gebhart/patrepeval huggingface dataset:
Synthesis of 3‘-Deoxy-3‘-difluoromethyl Azanucleosides from trans-4-Hydroxy-l-proline (2005)

[reaction: see text] Two strategies were tried to synthesize 3'-deoxy-3'-difluoromethyl azanucleosides. After the failure of the first route, the key intermediate 12 from trans-4-hydroxyproline 7 in 8 steps was stereoselectively prepared. The alcohol 12 was subjected to selective protection, oxidation, and difluoromethylenation to afford the fluorinated compound 18, whose hydrogenation was then systematically investigated. After a series of transformations of protecting groups, the resultant compounds 22 and 23 were oxidized to the desired lactams 24 and 25, which were successfully utilized to synthesize our target molecules, 3'-deoxy-3'-difluoromethyl azanucleosides 33, 34a, 34b, and 35.
Akt-Mediated YB-1 Phosphorylation Activates Translation of Silent mRNA Species (2005)

YB-1 is a broad-specificity RNA-binding protein that is involved in regulation of mRNA transcription, splicing, translation, and stability. In both germinal and somatic cells, YB-1 and related proteins are major components of translationally inactive messenger ribonucleoprotein particles (mRNPs) and are mainly responsible for storage of mRNAs in a silent state. However, mechanisms regulating the repressor activity of YB-1 are not well understood. Here we demonstrate that association of YB-1 with the capped 5' terminus of the mRNA is regulated via phosphorylation by the serine/threonine protein kinase Akt. In contrast to its nonphosphorylated form, phosphorylated YB-1 fails to inhibit cap-dependent but not internal ribosome entry site-dependent translation of a reporter mRNA in vitro. We also show that similar to YB-1, Akt is associated with inactive mRNPs and that activated Akt may relieve translational repression of the YB-1-bound mRNAs. Using Affymetrix microarrays, we found that many of the YB-1-associated messages encode stress- and growth-related proteins, raising the intriguing possibility that Akt-mediated YB-1 phosphorylation could, in part, increase production of proteins regulating cell proliferation, oncogenic transformation, and stress response.
Emerging antiobesity drugs (2003)

The healthcare burden that the obesity epidemic now poses in highly significant, in part due to increased risk of secondary chronic diseases such as hypertension. A lack of physical activity and high fat diets are major factors contributing to this condition. However, increasingly apparent is the genetic predisposition of individuals and ethnic groups to obesity. Present treatment strategies are currently inadequate and unlikely to have a major effect on the future prevalence of obesity. To slow the obesity epidemic, the source needs to be tackled now through fundamental research into the mechanisms by which obesity is manifest, and education on the risks and how to prevent it. This article will describe current and emerging treatments for obesity and review the recent advances in research that may provide the antiobesity treatments of the future. Research into obesity has escalated at considerable pace, catalysed by the discovery of the obese gene product leptin. Leptin is secreted by adipose tissue and acts via specific receptors in the brain to engage central neural pathways involved in regulating energy homeostasis. Since this discovery, numerous significant advances have been made in our understanding of how the brain integrates and responds to central and peripheral signals involved in maintaining energy homeostasis, and how disruption of these signalling mechanisms can manifest as obesity. As a consequence of these findings, numerous potential sites for therapeutic intervention into this condition have and are materializing. The aim of this review is to highlight current treatment strategies for obesity, recent advances in our understanding of the central neural control of energy balance, and what the authors consider to be the most promising targets for the development of novel antiobesity drugs in the future. Thus, the review focuses on leptin, neuropeptide Y, melanocortin and ghrelin signalling at the level of the CNS, and strategies targeting the sympathetic innervation of fat cells at the periphery.
Oligonucleotide-Based Fluorescence Probe for Sensitive and Selective Detection of Mercury(II) in Aqueous Solution (2008)

In this paper we unveil a new homogeneous assayusing TOTO-3 and the polythymine oligonucleotide T 33for the highly selective and sensitive detection of Hg (2+) in aqueous solution. The fluorescence of TOTO-3 is weak in the absence or presence of randomly coiled T 33. After T 33 interacts specifically with Hg (2+) ions through T-Hg (2+)-T bonding, however, its conformation changes to form a folded structure that preferably binds to TOTO-3. As a result, the fluorescence of a mixture of T 33 and TOTO-3 increases in the presence of Hg (2+). Our data from fluorescence polarization spectroscopy, capillary electrophoresis with laser-induced fluorescence detection, circular dichroism spectroscopy, and melting temperature measurements confirm the formation of folded T 33-Hg (2+) complexes. Under optimum conditions, the TOTO-3/T 33 probe exhibited a high selectivity (>or=265-fold) toward Hg (2+) over other metal ions, with a limit of detection of 0.6 ppb. We demonstrate the practicality of this TOTO-3/T 33 probe for the rapid determination of Hg (2+) levels in pond water and in batteries. This approach offers several advantages, including rapidity (<15 min), simplicity (label-free), and low cost.
Inhibition of the Interferon- Inducible Protein Kinase PKR by HCV E2 Protein (1999)

Most isolates of hepatitis C virus (HCV) infections are resistant to interferon, the only available therapy, but the mechanism underlying this resistance has not been defined. Here it is shown that the HCV envelope protein E2 contains a sequence identical with phosphorylation sites of the interferon-inducible protein kinase PKR and the translation initiation factor eIF2alpha, a target of PKR. E2 inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth. This interaction of E2 and PKR may be one mechanism by which HCV circumvents the antiviral effect of interferon.
The CD200 Receptor Is a Novel and Potent Regulator of Murine and Human Mast Cell Function (2005)

Abstract CD200R is a member of the Ig supergene family that is primarily expressed on myeloid cells. Recent in vivo studies have suggested that CD200R is an inhibitory receptor capable of regulating the activation threshold of inflammatory immune responses. Here we provide definitive evidence that CD200R is expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. CD200R-mediated inhibition of FcεRI activation was observed both in vitro and in vivo and did not require the coligation of CD200R to FcεRI. Unlike the majority of myeloid inhibitory receptors, CD200R does not contain a phosphatase recruiting inhibitory motif (ITIM); therefore, we conclude that CD200R represents a novel and potent inhibitory receptor that can be targeted in vivo to regulate mast cell-dependent pathologies.
Structural Basis for Hydroxycholesterols as Natural Ligands of Orphan Nuclear Receptor RORγ (2010)

The retinoic acid-related orphan receptor gamma (RORgamma) has important roles in development and metabolic homeostasis. Although the biological functions of RORgamma have been studied extensively, no ligands for RORgamma have been identified, and no structure of RORgamma has been reported. In this study, we showed that hydroxycholesterols promote the recruitment of coactivators by RORgamma using biochemical assays. We also report the crystal structures of the RORgamma ligand-binding domain bound with hydroxycholesterols. The structures reveal the binding modes of various hydroxycholesterols in the RORgamma pocket, with the receptors all adopting the canonical active conformation. Mutations that disrupt the binding of hydroxycholesterols abolish the constitutive activity of RORgamma. Our observations suggest an important role for the endogenous hydroxycholesterols in modulating RORgamma-dependent biological processes.
Pulse exposure of haematopoietic grafts to prostaglandin E2in vitro facilitates engraftment and recovery (2011)

These studies demonstrate that short-term PGE(2) exposure enhances HSC function and supports the concept of utility of PGE(2) as an ex vivo strategy to improve function of haematopoietic grafts, particularly those where HSC numbers are limited.
Standardized Shrinking LORETA-FOCUSS (SSLOFO): A New Algorithm for Spatio-Temporal EEG Source Reconstruction (2005)

This paper presents a new algorithm called Standardized Shrinking LORETA-FOCUSS (SSLOFO) for solving the electroencephalogram (EEG) inverse problem. Multiple techniques are combined in a single procedure to robustly reconstruct the underlying source distribution with high spatial resolution. This algorithm uses a recursive process which takes the smooth estimate of sLORETA as initialization and then employs the re-weighted minimum norm introduced by FOCUSS. An important technique called standardization is involved in the recursive process to enhance the localization ability. The algorithm is further improved by automatically adjusting the source space according to the estimate of the previous step, and by the inclusion of temporal information. Simulation studies are carried out on both spherical and realistic head models. The algorithm achieves very good localization ability on noise-free data. It is capable of recovering complex source configurations with arbitrary shapes and can produce high quality images of extended source distributions. We also characterized the performance with noisy data in a realistic head model. An important feature of this algorithm is that the temporal waveforms are clearly reconstructed, even for closely spaced sources. This provides a convenient way to estimate neural dynamics directly from the cortical sources.
Synthesis and Evaluation of Poly(hexamethylene-urethane) and PEG-Poly(hexamethylene-urethane) and Their Cholesteryl Oleyl Carbonate Composites for Human Blood Biocompatibility (2011)

Two new urethane-based acrylates (UAA and PEG-UAA) were synthesized as polymer blocks. The chemical composition of the two monomers was confirmed by IR and NMR. After cross-linking these blockers by radical polymerization, "hexamethylene PU" [poly(hexamethylene-urethane)] and "PEG-hexamethylene PU" [PEG-poly(hexa-methylene-urethane)] were obtained. The platelet adhesion and platelet activation of these polymers were evaluated in the presence of Platelet Rich Plasma (PRP) blood. The relative blood clotting indexes of the polymers were determined to measure their capability of reducing thrombogenicity. The hemolysis of red blood cells was also assessed to examine the haemocompatibility of the polymers. The hexamethylene PU and PEG-hexamethylene PU showed less platelet adhesion, platelet activation, blood clotting and hemolysis than a commercial PU (Tecoflex). The liquid crystal molecule, cholesteryl oleyl carbonate (COC), showed further improved biocompatibility to human blood, after COC was embedded in the PU polymers. PEG-hexamethylene PU + 10% COC demonstrated the best activity in reducing thrombogenicity and the best haemocompatibility. The inclusion of PEG segments into the PEG-UAA structure increased its hydrophilicity. The methylene bis(cyclohexyl) segments in Tecoflex PU decreased haemocompatibility. These observations are in good agreement with performed contact angle measurements. The PEG-hexamethylene PU loaded with COC might be a promising material for applications in bioengineering.
A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells (2006)

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.
Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan (2020)

A mysterious outbreak of atypical pneumonia in late 2019 was traced to a seafood wholesale market in Wuhan of China. Within a few weeks, a novel coronavirus tentatively named as 2019 novel coronavirus (2019-nCoV) was announced by the World Health Organization. We performed bioinformatics analysis on a virus genome from a patient with 2019-nCoV infection and compared it with other related coronavirus genomes. Overall, the genome of 2019-nCoV has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. The phylogenetic trees of their orf1a/b, Spike, Envelope, Membrane and Nucleoprotein also clustered closely with those of the bat, civet and human SARS coronaviruses. However, the external subdomain of Spike's receptor binding domain of 2019-nCoV shares only 40% amino acid identity with other SARS-related coronaviruses. Remarkably, its orf3b encodes a completely novel short protein. Furthermore, its new orf8 likely encodes a secreted protein with an alpha-helix, following with a beta-sheet(s) containing six strands. Learning from the roles of civet in SARS and camel in MERS, hunting for the animal source of 2019-nCoV and its more ancestral virus would be important for understanding the origin and evolution of this novel lineage B <i>betacoronavirus</i>. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection.
Use of Iodoacetylene as a Dipolarphile in the Synthesis of 5-Iodoisoxazole Derivatives (2001)

Iodoacetylene 1 was prepared in situ from the reactions of ethynylmagnesium bromide or tributyl(ethynyl)tin with iodine. It was used as a dipolarphile in the [2 + 3] cyclization reaction with 1,3-dipolar nitrile oxide derivatives to produce 2-(5-iodoisoxazol-3-yl)pyridine 2 and 3-(4-fluorophenyl)-5-iodoisoxazole 8 in good yield (70-90%). Subsequently, several 5-substituted isoxazole derivatives 3 were obtained by Pd-catalyzed reactions. [reaction: see text]
Chemokines as pain mediators and modulators (2008)

Our results suggest that specific chemokines/receptors are upregulated by sensory neurons following peripheral nerve injury and appear to participate in neural signal processing leading to chronic pain states. Taken together, chemokines and their receptors are potential targets for development of novel therapeutics.
The Saccharomyces cerevisiae Genome Contains Functional and Nonfunctional Copies of Transposon Ty1 (1988)

Saccharomyces cerevisiae Ty elements are transposons closely related to retroviruses. The DNA sequence of a functional Ty element (TyH3) is presented. The long terminal repeat sequences are different, suggesting that TyH3 is a recombinant Ty element. A chromosomal Ty element near the LYS2 gene, Ty173, was found to be nonfunctional, even though it has no detectable insertions or deletions. The defect in Ty173 transposition is caused by a missense mutation giving rise to a Leu-to-Ile substitution in the TYB (pol) open reading frame. Several chromosomal Ty elements carry this lesion in their DNA, indicating that nonfunctional Ty elements are common in the yeast genome.
Cytokine mRNA profiles in Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorders (1999)

Cytokine mRNA patterns were analyzed in 11 post-transplant lymphoproliferative disorder (PTLD) specimens using qualitative reverse-transcriptase polymerase chain reaction (RT-PCR). In each case, a pattern of IL2-, IFN gamma-, IL4+, IL10+ was seen. A similar pattern was observed in a spleen sample from 1 patient with contemporaneous PTLD elsewhere. Semiquantitative RT-PCR for cytokine message was performed using RNA from bronchoalveolar lavage (BAL) specimens obtained from 2 patients with pulmonary PTLD. In both cases, IL4 message predominated. Reduction of message coincided with resolution of the tumors. The pattern differed from that seen in 1 patient with acute pulmonary rejection, in which RT-PCR of BAL cells showed predominance of IL6 and IFN gamma. We conclude that at least some PTLDs exist within a T-helper cell type 2 (Th2)-like cytokine microenvironment. The presence of a similar mRNA pattern in an extratumoral specimen at the time of PTLD suggests that it may reflect a systemic phenomenon. Disappearance of this pattern following PTLD resolution indicates its dynamic nature and is consistent with the hypothesis that specific cytokines contribute to the development of PTLDs.
Desferrithiocin Analogues and Nephrotoxicity (2008)

The syntheses of a series of 4'-O-alkylated ( S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazole-carboxylic acid and 5'-O-alkylated ( S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, log P(app), is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of log P(app) versus ICE in a rodent model for both the 4'-O-alkylated 2,4-dihydroxy and 5'-O-alkylated 2,5-dihydroxy series produced an inverse parabola plot with r(2) values of 0.97 and 0.81, respectively. The plots indicate an optimum log P(app)/ICE relationship. Because of the nature of the data spread in the 4'-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?
Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men (2004)

Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin (r = 0.36-0.46, P < 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r = -0.37-0.40, P < 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU (P < 0.05). Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for. We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism.
Effect of peptide conformation on membrane permeability (2003)

The effect of peptide conformational constraint on the peptide permeation across the model membranes was examined by determining the permeability of pairs of cyclic and acyclic peptides related to c[d-Pen2, d-Pen5] enkephalin (DPDPE). The peptides were cyclized by formation of an intramolecular disulfide bridge between the second and fifth residues composed of either d-penicillamine or cysteine. In each case the acyclic peptide was three to seven times more permeable than corresponding cyclic peptide. The possibility that the differences in permeability of cyclic and acyclic peptides is based on the greater conformational freedom of the acyclic peptides in the presence of membrane was examined in more detail by isothermal titration calorimetric studies of Trp6-DPDPE and its acyclic analog. The membrane binding of the acyclic peptide is a more exothermic process than binding of its cyclic Trp6-DPDPE. The transfer of acyclic peptide from water to membrane is an enthalpy driven process, whereas the transfer of the cyclic peptide is driven by entropy.
GH and insulin affect fatty acid synthase activity in isolated porcine adipocytes in culture without any modifications of sterol regulatory element binding protein-1 expression (2004)

The ability of GH to decrease fatness and insulin-regulated events such as lipogenic enzyme activities is well known in pigs. Nevertheless, the precise mechanism underlying these actions has not been elucidated yet. Expression of the transcription factor sterol regulatory element binding protein (SREBP)-1 has been reported as a key mediator of insulin action in rat hepatocytes and adipose cell lines. The present study aimed to determine whether the regulation of lipogenesis by GH and/or insulin in porcine adipocytes also involved SREBP-1. Isolated adipocytes, obtained from perirenal or s.c. adipose tissue samples of female pigs (51+/-0.4 kg; n=17), were cultured in serum-free medium in the absence or presence of these hormones for up to 4 days. Glucose incorporation and fatty acid synthase activity were increased by insulin in a dose-dependent manner in adipocytes of both sites. The increase was maximal at 1.7 and 17 nM in s.c. and perirenal adipocytes respectively, suggesting inter-depot differences in the regulation of lipogenesis by insulin. These insulin-stimulated events were decreased by GH (1 nM). No change in SREBP-1 mRNA levels was observed in response to GH and/or insulin. Taken together, these data indicate that the regulation of lipogenesis by insulin and GH appears to not involve changes in SREBP-1 mRNA levels in porcine adipocytes.
The release of gentamicin from polymethylmethacrylate beads. An experimental and pharmacokinetic study (1978)

Gentamicin incorporated in beads of polymethylmethacrylate has been shown capable of being released over a period of several months in concentrations sufficiently high to control most pathogens. The therapeutic efficacy of such beads has been demonstrated in a model of osteomyelitis of the femur in the dog. Good tolerance has been shown, both in the animal model and in tissue cultures. In forty-one patients with infection of either bone or soft tissue, mainly of the lower limb, the findings were similar. The concentrations in serum and urine were low, which excludes side-effects. The insertion of gentamicin-PMMA beads may prove to be a valuable new form of local antibiotic therapy.
[Isolation and structural determination of 8-hydroxy damnacanthol-omega-ethyl ether from the root Damnacanthus subspinosus Hand-Mazz]. (1984)

The structure of a new anthraquinone isolated from the root of Damnacanthus subspinosus Hand-Mazz (Rubiaceae) was found to be 3,8-dihydroxy2-ethoxymethyl-1-methoxyanthraquinone Ⅳ by means of NMR, IR, UV and MS analyses. This anthraquinone is named 8-hydroxydamnacanthol-ω-ethyl ether. The compound was found to be active against Hela cells in culture.