gebhart/patrepeval huggingface dataset:
Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes (2011)

Dendritic cells (DCs) are the most potent APCs. Whereas immature DCs down-regulate T-cell responses to induce/maintain immunologic tolerance, mature DCs promote immunity. To amplify their functions, DCs communicate with neighboring DCs through soluble mediators, cell-to-cell contact, and vesicle exchange. Transfer of nanovesicles (< 100 nm) derived from the endocytic pathway (termed exosomes) represents a novel mechanism of DC-to-DC communication. The facts that exosomes contain exosome-shuttle miRNAs and DC functions can be regulated by exogenous miRNAs, suggest that DC-to-DC interactions could be mediated through exosome-shuttle miRNAs, a hypothesis that remains to be tested. Importantly, the mechanism of transfer of exosome-shuttle miRNAs from the exosome lumen to the cytosol of target cells is unknown. Here, we demonstrate that DCs release exosomes with different miRNAs depending on the maturation of the DCs. By visualizing spontaneous transfer of exosomes between DCs, we demonstrate that exosomes fused with the target DCs, the latter followed by release of the exosome content into the DC cytosol. Importantly, exosome-shuttle miRNAs are functional, because they repress target mRNAs of acceptor DCs. Our findings unveil a mechanism of transfer of exosome-shuttle miRNAs between DCs and its role as a means of communication and posttranscriptional regulation between DCs.
Pyrido [2, 3-d]pyrimidines and Pyrimido[5′, 4′:5, 6]pyrido[2, 3-d]pyrimidines as New Antiviral Agents: Synthesis and Biological Activity (2002)

A series of 7-amino- and 7-oxo-5-aryl-6-cyanopyrido[2, 3-d]pyrimidines, 4 and 11, respectively, and pyrimido [5', 4':5, 6]pyrido[2, 3-d]pyrimidine derivatives 6 and 7 was synthesized and investigated as antiviral agents. Different synthetic strategies for the preparation of the target compounds were explored. A synthetic procedure for 4 and 11 starting with 6-amino-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidine, proper aldehyde, and malononitrile or ethyl cyanoacetate, respectively, in a one-pot reaction proved to be the method of choice for preparation of compounds of such type. Construction of another pyrimidine ring on the pyridine nucleus of compound 4 was achieved either by reaction with phenyl iso(thio)cyanate or with formic acid to yield 6 and 7, respectively. The structure of the prepared compounds was confirmed through elemental analysis and spectral investigation. Most of the newly synthesized compounds were subjected to antiviral activity testing against herpes simplex virus (HSV) where some of them show good activities.
Restoring insulin production for type 1 diabetes (2012)

Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment. These barriers could be circumvented by designing a safe and efficient strategy to restore insulin production within the patient's body. Porcine islets have been considered as a possible alternative source of transplantable insulin-producing cells to replace human cadaveric islets. More recently, embryonic or induced pluripotent stem cells have also been examined for their ability to differentiate in vitro into pancreatic endocrine cells. Alternatively, it may be feasible to generate new β-cells by ectopic expression of key transcription factors in endogenous non-β-cells. Finally, engineering surrogate β-cells by in vivo delivery of the insulin gene to specific tissues is also being studied as a possible therapy for type 1 diabetes. In the present review, we discuss these different approaches to restore insulin production.
Integrating Silicon Nanowire Field Effect Transistor, Microfluidics and Air Sampling Techniques For Real-Time Monitoring Biological Aerosols (2011)

Numerous threats from biological aerosol exposures, such as those from H1N1 influenza, SARS, bird flu, and bioterrorism activities necessitate the development of a real-time bioaerosol sensing system, which however is a long-standing challenge in the field. Here, we developed a real-time monitoring system for airborne influenza H3N2 viruses by integrating electronically addressable silicon nanowire (SiNW) sensor devices, microfluidics and bioaerosol-to-hydrosol air sampling techniques. When airborne influenza H3N2 virus samples were collected and delivered to antibody-modified SiNW devices, discrete nanowire conductance changes were observed within seconds. In contrast, the conductance levels remained relatively unchanged when indoor air or clean air samples were delivered. A 10-fold increase in virus concentration was found to give rise to about 20-30% increase in the sensor response. The selectivity of the sensing device was successfully demonstrated using H1N1 viruses and house dust allergens. From the simulated aerosol release to the detection, we observed a time scale of 1-2 min. Quantitative polymerase chain reaction (qPCR) tests revealed that higher virus concentrations in the air samples generally corresponded to higher conductance levels in the SiNW devices. In addition, the display of detection data on remote platforms such as cell phone and computer was also successfully demonstrated with a wireless module. The work here is expected to lead to innovative methods for biological aerosol monitoring, and further improvements in each of the integrated elements could extend the system to real world applications.
Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young (2005)

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.
The Metabolic State of Diabetic Monkeys Is Regulated by Fibroblast Growth Factor-21 (2006)

Fibroblast growth factor (FGF)-21 has been recently characterized as a potent metabolic regulator. Systemic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in genetically compromised diabetic rodents. Importantly, these effects were durable and did not come at the expense of weight gain, hypoglycemia, or mitogenicity. To explore the therapeutic properties of FGF-21 in a nongenetically modified primate species, and thus demonstrate the potential for efficacy in humans, we evaluated its bioactivity in diabetic nonhuman primates. When administered daily for 6 wk to diabetic rhesus monkeys, FGF-21 caused a dramatic decline in fasting plasma glucose, fructosamine, triglycerides, insulin, and glucagon. Of significant importance in regard to safety, hypoglycemia was not observed at any point during the study. FGF-21 administration also led to significant improvements in lipoprotein profiles, including lowering of low-density lipoprotein cholesterol and raising of high-density lipoprotein cholesterol, beneficial changes in the circulating levels of several cardiovascular risk markers/factors, and the induction of a small but significant weight loss. These data support the development of FGF-21 for the treatment of diabetes and other metabolic diseases.
Noninvasive imaging of c-myc oncogene messenger RNA with indium-111-antisense probes in a mammary tumor-bearing mouse model. (1994)

The radiolabeled antisense probe may provide a new sensitive tool for noninvasive imaging of c-myc oncogene mRNA for a variety of malignant tumors at an earlier stage.
DNA Aptamer Raised Against AGEs Blocks the Progression of Experimental Diabetic Nephropathy (2013)

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy.
Molecular Reaction Dynamics (2005)

Molecular reaction dynamics is the study of chemical and physical transformations of matter at the molecular level. The understanding of how chemical reactions occur and how to control them is fundamental to chemists and interdisciplinary areas such as materials and nanoscience, rational drug design, environmental and astrochemistry. This book provides a thorough foundation to this area. The first half is introductory, detailing experimental techniques for initiating and probing reaction dynamics and the essential insights that have been gained. The second part explores key areas including photoselective chemistry, stereochemistry, chemical reactions in real time and chemical reaction dynamics in solutions and interfaces. Typical of the new challenges are molecular machines, enzyme action and molecular control. With problem sets included, this book is suitable for advanced undergraduate and graduate students, as well as being supplementary to chemical kinetics, physical chemistry, biophysics and materials science courses, and as a primer for practising scientists.
Pharmacokinetic study of ACT-132577 in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry. (2015)

It was reported that macitentan was metabolized predominantly by cytochrome P450 3A4, and ACT-132577, its pharmacologically active metabolite, is fivefold less potent at blocking ET receptors than macitentan. In this work, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of ACT-132577 in rat plasma was developed and validated. After addition of diazepam as an internal standard (IS), protein precipitation by acetonitrile was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm × 100 mm, 1.7 μm) with 0.2% formic acid and methanol as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 546.9→200.6 for ACT-132577, and m/z 285.1→193.1 for IS. Calibration plots were linear throughout the range 10-4000 ng/mL for ACT-132577 in rat plasma. Mean recovery of ACT-132577 in rat plasma ranged from 82.6% to 90.6%, matrix effect of ACT-132577 in rat plasma ranged from 101.4% to 115.2%. RSD of intra-day and inter-day precision were both less than 11%. The accuracy of the method ranged from 96.1% to 103.5%. The method was successfully applied to pharmacokinetic study of ACT-132577 after oral and intravenous administration of macitentan.
Picture-queries and picture databases (1993)

I mean by a picture a beautiful dream of something that never was, never will be. Burne-Jones c. 1871
Human growth and chronic disease: A memorial to Jim Tanner (2012)

Variations in the processes of development programme the function of a few key systems that are linked to chronic disease-the immune system, anti-oxidant defences, inflammatory responses, the number and quality of stem cells, neuro-endocrine settings and the balance of the autonomic nervous system. There is not a separate cause for each different disease. Which chronic disease originates during development may depend more on timing than on qualitative differences in exposures to external influences.
Undulations in the Time-Response Curve for Tumor Immunity after Primary Immunization with Washed Erythrocytes (1957)

Journal Article Undulations in the Time-Response Curve for Tumor Immunity after Primary Immunization with Washed Erythrocytes Get access Morris K. Barrett, Morris K. Barrett National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar Walter H. Hansen Walter H. Hansen National Cancer Institute,2Bethesda, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 18, Issue 1, January 1957, Pages 57–63, https://doi.org/10.1093/jnci/18.1.57 Published: 01 January 1957 Article history Received: 27 July 1956 Published: 01 January 1957
NMR spectroscopic studies of intermediary metabolites of cyclophosphamide. A comprehensive kinetic analysis of the interconversion of cis- and trans-4-hydroxycyclophosphamide with aldophosphamide and the concomitant partitioning of aldophosphamide between irreversible fragmentation and reversible conjugation pathways (1984)

Multinuclear (31P, 13C, 2H, and 1H) Fourier-transform NMR spectroscopy, with and without isotopically enriched materials, was used to identify and quantify, as a function of time, the following intermediary (short-lived) metabolites of the anticancer prodrug cyclophosphamide (1, Scheme I): cis-4-hydroxycyclophosphamide (cis-2), its trans isomer (trans-2), aldophosphamide (3), and its aldehyde-hydrate (5). Under a standard set of reaction conditions (1 M 2,6-dimethylpyridine buffer, pH 7.4, 37 degrees C), the stereospecific deoxygenation of synthetic cis-4-hydroperoxycyclophosphamide (cis-12, 20 mM) with 4 equiv of sodium thiosulfate (Na2S2O3) afforded, after approximately 20 min, a "pseudoequilibrium" distribution of cis-2, 3, 5, and trans-2, i.e., the relative proportions of these reactants (57:4:9:30, respectively) remained constant during their continual disappearance. NMR absorption signals indicative of "iminophosphamide" (8) and enol 6 were not detected (less than 0.5-1% of the synthetic metabolite mixture). A computerized least-squares fitting procedure was applied to the individual 31P NMR derived time courses for conversion of cis-2, 3 plus 5 (i.e., "3"), and trans-2 into acrolein and phosphoramide mustard (4), the latter of which gave an expected array of thiosulfate S-alkylation products (e.g., 16) and other phosphorus-containing materials derived from secondary decomposition reactions. This kinetic analysis gave the individual forward and reverse rate constants for the apparent tautomerization processes, viz., cis-2 in equilibrium "3" in equilibrium trans-2, as well as the rate constant (k3) for the irreversible fragmentation of 3. The values of k3 at pH 6.3, 7.4, and 7.8 were equal to 0.030 +/- 0.004, 0.090 +/- 0.008, and 0.169 +/- 0.006 min-1, respectively. Replacement of the HC(O)CH2 moiety n 3 with HC(O)CD2 led to a primary kinetic isotope effect (kH/kD = 5.6 +/- 0.4) for k3. The apparent half-lives (tau 1/2) for cis-2, "3", and trans-2 under the standard reaction conditions, at "pseudoequilibrium" (constant ratio of cis-2/"3"/trans-2), were each equal to approximately 38 min, which is considerably shorter than the widely cited colorimetrically derived half-lives reported by earlier investigators. The values of tau 1/2 for cis-2, "3", and trans-2 were affected by pH in the same manner as that found for k3 but were relatively insensitive to the presence of either K+, Na+, Ca2+, or Mg2+. The presence of certain primary amines led to marked decreases in tau 1/2 and, in some cases, the formation of acyclic adducts of aldehyde 3.(ABSTRACT TRUNCATED AT 400 WORDS)
Aromatic haloethylation with palladium and copper halides (1968)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAromatic haloethylation with palladium and copper halidesRichard F. HeckCite this: J. Am. Chem. Soc. 1968, 90, 20, 5538–5542Publication Date (Print):September 1, 1968Publication History Published online1 May 2002Published inissue 1 September 1968https://pubs.acs.org/doi/10.1021/ja01022a038https://doi.org/10.1021/ja01022a038research-articleACS PublicationsRequest reuse permissionsArticle Views1459Altmetric-Citations108LEARN 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-Alertsclose Get e-Alerts
Novel Metabolite of Trichloroethylene in a Methanotrophic Bacterium,Methylocystissp. M, and Hypothetical Degradation Pathway (1992)

Previously, a new type II methanotrophic bacterium, Methylocystis sp. M (strain M), was isolated in our laboratory [H. Uchiyama et al., Agric. Bioi. Chem., 53, 2903-2907 (1989)]. In this paper, metabolites resulting from the degradation of trichloroethylene (TCE) by strain M were studied with gas chromatography-mass spectrometry. Trichloroacetic acid, dichloroacetic acid, and a small amount of 2,2,2-trichloroethanol were detected in the water-soluble fraction of the reaction mixture. These results suggest that the conversion of TCE to trichloroacetaldehyde via a CI-shift reaction, followed by the formation of trichloroacetic acid and 2,2,2-trichloroethanol, as well as a spontaneous breakdown of TCE oxide, with subsequent formation of dichloroacetic acid, etc., is involved in the TCE degradation pathway of the methanotrophic bacterium.
Mild Copper‐Catalyzed Vinylation Reactions of Azoles and Phenols with Vinyl Bromides (2006)

An efficient and straightforward copper-catalyzed method allowing vinylation of N- or O-nucleophiles with di- or trisubstituted vinyl bromides is reported. The procedure is applicable to a broad range of substrates since N-vinylation of mono-, di-, and triazoles as well as O-vinylation of phenol derivatives can be performed with catalytic amounts of copper iodide and inexpensive nitrogen ligands 3 or 8. In the case of more hindered vinyl bromides, the use of the original bidentate chelator 8 was shown to be more efficient to promote the coupling reactions than our key tetradentate ligand 3. The corresponding N-(1-alkenyl)azoles and alkenyl aryl ethers are obtained in high yields and selectivities under very mild temperature conditions (35-110 degrees C for N-vinylation reactions and 50-80 degrees C for O-vinylation reactions). Moreover, to our knowledge, this method is the first example of a copper-catalyzed vinylation of various azoles. Finally, this protocol, practical on a laboratory scale and easily adaptable to an industrial scale, is very competitive compared to the existing methods that allow the synthesis of such compounds.
The Control of Dopamine Neuron Development, Function and Survival: Insights From Transgenic Mice and The Relevance to Human Disease (2003)

Transgenic technology, especially the use of homologous recombination to disrupt specific genes to produce knockout mice, has added considerably to the understanding of dopamine (DA) neuron develop, survival and function. The current review summarizes results from knockout mice with the target disruption of genes involved in the development of DA neurons (engrailed 1 and 2, lmx1b, and Nurr1), in maintaining DA neurotransmission (tyrosine hydroxylase, vesicular monoamine transporter, DA transporter, DA D2 and D3 receptors) and important for DA neuron survival (alpha-synuclein, glia cell line-derived neurotrophic factor and superoxide dismutase). As alterations in DA neurotransmission have been implicated in a number of human neuropathologies including Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder, understanding how specific genes are involved in the function of DA neurons and the compensatory changes that result from loss or reduction in gene expression could provide important insight for the treatment of these diseases.
Reproducibility of Glucose Measurements Using the Glucose Sensor (2002)

In a real-life setting, the accuracy of data provided by the Minimed glucose sensor may be less than expected. To avoid therapeutic errors, sensor findings should be confirmed by independent means before clinical decisions are made.
Isolation and characterization of mutants blocked in T-2 toxin biosynthesis (1987)

Mutants of Fusarium sporotrichioides NRRL 3299 that were blocked or altered in the biosynthesis of the trichothecene T-2 toxin were generated by UV treatment and identified by a rapid screen in which monoclonal antibodies to T-2 were used. Three stable mutants were isolated and chemically characterized. Two mutants accumulated diacetoxyscirpenol, which suggests that they were defective in the step required for the addition of a hydroxyl group to the C-8 position in the trichothecene core structure. The third mutant appeared to be partially blocked at an early step or regulatory point in the pathway. This represents the first isolation of mutants in a trichothecene biosynthetic pathway.