gebhart/patrepeval huggingface dataset:
Extension of in vivo half-life of biologically active peptides via chemical conjugation to XTEN protein polymer (2013)

XTEN, unstructured biodegradable proteins, have been used to extend the in vivo half-life of genetically fused therapeutic proteins and peptides. To expand the applications of XTEN technology to half-life extension of other classes of molecules, XTEN protein polymers and methods for chemical XTENylation were developed. Two XTEN precursors were engineered to contain enzymatically removable purification tags. The proteins were readily expressed in bacteria and purified to homogeneity by chromatography techniques. As proof-of-principle, GLP2-2G peptide was chemically conjugated to each of the two XTEN protein polymers using maleimide-thiol chemistry. The monodisperse nature of XTEN protein polymer enabled reaction monitoring as well as the detection of peptide modifications in the conjugated state using reverse phase-high performance liquid chromatography (RP-HPLC) and electrospray ionization mass spectrometry. The resulting GLP2-2G-XTEN conjugates were purified by preparative RP-HPLC to homogeneity. In comparison with recombinantly fused GLP2-2G-XTEN, chemically conjugated GLP2-2G-XTEN molecules exhibited comparable in vitro activity, in vitro plasma stability and pharmacokinetics in rats. These data suggest that chemical XTENylation could effectively extend the half-life of a wide spectrum of biologically active molecules, therefore broadening its applicability.
17th Century Political Cartesianism and Its Opponents, or Imaging the State from Point Fixe (2012)

This article examines the relation of two models of civil science in the early modern political literature: the rhetorical science of contingency (rhetorica primaria), and mathesis politica, associated with Descartes by some early Enlightenment authors. The authors analyze the reception of the rhetorical aspect of Hobbes’s civil science with a special focus on Vico’s criticism of Hobbes’s constructivist state model, showing how Vico counters the Hobbesian ‘protosociological’ style of theorizing with his own historical way of reflecting on the social and ‘open’ structure of political action.
EVALUATION OF FOCUSED AND UNFOCUSED SHOCK WAVE PROPAGATION IN POLYACRYLAMIDE GEL AND PORCINE TISSUE. (2007)

Background Extracorporeal shock wave therapy (ESWT) has been shown to increase perfusion in ischemic cardiac tissue and increase autograft healing in both animal models and clinical studies. To help clarify the mechanisms by which ESWT induces tissue healing, we studied the propagation of focused and unfocused shock wave sources in animal tissue by comparing the cavitation pattern in polyacrylamide gel and porcine tissue. Study Design and Method Fifteen percent polyacrylamide blocks, marble-embedded polyacrylamide, and porcine thigh were treated with a focused shock wave source with an OssatronTM machine and unfocused shock wave source with a StorzTM device. Cavitation patterns were visualized using a MicroMaxxTM ultrasound machine immediately after a treatment. Results Focused shock wave treatment of polyacrylamide gel with the OssatronTM produced a focal ellipsoidal cavitation field with a 2 cm depth. An increase in treatment energy or intensity resulted in a more intense cavitation field with a larger diameter. Focused treatment of the marble-embedded gel produced a disturbance of the marble-gel interface with increased cavitation intensity at increased treatment energy. Unfocused shockwave treatment of the polyacrylamide gel produced a focal cavitation field superficially at the site of treatment. However, the cavitation field displayed a radiating pattern with deeper propagation into the gel. Increasing the treatment intensity led to a corresponding increase in the intensity of the cavitation field. Unfocused shock wave treatment of marble-embedded gel showed no observable change in the marble-gel interface. Treatment of porcine thigh with both focused and unfocused shock wave at low and high energy and intensity did not produce any observable changes. Conclusion The result of ESWT in polyacrylamide gel indicates that deep tissue stimulation with an unfocused shock wave source may not yield any benefits because high tissue impedance may reduce shock wave propagation. However, focused shock wave may be more favorable for deep tissue stimulation.
ChemInform Abstract: The Polyhydroxy Cyclopentene, a Total Synthesis of (‐)‐Pentenomycin. (2000)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Bacillus anthracis and the Pathogenesis of Anthrax (2005)

Bacillus anthracis is the causative agent of anthrax, a disease of animals that is transmissible to humans. Because B. anthracis forms spores that can be aerosolized and sprayed with the intent to kill, this pathogen can also be viewed as an agent of biological warfare and bioterrorism (1). The accidental release of spores into the air in Sverdlosk, Russia, and the recent mail attacks in the United States in the Fall of 2001 led to human casualties that sadly document the pathogenic potential and bioterrorism threat of B. anthracis (2,3). Furthermore, it appears that B. anthracis has been a research focus of biological warfare industries and subject to genetic manipulation with the intent of generating pathogen variants with increased virulence or with resistance to medical therapies and vaccine prevention strategies (1,4,5). B. anthracis can be obtained from infected animals or soil and anthrax spores are easily prepared. Furthermore, B. anthracis spores display very low visibility when delivered as an aerosol spray or powder. Inhalational anthrax is the primary target disease of biological warfare schemes (6). The LD50 for human inhalation of anthrax is not known, but has been estimated from animal studies to be of the order of 10,000 spores, corresponding to approx 0.01 µg (2,7), and a kilogram amount of spores, if sprayed intentionally on an urban area, is capable of killing hundreds of thousands of people. Biological warfare is an evolving research enterprise, and B. anthracis strains resistant to the commonly used antibiotic therapies may be available to several countries and terrorist organizations (6). American defense strategies against bioterrorist or biological warfare attacks must focus on the development of novel therapies that circumvent drug and vaccine-resistant B. anthracis strains (8). Much attention is directed toward finding inhibitors that disrupt the function of anthrax toxin. Anthrax toxin is the major virulence factor of B. anthracis (9) and consists of three proteins: lethal factor (LF), edema factor (EF), and protective antigen (PA). PA combines with either LF or EF enzymes to mediate their translocation across the plasma membrane (10). The combination of PA and LF forms lethal toxin (LeTx) and that of PA and EF forms edema toxin (EdTx). Once bacteria have secreted a large amount of anthrax toxin, antibiotic treatment becomes far less effective. At this later stage of anthrax pathogenesis, it might be useful to disrupt the biological activity of the toxin. This chapter reviews current knowledge of the factors that contribute to the pathogenesis of B. anthracis and highlights recent reports of possible strategies for blocking toxin action (11–13). Additionally, based on the known mechanisms of listeria-mediated invasion and virulence, the currently available genome sequences of B. anthracis were searched in an attempt to identify B. anthracis genes that may act early during pathogenesis by contributing to bacterial attachment to host tissues or to toxin secretion
Photochemical manipulation of discotic liquid crystal alignment by a poly(vinyl cinnamate) thin film (2000)

This letter describes the surface-assisted orientational photocontrol of discotic liquid crystals (DLCs) using thin films of a conventional photoresist, poly(vinyl cinnamate). Oblique illumination of a thin film of the polymer with nonpolarized UV light gave rise to inclined orientation of cinnamoyl moieties toward the light propagation through their direction-selective photochemical reactions. The DLCs were aligned on the photoirradiated film in a tilted hybrid manner, whereas the orientational direction of DLC molecules corresponds to the light propagation as a result of three-dimensional orientation of the cinnamoyl residues.
Identification and Characterization of Novel Adhesins in Leptospira (2010)

Leptospirosis is a worldwide zoonosis of human and veterinary concern, caused by pathogenic spirochetes of the genus Leptospira. This work reviews the ability of six putative leptospiral outer membrane proteins to interact with extracellular matrix (ECM) molecules. The chosen the genes, LIC10314, LIC10368, LIC12099, LIC12895, LIC12906 and LIC12690, were selected from the genome sequences of L. interrogans serovar Copenhageni mostly based on their cellular localization. The purified proteins were evaluated for their binding capacity by ELISA, except for LIC12690 coding sequence that was tested under denaturing conditions by Western blotting. Binding characterization and specificity of the proteins to ECM components were also studied. Our data show that the attachment of the recombinant proteins to ECM molecules was specific, dose-dependent and saturable, fulfilling the properties of a typical receptor-ligand interaction. These novel identified membrane proteins may play a role in mediating adhesion of L. interrogans to the hosts and therefore in bacterial pathogenesis.
XPOMET – Klinische Studien: Neue Technologien revolutionieren die Welt der klinischen Studien (2018)

XPOMET hat João Bocas eingeladen, um über die sich verändernde Welt klinischer Studien zu sprechen. Der Digital-Health-Experte plädiert dafür, herkömmliche Vorstellungen über Bord zu werfen und althergebrachte Verfahren und Beziehungen neu zu denken.
Whole blood transcriptional responses of very preterm infants during late-onset sepsis (2020)

Blood responses in very preterm infants with LOS are characterised by altered host immune responses that appear to reflect unbalanced immuno-metabolic homeostasis.
Effect of Lysolecithin Supplementation to Low-energy Broiler Diets on Performance and Subsequent Cost-benefit Analysis (2021)

The use of lysolecithin as an emulsifier in the diet of chickens could improve the growth performance. Its commercial application in broiler diets containing medium to high levels of added oil is increasingly adopted. However, few studies have assessed the impact of lysolecithin supplementation in diets formulated with no added oil. Therefore, this study aimed to compare two feeding diets based on commercial low-energy diets with no added oil, with or without a nutrient absorption enhancer based on lysolecithin (LEX). The performance was recorded on days 7, 14, 21, and 28. The net benefit per chicken of LEX supplementation was determined across a range of cost and performance scenarios. At slaughter, average body weight and feed conversion ratio were significantly improved in LEX-treated chickens, compared to non-treated chickens. The net benefit per chicken of LEX supplementation was 0.023 under representative market conditions and remained profitable under all considered scenarios. In conclusion, the application of absorption enhancers based on lysolecithin could improve the performance and profitability of broiler production, even in low energy-dense diets formulated with no added oil.
Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS (2018)

Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).
Molecular Imaging of Drug-Modulated Protein-Protein Interactions in Living Subjects (2004)

Networks of protein interactions mediate cellular responses to environmental stimuli and direct the execution of many different cellular functional pathways. Small molecules synthesized within cells or recruited from the external environment mediate many protein interactions. The study of small molecule-mediated interactions of proteins is important to understand abnormal signal transduction pathways in cancer and in drug development and validation. In this study, we used split synthetic renilla luciferase (hRLUC) protein fragment-assisted complementation to evaluate heterodimerization of the human proteins FRB and FKBP12 mediated by the small molecule rapamycin. The concentration of rapamycin required for efficient dimerization and that of its competitive binder ascomycin required for dimerization inhibition were studied in cell lines. The system was dually modulated in cell culture at the transcription level, by controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis factor alpha, and at the interaction level, by controlling the concentration of the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera. This split reporter system can be used to efficiently screen small molecule drugs that modulate protein-protein interactions and also to assess drugs in living animals. Both are essential steps in the preclinical evaluation of candidate pharmaceutical agents targeting protein-protein interactions, including signaling pathways in cancer cells.
Dynamic Links and Evolutionary History in Simulated Gene Regulatory Networks (2010)

In this chapter, we describe the use of evolutionary methods for the in silico generation of artificial gene regulatory networks (GRNs). These usually serve as models for biological networks and can be used for enhancing analysis methods in biology. We clarify our motivation in adopting this strategy by showing the importance of detailed knowledge of all processes, especially the regulatory dynamics of interactions undertaken during gene expression. To illustrate how such a methodology works, two different approaches to the evolution of small-scale GRNs with specified functions, are briefly reviewed and discussed. Thereafter, we present an approach to evolve medium sized GRNs with the ability to produce stable multi-cellular growth. The computational method employed allows for a detailed analysis of the dynamics of the GRNs as well as their evolution. We have observed the emergence of negative feedback during the evolutionary process, and we suggest its implication to the mutational robustness of the regulatory network which is further supported by evidence observed in additional experiments.
Control of Ablation Depth and Surface Structure in P3 Scribing of Thin-Film Solar Cells by a Picosecond Laser (2014)

In this paper, precise P3 scribing of thin-film solar cells (AZO/CIGS/Mo/Glass) via a picosecond laser is investigated. A parametric study is carried out for P3 scribing to study the effects of laser fluence and overlap ratio on ablation depth and slot quality, supported by the numerical prediction using a two-temperature model. The optimum scribing conditions are determined, and the potential processing speed is increased. Laser induced periodic surface structures are also presented after the scribing process, which can potentially enhance the absorption of the cell surface and consequently increase the cell efficiency.
Accelerated Scaling to Rapid Open-Air Fabrication of Durable Perovskite Solar Modules (2021)

By using an ultra-fast scalable open-air plasma deposition technique to deposit the perovskite layer and combining that with monolithic scribing, we are able to achieve high efficiency and large area perovskite solar modules.
α-Alkylation of Aldehydes by Combining Transition-Metal and Organocatalysis (2006)

A catalytic, intermolecular allylic α-alkylation of aldehydes and cyclic ketones employing enamine intermediates is presented. Initial experiments towards an organocatalytic, intermolecular alkylation using alkyl halides proved futile, since the amine catalyst was N-alkylated itself. However, when electrophilic π-complexes of palladium, generated in a second catalytic reaction, are present, the desired α-alkylation proceeds smoothly. The reaction was found to be highly regioselective in case of substituted allylic acetates and carbonates, and it gives good to high yields. Moreover, an asymmetric version of this reaction is presented. This variant achieves good enantiomeric excesses, yet so far only poor yields and is currently under investigation.
End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts (2013)

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy and waste minimization is described. Combining a 1 : 1 molar ratio of the two starting material streams (chlorodiphenylmethane and N,N-dimethylaminoethanol) in the absence of additional solvent at high temperature gives the target compound directly as a molten salt (ionic liquid above 168 °C) in high yield. This represents the first example of continuous active pharmaceutical ingredient (API) production in this manner. Six of the twelve principles of green chemistry as defined by the American Chemical Society are achieved, most prominently waste minimization and atom economy.
Abstract PR10: Serine biosynthesis from glucose regulates folate availability (2016)

Abstract It has been established that de novo serine biosynthesis is important for some cancers. We have previously shown that phosphoglycerate dehydrogenase (PHGDH), the enzyme responsible for catalyzing the first step in glycolytic serine biosynthesis, is amplified in certain cancers, including breast cancer and melanoma. Knockdown of PHGDH results in decreased proliferation of PHGDH-amplified cells, demonstrating a dependence on PHDGH in these cells; however, it has not been possible to rescue this defect with exogenous serine, suggesting that glycolytic serine biosynthesis has an alternate function in cells. Here we have investigated four mutually exclusive hypotheses each consistent with the inability of serine to rescue decreased glycolytic serine biosynthesis: 1: There exists an alternative function of PHGDH; 2: Pathway activity is important for TCA cycle anapleurosis; 3: Metabolic channeling of de novo serine; and 4: A unique product of this pathway other than serine is critical for proliferation. Using a combination of genetic and biochemical approaches, we show that flux through the serine biosynthesis pathway is required for cytosolic serine-glycine conversion via serine hydroxymethyltransferase 1 (SHMT1). In many cells flux through SHMT1 occurs in the glycine-to-serine direction, including PHDGH-dependent cell lines, and loss of PHGDH activity results in wasting of folates from the one-carbon pool to make serine. This reduces availability of one-carbon units in the folate pool for nucleotide biosynthesis, resulting in S-phase arrest and eventual cell death. These data link serine biosynthesis from glucose with the regulation of one-carbon folate metabolism, and provide an explanation for why cancer cells are dependent on de novo serine production even when serine is abundant. Citation Format: Caroline A. Lewis, Brian P. Fiske, Michael E. Pacold, Aaron M. Hosios, Katherine R. Mattaini, David M. Sabatini, Matthew G. Vander Heiden. Serine biosynthesis from glucose regulates folate availability. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR10.
Discovery of an in Vivo Tool to Establish Proof-of-Concept for MAP4K4-Based Antidiabetic Treatment (2015)

Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be a viable target for antidiabetic drugs. As part of the evaluation of MAP4K4 as a novel antidiabetic target, a tool compound, 16 (PF-6260933) and a lead 17 possessing excellent kinome selectivity and suitable properties were delivered to establish proof of concept in vivo. The medicinal chemistry effort that led to the discovery of these lead compounds is described herein together with in vivo pharmacokinetic properties and activity in a model of insulin resistance.
The Role of Elastases Secreted by Fibroblasts in Wrinkle Formation: Implication Through Selective Inhibition of Elastase Activity¶ (2001)

We have previously demonstrated that decreases in skin elasticity, accompanied by increases in the tortuosity of elastic fibers, are important early events in wrinkle formation. In order to study the role of elastases in the degeneration of elastic fibers during wrinkle formation we examined the effects of an inhibitor of skin fibroblast elastase, N-phenethylphosphonyl-L-leucyl-L-tryptophane (NPLT), on wrinkle formation in hairless mice skin following UV irradiation. Dorsal skins of hairless mice were exposed daily to UV light for 18 weeks at doses of 65-95 mJ/cm2 and treated topically with 100 microL of 1 mM NPLT immediately after each UV irradiation. Wrinkles on dorsal skins were evaluated from week 6 through week 18. The daily exposure of mouse skin to UV light with less than 1 minimal erythemal dose significantly enhanced the activity of elastase in the exposed skin by week 4, and the elevated levels of elastase activity were significantly reduced by the in vitro incubation with NPLT in a dose-dependent manner to a level similar to that in unexposed mice skin, indicating that NPLT can efficiently inhibit the UV-inducible elastase activity. Topical application of NPLT significantly suppressed wrinkle formation when compared with vehicle controls by week 15 of treatment (P < 0.05). Histochemistry of elastic fibers with Orcein staining demonstrated that there were no obvious decreases of the fine elastic fibers in UV-exposed NPLT-treated skin in contrast to their marked decreases in the UV-exposed vehicle-treated skin. These findings suggest that skin fibroblast elastase plays a decisive role in wrinkle formation through the degeneration of elastic fiber.
Development of functional cytokines as novel mucosal vaccine adjuvants (2010)

粘膜ワクチンは，全身面と粘膜面の二重の防御免疫を誘導可能な唯一の方法であることから，新興・再興感染症に対する予防法として期待されている．しかし，生ワクチンを除いて，いまだ実用的な粘膜ワクチンは皆無であり，その実現に向けては，有効かつ安全なアジュバント開発が必要とされている．筆者らが開発を進めている機能性サイトカインは，防御免疫を効率よく誘導しうることから，粘膜アジュバントとしての可能性が大きく期待されるものである．本稿では，粘膜ワクチンおよびアジュバント開発の現状と，筆者らの成果について概説する．
Socioeconomic Status and Wait Times for Pediatric Surgery in Canada (2014)

SES does not predict the timeliness of delivery for pediatric surgical services.
Direct Hydrogenation of Biomass‐Derived Butyric Acid to n‐Butanol over a Ruthenium–Tin Bimetallic Catalyst (2014)

Catalytic hydrogenation of organic carboxylic acids and their esters, for example, cellulosic ethanol from fermentation of acetic acid and hydrogenation of ethyl acetate is a promising possibility for future biorefinery concepts. A hybrid conversion process based on selective hydrogenation of butyric acid combined with fermentation of glucose has been developed for producing biobutanol. ZnO-supported Ru-Sn bimetallic catalysts exhibits unprecedentedly superior performance in the vapor-phase hydrogenation of biomass-derived butyric acid to n-butanol (>98% yield) for 3500 h without deactivation.