algorithm optimization by introducing a penalty cost function. The optimal or near optimal solution is found when the pressures at some nodes are close to the minimum required pressure or at the boundary of critical constraints. This paper presents a new approach called the self-adaptive boundary search strategy for selection of penalty factor within genetic algorithm optimization. The approach co-evolves and self-adapts the penalty factor such that the genetic algorithm search is guided towards and preserved around constraint boundaries. Thus it reduces the amount of simulation computations within the GA search and enhances the efficacy at reaching the optimal or near optimal solution. To demonstrate its effectiveness, the self-adaptive boundary search strategy is applied to a case study of the optimization of a water distribution system in this paper. It has been shown that the boundary GA search strategy is effective at adapting the feasibility of GA populations for a wide range of penalty factors. As a consequence, the boundary GA has been able to successfully find the least cost solution in the case study more effectively than a GA without the boundary search strategy. Thus a reliable least cost solution is guaranteed for the GA optimization of a water distribution system.
Discovery of Two Clinical Histamine H <sub>3</sub> Receptor Antagonists: <i>trans</i> - <i>N</i> -Ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and <i>trans</i> -3-Fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]- <i>N</i> -(2-methylpropyl)cyclobutanecarboxamide (PF-03654764) (2011)

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.
Variational inference and learning for segmental switching state space models of hidden speech dynamics (2003)

This paper describes novel and powerful variational EM algorithms for the segmental switching state space models used in speech applications, which are capable of capturing key internal (or hidden) dynamics of natural speech production. Hidden dynamic models (HDMs) have recently become a class of promising acoustic models to incorporate crucial speech-specific knowledge and overcome many inherent weaknesses of traditional HMMs. However, the lack of powerful and efficient statistical learning algorithms is one of the main obstacles preventing them from being well studied and widely used. Since exact inference and learning are intractable, a variational approach is taken to develop effective approximate algorithms. We have implemented the segmental constraint crucial for modeling speech dynamics and present algorithms for recovering hidden speech dynamics and discrete speech units from acoustic data only. The effectiveness of the algorithms developed are verified by experiments on simulation and Switchboard speech data.
Detection of trace amount of NO<sub>2</sub> gas using tunable blue laser diode (2017)

Nitrogen dioxide, one of the main air pollutants, has strong light absorption cross section in the blue region of the optical spectrum. Recent availability of blue laser diodes provides possibility of detecting NO<sub>2</sub> in open-air paths with very low detection limits. However, in the blue region, the sharp features of the NO<sub>2</sub> spectrum is relatively broad with typical width of tenths of nanometer. This poses a serious challenge for implementing traditional direct or wave-modulated tunable diode laser absorption spectroscopy. In this study, we report the usage of a blue laser diode with multi longitudinal modes tuned over about one nanometer in detecting trace amount of NO<sub>2</sub> gas. Details of the setup and its optimization will be presented along with a comparison of its performance with other NO<sub>2</sub> detection optical methods.
Co-Injection of a Targeted, Reversibly Masked Endosomolytic Polymer Dramatically Improves the Efficacy of Cholesterol-Conjugated Small Interfering RNAs <i>In Vivo</i> (2012)

Effective in vivo delivery of small interfering (siRNA) has been a major obstacle in the development of RNA interference therapeutics. One of the first attempts to overcome this obstacle utilized intravenous injection of cholesterol-conjugated siRNA (chol-siRNA). Although studies in mice revealed target gene knockdown in the liver, delivery was relatively inefficient, requiring 3 daily injections of 50 mg/kg of chol-siRNA to obtain measurable reduction in gene expression. Here we present a new delivery approach that increases the efficacy of the chol-siRNA over 500-fold and allows over 90% reduction in target gene expression in mice and, for the first time, high levels of gene knockdown in non-human primates. This improved efficacy is achieved by the co-injection of a hepatocyte-targeted and reversibly masked endosomolytic polymer. We show that knockdown is absolutely dependent on the presence of hepatocyte-targeting ligand on the polymer, the cognate hepatocyte receptor, and the cholesterol moiety of the siRNA. Importantly, we provide evidence that this increase in efficacy is not dependent on interactions between the chol-siRNA with the polymer prior to injection or in the bloodstream. The simplicity of the formulation and efficacy of this mode of siRNA delivery should prove beneficial in the use of siRNA as a therapeutic.
Inhibition of Protein Tyrosine Phosphatase 1B as a Potential Treatment of Diabetes and Obesity (2004)

Diabetes is a prevalent disease which effects over 150 million people worldwide and there is a great medical need for new therapeutic agents to treat it. Inhibition of protein tyrosine phosphatase 1B (PTP1B) has emerged as a highly validated, attractive target for treatment of not only diabetes but also obesity. Discovery of small-molecule inhibitors has been pursued extensively in both academia and industry and a number of very potent and selective inhibitors have been identified. With X-ray crystallography, the binding interactions of several classes of inhibitors have been elucidated. This has resulted in significant progress in understanding important interactions between inhibitors and specific residues of PTP1B, which could help the design of future inhibitors. However, since the active site of PTP1B that most of these inhibitors bind to is highly hydrophilic, it remains a challenge to identify inhibitors with both excellent in vitro potency and drug-like physiochemical properties which would lead to good in vivo activities.
Potential of Ramalin and Its Derivatives for the Treatment of Alzheimer’s Disease (2021)

The pathogenesis of Alzheimer's disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen, <i>Ramalina terebrata</i>), which exhibits various physiological activities, in AD. Specifically, derivatives were synthesized based on the structure of ramalin, which has a strong antioxidant effect, BACE-1 inhibition activity, and anti-inflammatory effects. Therefore, ramalin and its derivatives exhibit activity against multiple targets associated with AD and can serve as potential therapeutic agents for the disease.
Reaction Center Models in Liquid Crystals: Identification of Paramagnetic Intermediates (2003)

Photoinduced charge separation and recombination to the triplet state in a carotene (C) porphyrin (P) fullerene (C 60 ) triad have been followed by time-resolved electron paramagnetic resonance (EPR). The electron transfer process has been studied at different temperatures in both a glassy isotropic matrix (2-methyltetrahydrofuran) and uniaxial liquid crystal (E-7). In both media, the triad undergoes two-step photoinduced electron transfer, with the generation of a long-lived charge separated state (C ” + -P-C 60 ” m ), and charge recombination to the triplet state, localized in the carotene moiety. The carotenoid triplet state is initially polarized according to the mechanism of recombination of a radical pair with singlet precursor. Both the photoinduced spin-correlated radical pair and the carotene triplet are observed in E-7 starting from the glass to the liquid crystal phase. The exchange interaction between the electrons in the radical pair (J=1.2 Gauss) has been evaluated by simulation of the EPR spectrum in the isotropic glass and comparison with the corresponding spectrum in the oriented medium.
A DSP-based real time contour tracking system (2003)

In this paper the real-time implementation of an automatic contour tracking procedure is presented. If a rough contour of the desired structure is available on the first frame of a sequence, the contours on the subsequent frames are automatically outlined. The mass center of the first-order absolute moment operator is used to locate the contour of interest on every frame. The contour tracking procedure was implemented on an integrated software/hardware environment based on the interaction of a PC and a DSP processor (TMS320C80). Standard PAL images at 25 frame/s were used as an input signal; the contour was computed in real time and was then drawn on the images and displayed on a VGA monitor. The results are illustrated both on clinical images recorded on a SVHS videocassette and on images of a test object acquired by means of a video camera.
Purification and immunological characterization of HPLC-purified pertussis toxin subunits (1991)

Pertussis toxin (PT), an oligomeric exotoxin of Bordetella pertussis containing five dissimilar subunits, is considered to be an essential immunogen in acellular and component pertussis vaccines against whooping cough. A rapid single-step procedure for isolating PT subunits was developed using reverse-phase high-performance liquid chromatography. Recoveries of individual subunits were 75% (S1), 70% (S2), greater than 90% (S3), greater than 90% (S4), and 50% (S5), as judged by SDS-PAGE and amino acid analysis. Lyophilized subunits were solubilized in urea followed by step-wise dialysis to remove the urea. All subunits were inactive in histamine sensitization, lymphocytosis, and hemagglutination assays. However, purified S1 retained residual NAD-glycohydrolase and ADP-ribosyltransferase activity. A partially active holotoxin could be generated by mixing the five individual subunits. All subunits were immunogenic in rabbits and mice. Monospecific antisera raised in both animal species were able to neutralize the PT-mediated clustering of Chinese hamster ovary cells, but active immunization of mice with single subunits failed to protect them in the intracerebral challenge assay. These subunit preparations therefore retained neutralizing determinants, but did not contain protective epitopes.
Evidence for altered DNA methylation as a major regulator of gene expression in calcific aortic valve disease (671.15) (2014)

Aging is a major risk factor for calcific aortic valve disease (CAVD). While recent work suggests that DNA methylation patterns are dramatically altered with aging, changes in DNA methylation patterns in age‐related cardiovascular diseases remain largely uncharacterized. Thus, we tested the working hypothesis that de novo DNA methyltransferase levels (DNMT3b in particular) are significantly increased in stenotic human aortic valves and would serve to repress expression of protective genes. We used human aortic valves that were either normal (NORM) or stenotic (STEN). qRT‐PCR and Western blotting were used to examine analyze changes in DNMT3b levels and markers of osteogenesis. DNA methylation was examined using ELISA‐based methods for total methylation and Illumina 450k Beadchip assays for site‐specific methylation between NORM and STEN valves. The pro‐osteogenic marker expression, Sp7, was increased by 4±1 fold in STEN valves compared to NORM tissue. While mRNA levels of DNMT3b only tended to be increased in STEN valves, protein levels of DNMT3b were dramatically increased in STEN valves compared to NORM valves (13.9±3‐fold increase). Increases in DNMT3b levels were associated with an increase in global DNA methylation, and 450k beadchip analysis identified more than 6,000 differentially‐methylated sites between NORM and STEN tissue. Collectively, these data identify DNA methylation as a potentially novel and major regulator of gene expression in end‐stage calcific aortic valve stenosis. NHLBI Grant Funding Source : NHLBI