gebhart/patrepeval huggingface dataset:
An Antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) Inhibits Arthritis in the MRL-lpr Mouse Model (1997)

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.
Covariance analysis of motion-compensated frame differences (1999)

The second-order statistics of motion-compensated frame differences in a low-bit-rate hybrid video coding scheme with overlapped block motion compensation are investigated. Based on the empirical covariance sequence, an adequate compound covariance model is developed. The prediction gain for motion-compensated frame differences is evaluated, and the performance of the discrete cosine transform for interframe transform coding is discussed.
LTS SQUID sensor with a new configuration (1999)

We have developed highly sensitive SQUID-based magnetometers and gradiometers, fabricated in a standard Nb/AlOX/Nb technology. The SQUID itself is designed as a current sensor having an input coil and a feedback coil. The number of turns of the input coil can be adjusted to ensure optimal coupling to the pickup loops with an inductance in the range from 5 nH to 300 nH. Several types of planar pickup loop configurations have been realized. The magnetometer has a pickup loop with a size of 1 cm × 1 cm. With a typical white noise level better than 4 µ0 Hz-1/2 and an effective area of 2.6 mm2 a field resolution of 3.2 fT Hz-1/2 results for the magnetometer. Two loops connected in series with an area of 2 cm × 2 cm each and a baseline of 4 cm were used in the gradiometer. We measured a 7.5 mm2 effective area for each loop and a field gradient resolution of 36 fT m-1 Hz-1/2 corresponding to a field resolution in the loop of 1.6 fT Hz-1/2.
Enhanced permeability and retention of macromolecular drugs in solid tumors: A royal gate for targeted anticancer nanomedicines (2007)

Over the past two decades cancer has ascended the causes of human death to be number one or two in many nations world wide. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely, hypervascularisation; aberrant vascular architecture; extensive production of vascular permeability factors stimulating extravasation within tumor tissues; and lack of lymphatic drainage. Maeda and his colleagues have extensively studied tumor vascular abnormalities in terms of active and selective delivery of anticancer drugs to tumor tissues, notably defining the enhanced permeability and retention effect (EPR effect) of macromolecular drugs in solid tumors. Due to their large molecular size, nanosized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Often they can not penetrate the tight endothelial junctions of normal blood vessels, but they can extravasate in tumour vasculature and become trapped in the tumor vicinity. With time the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor; an ideal application for EPR-based selective anticancer drug delivery. Establishing this principle hastened development of various polymer conjugates and polymeric micelles as well as multifunctional nanoparticles for targeted cancer chemotherapy. Indeed this selective high local concentration of nanosized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings. In this review the mechanisms and factors involved in the EPR effect, as well as the uniqueness of nanoscale drugs for tumor targeting through EPR effect, will be discussed in detail.
Phosphonylmethoxyalkyl and phosphonylalkyl derivatives of adenine (1988)

Analogues of the antivirals (2 S )-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ( Ia ) and 9-(2-phosphonylmethoxyethyl)adenine ( Ib ), modified in the alkyl chain, are described. The phosphonylmethoxyalkyl derivatives were prepared by condensation of sodium alkoxides of hydroxyalkyladenines (or their N-protected derivatives) with dimethyl p -toluenesulfonyloxymethanephosphonate ( II ) followed by alkaline hydrolysis and reactions with halotrimethylsilane, or by reaction of vicinal dihydroxyalkyl derivatives with chloromethanephosphonyl dichloride ( XIV ) and subsequent cyclization of the intermediates XV in aqueous alkali. In the second case the pure regioisomers were also obtained from substituted dihydroxy derivatives with one free hydroxyl group. The following compounds were prepared in this way: 3-O-methyl ether IIIc and 3-O-octyl ether IVc , 9-(3-phosphonylmethoxypropyl)- ( Vc ), 9-(4-phosphonylmethoxybutyl)- ( Vf ), 9-(5-phosphonylmethoxypentyl)- ( Vi ), 9-(2-phosphonylmethoxypropyl)- ( VIc ), 9-(1-phosphonylmethoxy-3-hydroxy-2-propyl)- ( XIIc ), 9-(2-methoxy-3-phosphonylmethoxypropyl)- ( XIIIc ), erythro -9-(2-phosphonylmethoxy-3,4-dihydroxybutyl)- ( VIIc ) and threo -9-(4-phosphonylmethoxy-2,3-dihydroxybutyl)adenine ( IXc ) and its enantiomer ( Xc ). 9-(2-Phosphonylmethoxy-3,3-dihydroxypropyl)adenine ( VIII ) was obtained by oxidation of VIIc with sodium periodate, 9-(2-phosphonylmethoxyethoxymethyl)adenine ( XIc ) by reaction of II with sodium salt of 9-(2-hydroxyethoxymethyl)adenine ( XIa ). 9-(1,2-Dihydroxy-2-methyl-3-propyl)adenine 1- and 2-phosphonylmethyl ether ( XVIb ), 9-(3,4-dihydroxybutyl)adenine 3- and 4-phosphonylmethyl ether ( XVIIb ) and 9-(2,3-dihydroxybutyl)adenine 2- and 3-phosphonylmethyl ether ( XVIIIb ) were prepared by reaction with chloromethanephosphonyl dichloride ( XIV ) followed by alkaline treatment. Analogous reaction was also employed in the preparation of regioisomerically pure 1-phosphonylmethyl ethers of 9-(1,2-dihydroxy-3-butyl)adenine ( XXIV ), 9-(1,2-dihydroxy-2-methyl-3-propyl)adenine ( XVIb ) and 9-(1,2-dihydroxy-3-nonyl)adenine ( XXV ). Alkylation of adenine with diethyl chloromethoxymethanephosphonate ( XXVII ) followed by hydrolysis afforded 9-(phosphonylmethoxymethyl)adenine ( XXVIIIb ). 9-(Phosphonylmethyl)adenine ( XLI ) was obtained by condensation of adenine with compound II . Conversion of 9-(ω-hydroxyalkyl)adenines into the ω-halogenoalkyl derivatives followed by reaction with trialkyl phosphite and cleavage was used in the preparation of 9-(2-phosphonylethyl)adenine ( XXXIVa ), 9-(4-phosphonylbutyl)adenine ( XXXIVb ) and 9-(2-phosphonylethoxymethyl)adenine ( XXXIX ). 9-(2-Phosphonyl-2-hydroxyethyl)adenine ( Lc ) and 9-(3-phosphonyl-3-hydroxypropyl)adenine ( Lb ) were synthesized by treatment of ω-(adenin-9-yl)alkanals with dialkyl phosphite and subsequent cleavage with halogenotrimethylsilane; the same procedure converted 9-(2-oxopropyl)adenine ( XLVIIIa ) into 9-(2-phosphonyl-2-hydroxypropyl)adenine ( La ).
Treatment of Primary Hypogonadism in Men by the Transdermal Administration of Testosterone* (1989)

We tested the efficacy of a thin flexible testosterone-impregnated membrane applied to the scrotum for the long term treatment of male hypogonadism. Ten men with primary hypogonadism were treated for 3 months (2 men) or 13 months (8 men). Serum testosterone concentrations increased in all 10 men, to within the normal range in 8. Serum dihydrotestosterone concentrations increased to supranormal values in all of the men, decreased to the normal range in 6, indicating the biological effectiveness of the testosterone in those subjects. Two men whose serum LH concentrations did not fall to normal had small or distorted scrotal surfaces. Seven of the 8 men whose serum testosterone concentrations became normal said that their hypogonadal symptoms were corrected by this treatment. We conclude that the transdermal administration of testosterone is an effective means of treating the majority of hypogonadal men who have a normal scrotum.
Bringing natural killer cells to the clinic: ex vivo manipulation (2013)

Recently, there has been a substantial gain in our understanding of the role that natural killer (NK) cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell-based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo-expanded NK populations.
Human AP Endonuclease 1: A Potential Marker for the Prediction of Environmental Carcinogenesis Risk (2014)

Human apurinic/apyrimidinic endonuclease 1 (APE1) functions mainly in DNA repair as an enzyme removing AP sites and in redox signaling as a coactivator of various transcription factors. Based on these multifunctions of APE1 within cells, numerous studies have reported that the alteration of APE1 could be a crucial factor in development of human diseases such as cancer and neurodegeneration. In fact, the study on the combination of an individual's genetic make-up with environmental factors (gene-environment interaction) is of great importance to understand the development of diseases, especially lethal diseases including cancer. Recent reports have suggested that the human carcinogenic risk following exposure to environmental toxicants is affected by APE1 alterations in terms of gene-environment interactions. In this review, we initially outline the critical APE1 functions in the various intracellular mechanisms including DNA repair and redox regulation and its roles in human diseases. Several findings demonstrate that the change in expression and activity as well as genetic variability of APE1 caused by environmental chemical (e.g., heavy metals and cigarette smoke) and physical carcinogens (ultraviolet and ionizing radiation) is likely associated with various cancers. These enable us to ultimately suggest APE1 as a vital marker for the prediction of environmental carcinogenesis risk.
Characteristics and diagnosis of NAFLD/NASH (2013)

Non-alcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome. NAFLD has become an important public health issue because of its high prevalence. NAFLD consists of two clinicopathological entities: simple steatosis, which generally follows a benign non-progressive clinical course, and non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. The diagnosis of NAFLD is based on the following three criteria: non-alcoholic, detection of steatosis either by imaging or by histology, and appropriate exclusion of other liver diseases. Alcoholic liver disease can occur when daily alcohol consumption exceeds 20 g in women or 30 g in men. Thus, non-alcoholic indicates lower levels of these alcohol consumptions. However, there is still no clear consensus regarding the threshold alcohol consumption for defining non-alcoholic liver disease. Then, there is the strong recommendation for a change in the nomenclature, such as use of the term metabolic fatty liver and metabolic steatohepatitis. NASH has emerged as a clinicopathological entity, and even now, a liver biopsy remains the gold standard for making a definitive diagnosis. However, liver biopsy has several drawbacks. In general practice, NAFLD is a convenient-to-use term for the diagnosis and management of these patients, and serum biomarkers that indicate the severity of fibrosis serve as clinically useful tools for the identification of NAFLD in patients with bridging fibrosis or cirrhosis. In the future, improved understanding of the pathogenesis of NASH and new technologies may contribute to the diagnostic process and provide reliable, non-invasive alternatives to liver biopsy.
Microtubule-active drugs taxol, vinblastine, and nocodazole increase the levels of transcriptionally active p53. (1995)

A range of DNA-damaging agents has been shown to increase cellular levels of the nuclear phosphoprotein p53 and to induce p53-dependent processes. We examined the ability of three microtubule-active agents, taxol, vinblastine, and nocodazole, to increase p53 levels and activate p53-dependent processes. When tested using a p53 DNA-binding assay, all three agents induced p53 in a dose-dependent manner. To varying degrees, these agents also induced p21WAF1/CIP1 mRNA and transcription in a chloramphenicol acetyl transferase reporter system. These data suggest there is an additional pathway for activating p53 and subsequent p53-dependent processes.
Neighboring Group Catalysis in the Design of Nucleotide Prodrugs (1996)

An approach is described for potential application to the delivery of polar nucleosides and nucleotides across lipophilic membranes, namely, nucleotide prodrugs based on salicyl phosphate. 3'-Azido-3'-deoxythymidine (AZT) and 3'-deoxythymidine (ddT) were chosen as models. For the synthesis of prototype compounds 1 and 2, the approach was first to react either methyl salicylate (for 1) or phenyl salicylate (for 2) with phosphorus oxychloride in dry methylene chloride at 0 degree C with the addition of triethylamine as acid scavenger. The resulting intermediate phosphorodichloridate was reacted immediately with excess nucleoside under the same conditions. The control model compound 3 was prepared by reaction of phenyl phosphorodichloridate and excess nucleoside in pyridine/methylene chloride at 0 degree C to give 3 in 82% yield. The synthesis of triester 7 involved reaction of alpha-(chloroacetyl)salicyl chloride with 2,3,4,6-tetra-O-benzyl-D-glucopyranose to give [[(2,3,4,6-tetra-O-benzyl-D-glucopyranosyl)-oxy]carbonyl]-2- (1-chloroacetoxy)benzene (4) which was dechloroacetylated to 5,2,3,4,6-tetra-O-benzyl-D-glucopyranosyl salicylate. Phosphorylation of 5 with phosphorus oxychloride provided the phosphorodichloridate which was directly converted to 6 by reaction with dideoxythymidine. Removal of benzyl groups by catalytic hydrogenation gave compound 7, bis(2',3'-dideoxythymidin-5'-yl) D-glucopyranosyl phosphate. The AZT prodrug triesters, 1 and 2, underwent much more rapid hydrolysis than the triester 3, most probably due to the formation of an acyl phosphate complex from the attack on phosphorus of the salicylate carboxylate. The hydrolysis of the less lipophilic 7 was significantly slower than that of 1 or 2. Both pig liver esterase and rat brain cytosol were able to effect the cleavage to dinucleotide or mononucleotide of prodrug forms 2 and 7, much more rapidly than either 3 or 1, suggesting that the esterase-like enzymatic activity of rat brain was similar to that of pig liver esterase. This study suggests the possibility of use of salicylic acid-based prodrugs for nucleotides, subject to specific refinements in the choice of carboxylate- and phosphoric acid ester-protecting groups.
CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel (2002)

CLIC1 is a member of the CLIC family of proteins, which has been shown to demonstrate chloride channel activity when reconstituted in phospholipid vesicles. CLIC1 exists in cells as an integral membrane protein and as a soluble cytoplasmic protein, implying that CLIC1 might cycle between membrane-inserted and soluble forms. CLIC1 was purified and detergent was removed, yielding an aqueous solution of essentially pure protein. Pure CLIC1 was mixed with vesicles, and chloride permeability was assessed with a chloride efflux assay and with planar lipid bilayer techniques. Soluble CLIC1 confers anion channel activity to preformed membranes that is indistinguishable from the previously reported activity resulting from reconstitution of CLIC1 into membranes by detergent dialysis. The activity is dependent on the amount of CLIC1 added, appears rapidly on mixing of protein and lipid, is inhibited by indanyloxyacetic acid-94, N-ethylmaleimide, and glutathione, is inactivated by heat, and shows sensitivity to pH and to membrane lipid composition. We conclude that CLIC1 in the absence of detergent spontaneously inserts into preformed membranes, where it can function as an anion-selective channel.
Identification of the Integrin VLA-2 as a Receptor for Echovirus 1 (1992)

Cell surface receptors for echovirus, a common human pathogen, were identified with monoclonal antibodies that protected susceptible cells from infection with echovirus 1. These monoclonal antibodies, which prevented virus attachment to specific receptor sites, recognized the alpha and beta subunits of the integrin VLA-2 (alpha 2 beta 1), a receptor for collagen and laminin. RD rhabdomyosarcoma cells expressed little VLA-2, did not bind to 35S-labeled virus, and resisted infection until transfected with complementary DNA encoding the alpha 2 subunit of VLA-2. Thus, integrins, adhesion receptors important in interactions between cells and with the extracellular matrix, can mediate virus attachment and infection.
Characterization of guanylate cyclase activity in single retinal rod outer segments (1995)

cGMP mediates vertebrate phototransduction by directly gating cationic channels on the plasma membrane of the photoreceptor outer segment. This second messenger is produced by a guanylate cyclase and hydrolyzed by a light-activated cGMP-phosphodiesterase. Both of these enzyme activities are Ca2+ sensitive, the guanylate cyclase activity being inhibited and the light-activated phosphodiesterase being enhanced by Ca2+. Changes in these activities due to a light-induced decrease in intracellular Ca2+ are involved in the adaptation of photoreceptors to background light. We describe here experiments to characterize the guanylate cyclase activity and its modulation by Ca2+ using a truncated rod outer segment preparation, in order to evaluate the enzyme's role in light adaptation. The outer segment of a tiger salamander rod was drawn into a suction pipette to allow recording of membrane current, and the remainder of the cell was sheared off with a probe to allow internal dialysis. The cGMP-gated channels on the surface membrane were used to monitor conversion of GTP, supplied from the bath, into cGMP by the guanylate cyclase in the outer segment. At nominal 0 Ca2+, the cyclase activity had a Km of 250 microM MgGTP and a Vmax of 25 microM cGMP s-1 in the presence of 1.6 mM free Mg2+; in the presence of 0.5 mM free Mg2+, the Km was 310 microM MgGTP and the Vmax was 17 microM cGMP s-1. The stimulation by Mg2+ had an EC50 of 0.2 mM Mg2+ for MgGTP at 0.5 mM. Ca2+ inhibited the cyclase activity. In a K+ intracellular solution, with 0.5 mM free Mg2+ and 2.0 mM GTP, the cyclase activity was 13 microM cGMP s-1 at nominal 0 Ca2+; Ca2+ decreased this activity with a IC50 of approximately 90 nM and a Hill coefficient of approximately 2.0.
Positive Regulation of Wee1 by Chk1 and 14-3-3 Proteins (2001)

Wee1 inactivates the Cdc2-cyclin B complex during interphase by phosphorylating Cdc2 on Tyr-15. The activity of Wee1 is highly regulated during the cell cycle. In frog egg extracts, it has been established previously that Xenopus Wee1 (Xwee1) is present in a hypophosphorylated, active form during interphase and undergoes down-regulation by extensive phosphorylation at M-phase. We report that Xwee1 is also regulated by association with 14-3-3 proteins. Binding of 14-3-3 to Xwee1 occurs during interphase, but not M-phase, and requires phosphorylation of Xwee1 on Ser-549. A mutant of Xwee1 (S549A) that cannot bind 14-3-3 is substantially less active than wild-type Xwee1 in its ability to phosphorylate Cdc2. This mutation also affects the intranuclear distribution of Xwee1. In cell-free kinase assays, Xchk1 phosphorylates Xwee1 on Ser-549. The results of experiments in which Xwee1, Xchk1, or both were immunodepleted from Xenopus egg extracts suggested that these two enzymes are involved in a common pathway in the DNA replication checkpoint response. Replacement of endogenous Xwee1 with recombinant Xwee1-S549A in egg extracts attenuated the cell cycle delay induced by addition of excess recombinant Xchk1. Taken together, these results suggest that Xchk1 and 14-3-3 proteins act together as positive regulators of Xwee1.
Protected-mode synthesis of N-linked glycopeptides: single-step preparation of building blocks as peracetyl glycosylated NαFmoc asparagine OPfp esters (1993)

The preparation of Nα-(fluoren-9-ylmethoxycarbonyl)asparagine pentafluorophenyl esters (Nα-Fmoc-Asn-OPfp) glycosylated with per-O-acetylated β-D-glucose, N-acetyl-β-D-glucosamine, β-D-mannose, 4-O-β-D-glucopyranosyl-β-D-glucose (cellobiose), 4-O-β-D-galactopyranosyl-β-D-glucose (lactose) and 4-O-α-D-glucopyranosyl-β-D-glucose (maltose) is described. The per-O-acetylated glycosylamines were treated selectively with the key compound Nα-Fmoc-Asp(Cl)-OPfp 2, to give, in a single step, the glycosylated building blocks. The acid chloride 2 was prepared in a quantitative one-pot reaction from commercially available Nα-Fmoc-Asp(OBut)-OPfp 1. The acid stability of the N-glycosidic linkage was investigated. The building block 7, containing a maltose moiety, was used in the synthesis of a glycosylated D-Ala1 Peptide-T amide analogue 14. CD spectra were recorded in 85% TFE. All compounds were fully characterized by 1H and 13C NMR spectroscopy.
X-ray absorption spectroscopy study on oxygen-deficient hafnium oxide film (2008)

We investigated the influence of oxygen vacancy on the electronic and atomic distributions in hafnium oxide, using hard and soft x-ray absorption spectroscopies. Analyses on the Hf L3-edge extended x-ray absorption fine structures revealed that the average Hf-O bond length reduces more than -0.1 Å in the presence of oxygen vacancy, consequently on the lattice relaxation. Furthermore, the O K-edge absorption spectrum shows additional band tail state beneath the genuine Hf 5d conduction band, which manifests a small occupation in Hf d shell in the oxygen-deficient oxide. However, the nonzero d occupation is found not to involve a ferromagnetic spin correlation by the absence of features in the Hf N3-edge magnetic circular dichroism.
Expanding the Genetic Code of an Animal (2011)

Genetic code expansion, for the site-specific incorporation of unnatural amino acids into proteins, is currently limited to cultured cells and unicellular organisms. Here we expand the genetic code of a multicellular animal, the nematode Caenorhabditis elegans.