gebhart/patrepeval huggingface dataset:
Rational Synthesis of β-Substituted Chlorin Building Blocks (2000)

Chlorins bearing synthetic handles at specific sites about the perimeter of the macrocycle constitute valuable building blocks. We previously developed methodology for preparing meso-substituted chlorin building blocks and now present methodology for preparing several complementary beta-substituted chlorin building blocks. The chlorins bear one or two beta substituents, one meso substituent, a geminal dimethyl group to lock in the chlorin hydrogenation level, and no flanking meso and beta substituents. The synthesis involves convergent joining of an Eastern half and a Western half. New routes have been developed to two beta-substituted bromo-dipyrromethane monocarbinols (Eastern halves). A new beta-substituted Western half was prepared following the method for preparing an unsubstituted Western half (3,3-dimethyl-2,3-dihydrodipyrrin). Chlorin formation is achieved by a two-flask process of acid-catalyzed condensation followed by metal-mediated oxidative cyclization. beta-Substituted chlorins have been prepared in 18-24% yield bearing a 4-iodophenyl group at the 8-position, a 4-iodophenyl group or a 4-[2-(trimethylsilyl)ethynyl]phenyl group at the 12-position, and a 4-iodophenyl group and a 4-[2-(trimethylsilyl)ethynyl]phenyl group at diametrically opposed beta-positions (2, 12). The latter building block makes possible the stepwise construction of linear multi-chlorin architectures. The chlorins exhibit typical absorption and fluorescence spectra. A systematic shift in the absorption maximum (637-655 nm for the free base chlorins, 606-628 nm for the zinc chlorins) and intensity of the chlorin Q(y)() band (epsilon up to 79 000 M(-)(1) cm(-)(1)) is observed depending on the location of the substituents. The characteristic spectral features and location of substituents in defined positions make these chlorins well suited for a variety of applications in biomimetic and materials chemistry.
Chiral Imidazolylidine Ligands for Asymmetric Hydrogenation of Aryl Alkenes (2001)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTChiral Imidazolylidine Ligands for Asymmetric Hydrogenation of Aryl AlkenesMark T. Powell, Duen-Ren Hou, Marc C. Perry, Xiuhua Cui, and Kevin BurgessView Author Information Department of Chemistry, Texas A & M University PO Box 30012, College Station, Texas 77842-3012 Cite this: J. Am. Chem. Soc. 2001, 123, 36, 8878–8879Publication Date (Web):August 18, 2001Publication History Received12 April 2001Revised14 June 2001Published online18 August 2001Published inissue 1 September 2001https://pubs.acs.org/doi/10.1021/ja016011phttps://doi.org/10.1021/ja016011prapid-communicationACS PublicationsCopyright © 2001 American Chemical SocietyRequest reuse permissionsArticle Views3730Altmetric-Citations235LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Group 15 compounds,Hydrocarbons,Hydrogenation,Ligands,Stereoselectivity Get e-Alerts
Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction (2001)

These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.
High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment (2000)

Rapid imaging by antitumor antibodies has been limited by the prolonged targeting kinetics and clearance of labeled whole antibodies. Genetically engineered fragments with rapid access and high retention in tumor tissue combined with rapid blood clearance are suitable for labeling with short-lived radionuclides, including positron-emitting isotopes for positron-emission tomography (PET). An engineered fragment was developed from the high-affinity anticarcinoembryonic antigen (CEA) monoclonal antibody T84.66. This single-chain variable fragment (Fv)-C(H)3, or minibody, was produced as a bivalent 80 kDa dimer. The macrocyclic chelating agent 1,4,7, 10-tetraazacyclododecane-N,N',N", N"'-tetraacetic acid (DOTA) was conjugated to the anti-CEA minibody for labeling with copper-64, a positron-emitting radionuclide (t(1/2) = 12.7 h). In vivo distribution was evaluated in athymic mice bearing paired LS174T human colon carcinoma (CEA positive) and C6 rat glioma (CEA negative) xenografts. Five hours after injection with (64)Cu-DOTA-minibody, microPET imaging showed high uptake in CEA-positive tumor (17.9% injected dose per gram +/- 3.79) compared with control tumor (6.0% injected dose per gram +/- 1.0). In addition, significant uptake was seen in liver, with low uptake in other tissues. Average target/background ratios relative to neighboring tissue were 3-4:1. Engineered antibody fragments labeled with positron-emitting isotopes such as copper-64 provide a new class of agents for PET imaging of tumors.
A Guide RNA Sequence Design Platform for the CRISPR/Cas9 System for Model Organism Genomes (2013)

Cas9/CRISPR has been reported to efficiently induce targeted gene disruption and homologous recombination in both prokaryotic and eukaryotic cells. Thus, we developed a Guide RNA Sequence Design Platform for the Cas9/CRISPR silencing system for model organisms. The platform is easy to use for gRNA design with input query sequences. It finds potential targets by PAM and ranks them according to factors including uniqueness, SNP, RNA secondary structure, and AT content. The platform allows users to upload and share their experimental results. In addition, most guide RNA sequences from published papers have been put into our database.
Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia (2013)

The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
True molecular resolution in tapping-mode atomic force microscopy with high-resolution probes (2004)

True molecular resolution was demonstrated in tapping-mode atomic force microscopy study of polydiacetylene crystal using carbon probes with an extremity of ∼1 nm. Images of the bc plane of the crystal, which were obtained at ambient conditions, reproduce the crystallographic molecular arrangement. The image features directly correspond to the edges of the individual side groups of the polymer chains, which form the crystal surface. In the consecutive images, the molecular-size defects have been observed on this surface as an additional proof of the true molecular resolution achieved with the probes.
GeoNotes: Social and Navigational Aspects of Location-Based Information Systems (2001)

Location-based information systems allow the user to access information in relation to the user's position in geographical space. This paper outlines navigational and social aspects of such systems. It is argued that location-based systems must allow users to participate as content providers in order to achieve a social and dynamic information space. Moreover, as these systems allow commercial and private users to annotate space with information on a mass-scale, information filtering techniques will become essential in order to prevent information overload and user disturbance. We present a number of content-based and social filtering techniques to support this. We discuss implications for implementation and we describe a system (GeoNotes), which takes some of these aspects into account.
Deep learning for digital pathology image analysis: A comprehensive tutorial with selected use cases (2016)

This paper represents the largest comprehensive study of DL approaches in DP to date, with over 1200 DP images used during evaluation. The supplemental online material that accompanies this paper consists of step-by-step instructions for the usage of the supplied source code, trained models, and input data.
The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand‐binding domain (2009)

The effect of retinoid X receptor (RXR) antagonists on the conformational exchange of the RXR ligand-binding domain (LBD) remains poorly characterized. To address this question, we used nuclear magnetic resonance spectroscopy to compare the chemical shift perturbations induced by RXR antagonists and agonists on the RXRalpha LBD when partnered with itself as a homodimer and as the heterodimeric partner with the peroxisome proliferator-activated receptor gamma (PPARgamma) LBD. Chemical shift mapping on the crystal structure showed that agonist binding abolished a line-broadening effect caused by a conformational exchange on backbone amide signals for residues in helix H3 and other regions of either the homo- or hetero-dimer, whereas binding of antagonists with similar binding affinities failed to do so. A lineshape analysis of a glucocorticoid receptor-interacting protein 1 NR box 2 coactivator peptide showed that the antagonists enhanced peptide binding to the RXRalpha LBD homodimer, but to a lesser extent than that enhanced by the agonists. This was further supported by a lineshape analysis of the RXR C-terminal residue, threonine 462 (T462) in the homodimer but not in the heterodimer. Contrary to the agonists, the antagonists failed to abolish a line-broadening effect caused by a conformational exchange on the T462 signal corresponding to the RXRalpha LBD-antagonist-peptide ternary complex. These results suggest that the antagonists lack the ability of the agonists to shift the equilibrium of multiple RXRalpha LBD conformations in favor of a compact state, and that a PPARgamma LBD-agonist complex can prevent the antagonist from enhancing the RXRalpha LBD-coactivator binding interaction.
2'-O-methyl-modified phosphorothioate antisense oligonucleotides have reduced non-specific effects in vitro (2004)

Antisense oligodeoxynucleotides (ODNs) have biological activity in treating various forms of cancer. The antisense effects of two types of 20mer ODNs, phosphorothioate-modified ODNs (S-ODNs) and S-ODNs with 12 2'-O-methyl groups (Me-S-ODNs), targeted to sites 109 and 277 of bcl-2 mRNA, were compared. Both types were at least as effective as G3139 (Genta, Inc.) in reducing the level of Bcl-2 protein in T24 cells following a 4 h transfection at a dose of 0.1 micro M. Circular dichroism spectra showed that both types formed A-form duplexes with the complementary RNA, and the melting temperatures were in the order of Me-S-ODN.RNA > normal DNA.RNA > S-ODN.RNA. In comparison with the S-ODN, the Me-S-ODN had reduced toxic growth inhibitory effects, was less prone to bind the DNA-binding domain A of human replication protein A, and was as resistant to serum nucleases. Neither type of oligomer induced apoptosis, according to a PARP-cleavage assay. Hybrids formed with Me-S-ODN sequences were less sensitive to RNase H degradation than those formed with S-ODN sequences. Despite this latter disadvantage, the addition of 2'-O-methyl groups to a phosphorothioate-modified ODN is advantageous because of increased stability of binding and reduced non-specific effects.
Dynamic changes in gene expression in vivo predict prognosis of tamoxifen-treated patients with breast cancer (2010)

Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.
Structural changes of tumor necrosis factor alpha associated with membrane insertion and channel formation. (1996)

Low pH enhances tumor necrosis factor alpha (TNF)-induced cytolysis of cancer cells and TNF-membrane interactions that include binding, insertion, and ion-channel formation. We have also found that TNF increases Na+ influx in cells. Here, we examined the structural features of the TNF-membrane interaction pathway that lead to channel formation. Fluorometric studies link TNF's acid-enhanced membrane interactions to rapid but reversible acquisition of hydrophobic surface properties. Intramembranous photolabeling shows that (i) protonation of TNF promotes membrane insertion, (ii) the physical state of the target bilayer affects the kinetics and efficiency of TNF insertion, and (iii) binding and insertion of TNF are two distinct events. Acidification relaxes the trimeric structure of soluble TNF so that the cryptic carboxyl termini, centrally located at the base of the trimer cone, become susceptible to carboxypeptidase Y. After membrane insertion, TNF exhibits a trimeric configuration in which the carboxyl termini are no longer exposed; however, the proximal salt-bridged Lys-11 residues as well as regional surface amino acids (Glu-23, Arg-32, and Arg-44) are notably more accessible to proteases. The sequenced cleavage products bear the membrane-restricted photoreactive probe, proof that surface-cleaved TNF has an intramembranous disposition. In summary, the trimer's structural plasticity is a major determinant of its channel-forming ability. Channel formation occurs when cracked or partially splayed trimers bind and penetrate the bilayer. Reannealing leads to a slightly relaxed trimeric structure. The directionality of bilayer penetration conforms with x-ray data showing that receptor binding to the monomer interfaces of TNF poises the tip of the trimeric cone directly above the target cell membrane.
Introduction (1998)

Mozart's six string quartets dedicated to Joseph Haydn (K.387, K.421, K.428, K.458, K.464, K.465) are established keystones of the chamber music repertoire and frequently feature in concert programmes, broadcasts and recordings by the most prestigious professional ensembles. While brief accounts of these quartets have previously appeared in articles and books over the years, reflecting the changing agendas of several generations of musicologists and speaking to a diversity of readerships, no single book exists devoted to these seminal works.
High-peak-power (>1.2 MW) pulsed fiber amplifier (2006)

We report results from Yb-doped fiber amplifiers seeded with two microchip lasers having 0.38-ns and 2.3-ns pulse durations. The shorter duration seed resulted in output pulses with a peak power of >1.2 MW and pulse energy of 0.67 mJ. Peak power was limited by nonlinear processes that caused breakup and broadening of the pulse envelope as the pump power increased. The 2.3-ns duration seed laser resulted in output pulses with a peak power of >300 kW and pulse energy of >1.1 mJ. Pulse energies were limited by the onset of stimulated Brillouin scattering and ultimately by internal optical damage (fluences in excess of 400 J/cm<sup>2</sup> were generated). In both experiments, nearly diffraction-limited beam profiles were obtained, with M<sup>2</sup> values of <1.2. Preliminary results of a pulse-amplification model are in excellent agreement with the experimental results of the amplifiers operating in the low-to-moderate gain-depletion regime.
Nonlinear mixed effects modelling for the analysis of longitudinal body core temperature data in healthy volunteers (2016)

Many longitudinal studies have collected serial body core temperature (T c) data to understand thermal work strain of workers under various environmental and operational heat stress environments. This provides the opportunity for the development of mathematical models to analyse and forecast temporal T c changes across populations of subjects. Such models can reduce the need for invasive methods that continuously measure T c. This current work sought to develop a nonlinear mixed effects modelling framework to delineate the dynamic changes of T c and its association with a set of covariates of interest (e.g. heart rate, chest skin temperature), and the structure of the variability of T c in various longitudinal studies. Data to train and evaluate the model were derived from two laboratory investigations involving male soldiers who participated in either a 12 (N = 18) or 15 km (N = 16) foot march with varied clothing, load and heat acclimatisation status. Model qualification was conducted using nonparametric bootstrap and cross validation procedures. For cross validation, the trajectory of a new subject's T c was simulated via Bayesian maximum a posteriori estimation when using only the baseline T c or using the baseline T c as well as measured T c at the end of every work (march) phase. The final model described T c versus time profiles using a parametric function with its main parameters modelled as a sigmoid hyperbolic function of the load and/or chest skin temperature. Overall, T c predictions corresponded well with the measured data (root mean square deviation: 0.16 °C), and compared favourably with those provided by two recently published Kalman filter models.
Lung dysfunction causes systemic hypoxia in estrogen receptor β knockout (ERβ −/− ) mice (2006)

Estrogen receptor beta (ERbeta) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERalpha is not detectable in the adult lung. Lungs of adult female ERbeta knockout (ERbeta-/-) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ERbeta-/- mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ERbeta-/- mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ERbeta-/- mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1alpha and chemical adducts (with Hypoxyprobe), was evident in the heart, ventral prostate, periovarian sac, kidney, liver, and brain of ERbeta-/- mice under resting conditions. Furthermore, both male and female adult ERbeta-/- mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise. We conclude that ERbeta is necessary for the maintenance of the extracellular matrix composition in the lung and loss of ERbeta leads to abnormal lung structure and systemic hypoxia. Systemic hypoxia may be responsible for the reported left and right heart ventricular hypertrophy and systemic hypertension in ERbeta-/- mice.
Renin, Angiotensin II, and Adrenal Corticosteroid Relationships during Sodium Deprivation and Angiotensin Infusion in Normotensive and Hypertensive Man (1972)

The responses of plasma renin activity, plasma angiotensin II, plasma aldosterone, cortisol, and corticosterone to sodium deprivation and to angiotensin II infusion (100 ng/min) were measured in 8 normotensive patients and in 17 patients with essential hypertension. Following sodium deprivations, plasma renin activity rose from 0.513 ± 0.100 to 1.029 ± 0.124 ng/ml hour -1 in normotensive patients and from 0.406 ± 0.077 to 0.629 ± 0.059 ng/ml hour -1 in hypertensive patients. Plasma angiotensin II did not parallel changes in plasma renin activity: in normotensive patients plasma angiotensin II was unchanged by sodium deprivation (31.8 ± 6.0 compared with 30.1 ± 4.6 pg/ml), but in hypertensive patients it rose from 22.2 ± 3.4 to 36.4 ± 5.1 pg/ml. Plasma aldosterone rose equally in both groups following sodium deprivation (5.8 ± 1.3 to 15.3 ± 2.4 ng/100 ml for normotensive patients and 5.9 ± 1.4 to 14.4 ± 1.6 ng/100 ml for hypertensive patients) and angiotensin infusion (5.8 ± 1.3 to 10.4 ± 2.1 ng/100 ml in sodium-loaded normotensive patients, 15.3 ± 2.4 to 19.6 ± 3.6 ng/100 ml in sodium-deprived normotensive patients, 5.9 ± 1.4 to 11.4 ± 2.7 ng/100 ml in sodium-loaded hypertensive patients, and 14.4 ± 1.6 to 22.2 ± 2.6 ng/100 ml in sodium-deprived hypertensive patients). However, changes in endogenous plasma angiotensin II did not correlate with the rise in plasma aldosterone caused by sodium deprivation, and, despite much larger increases in plasma angiotensin II during angiotensin II infusion, plasma aldosterone showed smaller rises than those accompanying sodium deprivation. Plasma renin activity fell during angiotensin II infusion, in both groups of patients during both sodium loading and sodium deprivation, and, hence, the infusion constitutes a potent feedback inhibition of renin release in normotensive and hypertensive man. Plasma cortisol and corticosterone were unaltered by sodium deprivation but fell significantly with the angiotensin II infusion.