Synthesis of Cycloveratrylene Macrocycles and Benzyl Oligomers Catalysed by Bentonite under Microwave/Infrared and Solvent-Free Conditions

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Manuel Salmón

2013-10-01

Full Text Available Tonsil Actisil FF, which is a commercial bentonitic clay, promotes the formation of cycloveratrylene macrocycles and benzyl oligomers from the corresponding benzyl alcohols in good yields under microwave heating and infrared irradiation in the absence of solvent in both cases. The catalytic reaction is sensitive to the type of substituent on the aromatic ring. Thus, when benzyl alcohol was substituted with a methylenedioxy, two methoxy or three methoxy groups, a cyclooligomerisation process was induced. Unsubstituted, methyl and methoxy benzyl alcohols yielded linear oligomers. In addition, computational chemistry calculations were performed to establish a validated mechanistic pathway to explain the growth of the obtained linear oligomers.

Formation of low-dimensional crystalline nucleus region during insulin amyloidogenesis process

International Nuclear Information System (INIS)

Amdursky, Nadav; Gazit, Ehud; Rosenman, Gil

2012-01-01

Highlights: ► We observe lag-phase crystallization process in insulin. ► The crystallization is a result of the formation of higher order oligomers. ► The crystallization also changes the secondary structure of the protein. ► The spectroscopic signature can be used for amyloid inhibitors assay. -- Abstract: Insulin, as other amyloid proteins, can form amyloid fibrils at certain conditions. The self-assembled aggregation process of insulin can result in a variety of conformations, starting from small oligomers, going through various types of protofibrils, and finishing with bundles of fibrils. One of the most common consensuses among the various self-assembly processes that are suggested in the literature is the formation of an early stage nucleus conformation. Here we present an additional insight for the self-assembly process of insulin. We show that at the early lag phase of the process (prior to fibril formation) the insulin monomers self-assemble into ordered nanostructures. The most notable feature of this early self-assembly process is the formation of nanocrystalline nucleus regions with a strongly bound electron–hole confinement, which also change the secondary structure of the protein. Each step in the self-assembly process is characterized by an optical spectroscopic signature, and possesses a narrow size distribution. By following the spectroscopic signature we can measure the potency of amyloid fibrils inhibitors already at the lag phase. We further demonstrate it by the use of epigallocatechin gallate, a known inhibitor for insulin fibrils. The findings can result in a spectroscopic-based application for the analysis of amyloid fibrils inhibitors.

Characteristics of tau oligomers

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Yan eRen

2013-07-01

Full Text Available In Alzheimer disease (AD and other tauopathies, microtubule-associated protein tau becomes hyperphosphorylated, undergoes conformational changes, aggregates, eventually becoming neurofibrillary tangles (NFTs. As accumulating evidence suggests that NFTs themselves may not be toxic, attention is now turning toward the role of intermediate tau oligomers in AD pathophysiology. Sarkosyl extraction is a standard protocol for investigating insoluble tau aggregates in brains. There is a growing consensus that sarkosyl-insoluble tau correlates with the pathological features of tauopathy. While sarkosyl-insoluble tau from tauopathy brains has been well characterized as a pool of filamentous tau, other dimers, multimers, and granules of tau are much less well understood. There are protocols for identifying these tau oligomers. In this mini review, we discuss the characteristics of tau oligomers isolated via different methods and materials.

Amyloid β oligomers in Alzheimer's disease pathogenesis, treatment, and diagnosis.

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Viola, Kirsten L; Klein, William L

2015-02-01

Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they

Interface Bond Improvement of Sisal Fibre Reinforced Polylactide Composites with Added Epoxy Oligomer.

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Hao, Mingyang; Wu, Hongwu; Qiu, Feng; Wang, Xiwen

2018-03-07

To improve the interfacial bonding of sisal fiber-reinforced polylactide biocomposites, polylactide (PLA) and sisal fibers (SF) were melt-blended to fabricate bio-based composites via in situ reactive interfacial compatibilization with addition of a commercial grade epoxy-functionalized oligomer Joncryl ADR @ -4368 (ADR). The FTIR (Fourier Transform infrared spectroscopy) analysis and SEM (scanning electron microscope) characterization demonstrated that the PLA molecular chain was bonded to the fiber surface and the epoxy-functionalized oligomer played a hinge-like role between the sisal fibers and the PLA matrix, which resulted in improved interfacial adhesion between the fibers and the PLA matrix. The interfacial reaction and microstructures of composites were further investigated by thermal and rheological analyses, which indicated that the mobility of the PLA molecular chain in composites was restricted because of the introduction of the ADR oligomer, which in turn reflected the improved interfacial interaction between SF and the PLA matrix. These results were further justified with the calculation of activation energies of glass transition relaxation (∆ E a ) by dynamic mechanical analysis. The mechanical properties of PLA/SF composites were simultaneously reinforced and toughened with the addition of ADR oligomer. The interfacial interaction and structure-properties relationship of the composites are the key points of this study.

Development of real-time reverse transcription polymerase chain reaction assays to quantify insulin-like growth factor receptor and insulin receptor expression in equine tissue

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Stephen B. Hughes

2013-08-01

Full Text Available The insulin-like growth factor system (insulin-like growth factor 1, insulin-like growth factor 2, insulin-like growth factor 1 receptor, insulin-like growth factor 2 receptor and six insulin-like growth factor-binding proteins and insulin are essential to muscle metabolism and most aspects of male and female reproduction. Insulin-like growth factor and insulin play important roles in the regulation of cell growth, differentiation and the maintenance of cell differentiation in mammals. In order to better understand the local factors that regulate equine physiology, such as muscle metabolism and reproduction (e.g., germ cell development and fertilisation, real-time reverse transcription polymerase chain reaction assays for quantification of equine insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid were developed. The assays were sensitive: 192 copies/µLand 891 copies/µL for insulin-like growth factor 1 receptor, messenger ribonucleic acid and insulin receptor respectively (95%limit of detection, and efficient: 1.01 for the insulin-like growth factor 1 receptor assay and 0.95 for the insulin receptor assay. The assays had a broad linear range of detection (seven logs for insulin-like growth factor 1 receptor and six logs for insulin receptor. This allowed for analysis of very small amounts of messenger ribonucleic acid. Low concentrations of both insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid were detected in endometrium, lung and spleen samples, whilst high concentrations were detected in heart, muscle and kidney samples, this was most likely due to the high level of glucose metabolism and glucose utilisation by these tissues. The assays developed for insulin-like growth factor 1 receptor and insulin receptor messenger ribonucleic acid expression have been shown to work on equine tissue and will contribute to the understanding of insulin and insulin-like growth factor 1

Synthesis and characterization of thermally stable oligomer-metal ...

African Journals Online (AJOL)

The thermal stabilities of the oligomer-metal complexes were compared by thermogravimetric (TG) and differential thermal (DTA) analyses. According to TG, oligomer-metal complexes were stable against to temperature and thermooxidative decomposition. The weight losses of oligomer-metal complexes were found to be 5 ...

Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers

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Rasool Suhail

2007-09-01

Full Text Available Abstract Background Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD, amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. Results We immunized rabbits with a morphologically homogeneous population of Aβ42 fibrils. The resulting immune serum (OC specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 × G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type

Investigation of the structure of isobutylene oligomers, used in the capacity of stock for succinimide additives, by the method of proton magnetic resonance

Energy Technology Data Exchange (ETDEWEB)

Iarmoliuk, V.M.; Garun, Ia.E.; Ostroverkhov, V.G.; Pustovit, V.E.; Tikhonov, V.P.

1980-01-01

By the method of proton magnetic resonance, investigation was made of the structure of hydrocarbon framework of isobutylene oligomers of the Salavatsk petrochemical plant, produced by the cation polymerization of the isobutane isobutylene fraction at a temperature from -10 to +20/sup 0/ with A1C1/sub 3/ and used in the production of succinide additives. Determination was made of the qualitative and quantitative compositions of the various structures in the oligomers. It is shown, that as a rule, oligobutenes are not pure oligomers of isobutylene, but represent, at least, fragments of four structures, which can be formed on the basis of isobutylene. The content of the given structures does not affect the reaction capacity of the oligomers in respect to the maleic anhydride. It was established, that the low molecular fraction, contained in oligomers up to 5%, are not isobutylene oligomers, but represent a low molecular polymer of butene-2 and its copolymer with isobutylene.

Amino siloxane oligomer-linked graphene oxide as an efficient adsorbent for removal of Pb(II) from wastewater

International Nuclear Information System (INIS)

Luo, Shenglian; Xu, Xiangli; Zhou, Guiyin; Liu, Chengbin; Tang, Yanhong; Liu, Yutang

2014-01-01

Graphical abstract: A high performance sorbent, oligomer-linked graphene oxide, was prepared by using oligomeric poly3-aminopropyltriethoxysilane as crosslinking agents. The sorbent could selectively remove Pb(II) with high adsorption capacity. - Highlights: • Oligomer-linked graphene oxide sharply fattened function groups. • The sorbent exhibited high adsorption capacity toward Pb(II). • Pb, Cu and Fe were selectively removed from smelter industrial effluent. • The sorption could be conducted at a wide pH range of about 4.0–7.0. - Abstract: A high performance sorbent, oligomer-linked graphene oxide (GO) composite, was prepared through simple cross-linking reactions between GO sheets and poly3-aminopropyltriethoxysilane (PAS) oligomers as crosslinking agents. The three-dimensional PAS oligomers prevented GO sheets from aggregation, provided foreign molecules with easier access, and introduced a large amount of amino functional groups. The morphology, structure and property of the PAS-GO composite were determined by scanning electron microscope (SEM), transmission electron microscope (TEM), Fourie transform infrared (FTIR), X-ray diffractometer (XRD), thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). The adsorption performance of PAS-GO was investigated in removing Pb(II) ions from water. Compared to 3-aminopropyltriethoxysilane functionalized GO (AS-GO) which was prepared by the direct reaction between 3-aminopropyltriethoxysilane and GO, PAS-GO exhibited much higher adsorptivity toward Pb(II) with the maximum adsorption capacity of 312.5 mg/g at 303 K and furthermore the maximum adsorption capacity increased with increasing temperature. The adsorption could be conducted in a wide pH range of 4.0–7.0. Importantly, PAS-GO had a priority tendency to adsorb Pb, Cu and Fe from a mixed solution of metal ions, especially from a practical industrial effluent

Dissecting the role of disulfide bonds on the amyloid formation of insulin

International Nuclear Information System (INIS)

Li, Yang; Gong, Hao; Sun, Yue; Yan, Juan; Cheng, Biao; Zhang, Xin; Huang, Jing; Yu, Mengying; Guo, Yu; Zheng, Ling; Huang, Kun

2012-01-01

Highlights: ► We dissect how individual disulfide bond affects the amyloidogenicity of insulin. ► A controlled reduction system for insulin is established in this study. ► Disulfide breakage is associated with unfolding and increased amyloidogenicity. ► Breakage of A6-A11 is associated with significantly increased cytotoxicity. ► Analogs without A6-A11 have a higher potency to form high order toxic oligomers. -- Abstract: Disulfide bonds play a critical role in the stability and folding of proteins. Here, we used insulin as a model system, to investigate the role of its individual disulfide bond during the amyloid formation of insulin. Tris(2-carboxyethyl)phosphine (TCEP) was applied to reduce two of the three disulfide bonds in porcine insulin and the reduced disulfide bonds were then alkylated by iodoacetamide. Three disulfide bond-modified insulin analogs, INS-2 (lack of A6-A11), INS-3 (lack of A7-B7) and INS-6 (lack of both A6-A11 and A7-B7), were obtained. Far-UV circular dichroism (CD) spectroscopy results indicated that the secondary structure of INS-2 was the closest to insulin under neutral conditions, followed by INS-3 and INS-6, whereas in an acidic solution all analogs were essentially unfolded. To test how these modifications affect the amyloidogenicity of insulin, thioflavin-T (ThT) fluorescence and transmission electronic microscopy (TEM) were performed. Our results showed that all analogs were more prone to aggregation than insulin, with the order of aggregation rates being INS-6 > INS-3 > INS-2. Cross-linking of unmodified proteins (PICUP) assay results showed that analogs without A6-A11 (INS-2 and INS-6) have a higher potential for oligomerization than insulin and INS-3, which is accompanied with a higher cytotoxicity as the hemolytic assays of human erythrocytes suggested. The results indicated that breakage of A7-B7 induced more unfolding of the insulin structure and a higher amyloidogenicity than breakage of A6-A11, but breakage of A6

Analysis of linear and cyclic oligomers in polyamide-6 without sample preparation by liquid chromatography using the sandwich injection method. II. Methods of detection and quantification and overall long-term performance.

Science.gov (United States)

Mengerink, Y; Peters, R; Kerkhoff, M; Hellenbrand, J; Omloo, H; Andrien, J; Vestjens, M; van der Wal, S

2000-05-05

By separating the first six linear and cyclic oligomers of polyamide-6 on a reversed-phase high-performance liquid chromatographic system after sandwich injection, quantitative determination of these oligomers becomes feasible. Low-wavelength UV detection of the different oligomers and selective post-column reaction detection of the linear oligomers with o-phthalic dicarboxaldehyde (OPA) and 3-mercaptopropionic acid (3-MPA) are discussed. A general methodology for quantification of oligomers in polymers was developed. It is demonstrated that the empirically determined group-equivalent absorption coefficients and quench factors are a convenient way of quantifying linear and cyclic oligomers of nylon-6. The overall long-term performance of the method was studied by monitoring a reference sample and the calibration factors of the linear and cyclic oligomers.

Biophysical characterization data on Aβ soluble oligomers produced through a method enabling prolonged oligomer stability and biological buffer conditions

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Amanda C. Crisostomo

2015-09-01

Aβ1-40 soluble oligomers are produced that are suitable for biophysical studies requiring sufficient transient stability to exist in their “native” conformation in biological phosphate-saline buffers for extended periods of time. The production involves an initial preparation of highly monomeric Aβ in a phosphate saline buffer that transitions to fibrils and oligomers through time incubation alone, without added detergents or non-aqueous chemicals. This criteria ensures that the only difference between initial monomeric Aβ reactant and subsequent Aβ oligomer products is their degree of peptide assembly. A number of chemical and biophysical methods were used to characterize the monomeric reactants and soluble oligomer and amyloid fibril products, including chemical cross-linking, Western blots, fraction solubility, thioflvain T binding, size exclusion chromatography, transmission electron micrscopy, circular dichroism spectroscopy, and fluorescence resonance energy transfer.

Preparation of Stable Amyloid-β Oligomers Without Perturbative Methods.

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Kotler, Samuel A; Ramamoorthy, Ayyalusamy

2018-01-01

Soluble amyloid-β (Aβ) oligomers have become a focal point in the study of Alzheimer's disease due to their ability to elicit cytotoxicity. A number of recent studies have concentrated on the structural characterization of soluble Aβ oligomers to gain insight into their mechanism of toxicity. Consequently, providing reproducible protocols for the preparation of such oligomers is of utmost importance. The method presented in this chapter details a protocol for preparing an Aβ oligomer, with a primarily disordered secondary structure, without the need for chemical modification or amino acid substitution. Due to the stability of these disordered Aβ oligomers and the reproducibility with which they form, they are amenable for biophysical and high-resolution structural characterization.

Structural and functional properties of prefibrillar α-synuclein oligomers.

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Pieri, Laura; Madiona, Karine; Melki, Ronald

2016-04-14

The deposition of fibrillar alpha-synuclein (α-syn) within inclusions (Lewy bodies and Lewy neurites) in neurons and glial cells is a hallmark of synucleinopathies. α-syn populates a variety of assemblies ranging from prefibrillar oligomeric species to fibrils whose specific contribution to neurodegeneration is still unclear. Here, we compare the specific structural and biological properties of distinct soluble prefibrillar α-syn oligomers formed either spontaneously or in the presence of dopamine and glutaraldehyde. We show that both on-fibrillar assembly pathway and distinct dopamine-mediated and glutaraldehyde-cross-linked α-syn oligomers are only slightly effective in perturbing cell membrane integrity and inducing cytotoxicity, while mature fibrils exhibit the highest toxicity. In contrast to low-molecular weight and unstable oligomers, large stable α-syn oligomers seed the aggregation of soluble α-syn within reporter cells although to a lesser extent than mature α-syn fibrils. These oligomers appear elongated in shape. Our findings suggest that α-syn oligomers represent a continuum of species ranging from unstable low molecular weight particles to mature fibrils via stable elongated oligomers composed of more than 15 α-syn monomers that possess seeding capacity.

Boron-rich oligomers for BNCT

International Nuclear Information System (INIS)

Gula, M.; Perleberg, O.; Gabel, D.

2000-01-01

The synthesis of two BSH derivatives is described, which can be used for oligomerization in DNA-synthesizers. Synthesis pathways lead to final products in five and six steps, respectively. Because of chirality interesting results were expected. NMR-measurements confirm this expectation. Possible oligomers with high concentrations of boron can be attached to biomolecules. These oligomers can be explored with several imaging methods (EELS, PEM) to determine the lower detection limit of boron with these methods. (author)

Electrografting of conductive oligomers and polymers using diazonium electroreduction

International Nuclear Information System (INIS)

Lacroix, Jean Christophe; Trippe-Allard, Gaelle; Ghilane, Jalal; Martin, Pascal

2014-01-01

This paper describes the attachment of conjugated oligomers onto electrode surface through the reduction of diazonium compounds. In this connection some properties of conjugated oligomers and of layers grafted through diazonium electroreduction will first be briefly presented. The electrochemical behavior of conjugated oligomers grafted on a surface using diazonium electroreduction will then be discussed. (paper)

Electrografting of conductive oligomers and polymers using diazonium electroreduction

Science.gov (United States)

Lacroix, Jean Christophe; Trippe-Allard, Gaelle; Ghilane, Jalal; Martin, Pascal

2014-03-01

This paper describes the attachment of conjugated oligomers onto electrode surface through the reduction of diazonium compounds. In this connection some properties of conjugated oligomers and of layers grafted through diazonium electroreduction will first be briefly presented. The electrochemical behavior of conjugated oligomers grafted on a surface using diazonium electroreduction will then be discussed.

Tau Oligomers as Pathogenic Seeds: Preparation and Propagation In Vitro and In Vivo.

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Gerson, Julia E; Sengupta, Urmi; Kayed, Rakez

2017-01-01

Tau oligomers have been shown to be the main toxic tau species in a number of neurodegenerative disorders. In order to study tau oligomers both in vitro and in vivo, we have established methods for the reliable preparation, isolation, and detection of tau oligomers. Methods for the seeding of tau oligomers, isolation of tau oligomers from tissue, and detection of tau oligomers using tau oligomer-specific antibodies by biochemical and immunohistochemical methods are detailed below.

The correlation of insulin resistance with the cerebral injury and stress reaction in patients with traumatic brain injury

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Zhan Lan

2017-04-01

Full Text Available Objective: To study the correlation of insulin resistance with the cerebral injury and stress reaction in patients with traumatic brain injury (TBI. Methods: 78 patients who were diagnosed with acute traumatic brain injury in our hospital between May 2014 and August 2016 were selected as the TBI group, and 90 healthy volunteers who received physical examination during the same period were selected as the control group. The peripheral blood was collected to detect glucose, insulin and nerve injury marker molecules, stress hormones as well as oxidative stress reaction products, and the insulin resistance index (HOMA-IR was calculated. Results: The HOMA-IR index of TBI group was significantly higher than that of control group (P<0.05; serum neuron-specific enolase (NSE, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1, S100β, myelin basic protein (MBP, glucagon, growth hormone, cortisol, malondialdehyde (MDA and 8-hydroxy-deoxyguanosine (8-OHdGlevels of TBI group were significantly higher than those of control group (P<0.05; serum NSE, UCH-L1, S100β, MBP, glucagon, growth hormone, cortisol, MDA and 8-OHdG levels of patients with high HOMA-IR were significantly higher than those of patients with low HOMA-IR (P<0.05. Conclusion: The insulin resistance increases significantly in patients with traumatic brain injury, and is closely related to the degree of cerebral injury and stress reaction.

Electron beam curing polyurethane acrylate oligomer in air

International Nuclear Information System (INIS)

Zhu, Zhenkang; Chen, Xing; Zhou, Jichun; Ma, Zue-Teh

1988-01-01

It has been found according to our synthesis that a novel kind of polyurethane acrylate oligomer can be cured by electron beam in the presence of oxygen, even at normal atomospheric levels, without any additives. Irradiation of the oligomer with substantially complete cure to a solid non-tacky state is quite remarkable. It has the same gel content (90 %) in air as in nitrogen at dose of 33 kGy. Double bond conversion of the oligomer is about 50 % by I.R. (author)

Two Cases of Allergy to Insulin in Gestational Diabetes

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Gi Jun Kim

2015-09-01

Full Text Available Allergic reaction to insulin is uncommon since the introduction of human recombinant insulin preparations and is more rare in pregnant than non-pregnant females due to altered immune reaction during pregnancy. Herein, we report two cases of allergic reaction to insulin in gestational diabetes that were successfully managed. One case was a 33-year-old female using isophane-neutral protamine Hagedorn human insulin and insulin lispro. She experienced dyspnea, cough, urticaria and itching sensation at the sites of insulin injection immediately after insulin administration. We discontinued insulin therapy and started oral hypoglycemic agents with metformin and glibenclamide. The other case was a 32-year-old female using insulin lispro and insulin detemer. She experienced pruritus and burning sensation and multiple nodules at the sites of insulin injection. We changed the insulin from insulin lispro to insulin aspart. Assessments including immunoglobulin E (IgE, IgG, eosinophil, insulin antibody level and skin biopsy were performed. In the two cases, the symptoms were resolved after changing the insulin to oral agents or other insulin preparations. We report two cases of allergic reaction to human insulin in gestational diabetes due to its rarity.

In vitro synthesis and purification of PhIP-deoxyguanosine and PhIP-DNA oligomer covalent complexes

Energy Technology Data Exchange (ETDEWEB)

Freeman, J.

1994-12-01

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine compound formed when meats are cooked at high temperatures. PhIP damages DNA by forming covalent complexes with DNA carcinogen. In an effort to understand how the binding of PhIP to DNA may cause cancer, it is important to characterize the structures of PhIP-damaged DNA molecules. Our HPLC data support fluorescence and {sup 32}P Post-labeling studies which indicate the formation of several species of 2{prime}deoxyguanosine-(dG) or oligodeoxynucleotide-PhIP adducts. The reaction of PhIP with dG resulted in a reddish precipitate that was likely the major adduct, N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP) adduct, with a more polar adduct fraction remaining in the supernatant. Reversed-phase HPLC analysis of the adducts in the supernatant revealed the existence of species of much shorter retention times than the dG-C8-PhIP adduct, confirming that these species are more polar than dG-C8-PhIP. At least four adducts were formed in the reaction of PhIP with DNA oligomer. HPLC analysis of the PhIP-DNA oligomer supernatant after butanol extractions revealed four unresolved peaks which spectra had maximum wavelengths between 340 and 360 nm. Though adduct peaks were not completely resolved, there was {approximately}3 minutes interval between the DNA oligomer peak and the adduct peaks. Furthermore, fluorescence emission data of the DNA oligomer-PhIP adduct solution show heterogeneous binding. The more polar PhIP adducts were fraction-collected and their structures will be solved by nuclear magnetic resonance or x-ray crystallography.

Pigments and oligomers for inks - moving towards the best combination

International Nuclear Information System (INIS)

Hutchinson, I.; Smith, S.; Grierson, W.; Devine, E.

1999-01-01

The formulation of UV curable printing inks depends on several complex factors. If the individual components of the ink are not complementary, then performance problems can arise. One critical combination is that between the pigment and the oligomer. In a new approach to improve understanding of pigment/oligomer interactions, the resources of a pigment manufacturer and an oligomer manufacturer have been combined to investigate the problem. Initial screening of process yellow pigments and several oligomer types highlighted performance variations which were then examined in more detail

Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity

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Smith, Levi M.; Strittmatter, Stephen M.

2017-01-01

In Alzheimer’s disease (AD), insoluble and fibrillary amyloid-β (Aβ) peptide accumulates in plaques. However, soluble Aβ oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Aβ oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Aβ binding proteins, and one or more are likely to mediate Aβ oligomer toxicity in AD. Cellular prion protein (PrPC) is a high-affinity Aβ oligomer binding site, and a range of data delineates a signaling pathway leading from Aβ complexation with PrPC to neuronal impairment. Further study of Aβ binding proteins will define the molecular basis of this crucial step in AD pathogenesis. PMID:27940601

Insulin structure and stability.

Science.gov (United States)

Brange, J; Langkjoer, L

1993-01-01

property of being able to counteract associated insulin from being disassembled. Chemical deterioration of insulin during storage of pharmaceutical preparations is mainly due to two categories of chemical reactions, hydrolysis and intermolecular transformation reactions leading to insulin HMWT products. The predominant hydrolysis reaction is deamidation of Asn residues which in acid solution takes place at residue A21, in neutral medium at residue B3. An amazing hydrolytic cleavage of the backbone A chain, presumably autocatalyzed by an adjacent insulin molecule, has been identified in insulin preparations containing rhombohedral crystals in combination with free zinc ions.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis of Dicyclopentadiene Oligomer Over Nanoporous Al-MCM-41 Catalysts.

Science.gov (United States)

Park, Eunseo; Kim, Jinhan; Yim, Jin-Heong; Han, Jeongsik; Kwon, Tae Soo; Park, Y K; Jeon, Jong-Ki

2016-05-01

One step reaction composed of DCPD oligomerization and DCPD oligomer isomerization was investigated over nanoporous Al-MCM-41 catalysts. The effects of aluminum grafting over MCM-41 on the catalyst characteristics were studied with respect to the synthesis of TCPD isomer. Physical and chemical properties of the catalysts were analyzed by N2 adsorption, temperature-programmed desorption of ammonia, and infrared spectroscopy of adsorbed pyridine. The overall number of acid sites as well as the number of Lewis acid sites increased with increasing of aluminum content over MCM-41. When utilizing MCM-41 and Al-MCM-41 as the catalyst, DCPD oligomerization reaction activity greatly increased compared to the thermal reaction. The highest TCPD isomer selectivity over the Al-MCM-41 catalyst with the highest aluminum content could be ascribed to the largest amount of acid sites. This study showed an increased level of TCPD isomer selectivity by an increasing level of Lewis acid sites through aluminum addition over MCM-41.

An approach for degradation of grape seed and skin proanthocyanidin polymers into oligomers by sulphurous acid.

Science.gov (United States)

Luo, Lanxin; Cui, Yan; Cheng, Jinhui; Fang, Bairui; Wei, Zongmin; Sun, Baoshan

2018-08-01

To develop an efficient method for degradation of grape seed and skin proanthocyanidins polymers into oligomers, an optimized sulphurous acid degradation conditions for grape seed with the temperature of 60 °C, reaction time of 60 min and sample-sulphurous acid ratio of 1:0.2, and for grape skin with the temperature of 40 °C, reaction time of 60 min and sample-sulphurous acid ratio of 1:0.2, were established. Afterwards, HSCCC and prep-HPLC were used to fractionate and isolate individual proanthocyanidin oligomers from the degradation products. Total of ten dimeric or trimeric procyanidins were obtained, and most of them presented high yield (from 0.7 mg to 13.6 mg per run in grape seed and from 0.5 mg to 4.1 mg per run in grape skin) and high purity (over 90%). The proposed method provides a new way for large preparation of oligomeric proanthocyanidins from naturally abundant and wasted polymeric ones. Copyright © 2018 Elsevier Ltd. All rights reserved.

α-Synuclein oligomers induced by docosahexaenoic acid affect membrane integrity.

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Chiara Fecchio

Full Text Available A key feature of Parkinson disease is the aggregation of α-synuclein and its intracellular deposition in fibrillar form. Increasing evidence suggests that the pathogenicity of α-synuclein is correlated with the activity of oligomers formed in the early stages of its aggregation process. Oligomers toxicity seems to be associated with both their ability to bind and affect the integrity of lipid membranes. Previously, we demonstrated that α-synuclein forms oligomeric species in the presence of docosahexaenoic acid and that these species are toxic to cells. Here we studied how interaction of these oligomers with membranes results in cell toxicity, using cellular membrane-mimetic and cell model systems. We found that α-synuclein oligomers are able to interact with large and small unilamellar negatively charged vesicles acquiring an increased amount of α-helical structure, which induces small molecules release. We explored the possibility that oligomers effects on membranes could be due to pore formation, to a detergent-like effect or to fibril growth on the membrane. Our biophysical and cellular findings are consistent with a model where α-synuclein oligomers are embedded into the lipid bilayer causing transient alteration of membrane permeability.

Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and brain tissue.

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Bruggink, Kim A; Jongbloed, Wesley; Biemans, Elisanne A L M; Veerhuis, Rob; Claassen, Jurgen A H R; Kuiperij, H Bea; Verbeek, Marcel M

2013-02-15

Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer's disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for Aβ oligomers by using the same capture and (labeled) detection antibody. The ELISA predominantly recognizes relatively small oligomers (10-25 kDa) and not monomers. In brain tissue of APP/PS1 transgenic mice, we found that Aβ oligomer levels increase with age. However, for measurements in human samples, pretreatment to remove human anti-mouse antibodies (HAMAs) was required. In HAMA-depleted human hippocampal extracts, the Aβ oligomer concentration was significantly increased in AD compared with nondemented controls. Aβ oligomer levels could also be quantified in pretreated cerebrospinal fluid (CSF) samples; however, no difference was detected between AD and control groups. Our data suggest that levels of small oligomers might not be suitable as biomarkers for AD. In addition, we demonstrate the importance of avoiding HAMA interference in assays to quantify Aβ oligomers in human body fluids. Copyright © 2012 Elsevier Inc. All rights reserved.

Star-shaped tetrathiafulvalene oligomers towards the construction of conducting supramolecular assembly.

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Iyoda, Masahiko; Hasegawa, Masashi

2015-01-01

The construction of redox-active supramolecular assemblies based on star-shaped and radially expanded tetrathiafulvalene (TTF) oligomers with divergent and extended conjugation is summarized. Star-shaped TTF oligomers easily self-aggregate with a nanophase separation to produce supramolecular structures, and their TTF units stack face-to-face to form columnar structures using the fastener effect. Based on redox-active self-organizing supramolecular structures, conducting nanoobjects are constructed by doping of TTF oligomers with oxidants after the formation of such nanostructures. Although radical cations derived from TTF oligomers strongly interact in solution to produce a mixed-valence dimer and π-dimer, it seems to be difficult to produce nanoobjects of radical cations different from those of neutral TTF oligomers. In some cases, however, radical cations form nanostructured fibers and rods by controlling the supramolecular assembly, oxidation states, and counter anions employed.

Oligomers and Polymers Based on Pentacene Building Blocks

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Lehnherr, Dan; Tykwinski, Rik R.

2010-01-01

Functionalized pentacene derivatives continue to provide unique materials for organic semiconductor applications. Although oligomers and polymers based on pentacene building blocks remain quite rare, recent synthetic achievements have provided a number of examples with varied structural motifs. This review highlights recent work in this area and, when possible, contrasts the properties of defined-length pentacene oligomers to those of mono- and polymeric systems.

Electrorheology of aniline oligomers

Czech Academy of Sciences Publication Activity Database

Mrlík, M.; Sedlačík, M.; Pavlínek, V.; Bober, Patrycja; Trchová, Miroslava; Stejskal, Jaroslav; Sáha, P.

2013-01-01

Roč. 291, č. 9 (2013), s. 2079-2086 ISSN 0303-402X R&D Projects: GA ČR GA202/09/1626 Institutional support: RVO:61389013 Keywords : anilin e oligomers * polyaniline * electrorheology Subject RIV: JI - Composite Materials Impact factor: 2.410, year: 2013

Driving Chemical Reactions in Plasmonic Nanogaps with Electrohydrodynamic Flow.

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Thrift, William J; Nguyen, Cuong Q; Darvishzadeh-Varcheie, Mahsa; Zare, Siavash; Sharac, Nicholas; Sanderson, Robert N; Dupper, Torin J; Hochbaum, Allon I; Capolino, Filippo; Abdolhosseini Qomi, Mohammad Javad; Ragan, Regina

2017-11-28

Nanoparticles from colloidal solution-with controlled composition, size, and shape-serve as excellent building blocks for plasmonic devices and metasurfaces. However, understanding hierarchical driving forces affecting the geometry of oligomers and interparticle gap spacings is still needed to fabricate high-density architectures over large areas. Here, electrohydrodynamic (EHD) flow is used as a long-range driving force to enable carbodiimide cross-linking between nanospheres and produces oligomers exhibiting sub-nanometer gap spacing over mm 2 areas. Anhydride linkers between nanospheres are observed via surface-enhanced Raman scattering (SERS) spectroscopy. The anhydride linkers are cleavable via nucleophilic substitution and enable placement of nucleophilic molecules in electromagnetic hotspots. Atomistic simulations elucidate that the transient attractive force provided by EHD flow is needed to provide a sufficient residence time for anhydride cross-linking to overcome slow reaction kinetics. This synergistic analysis shows assembly involves an interplay between long-range driving forces increasing nanoparticle-nanoparticle interactions and probability that ligands are in proximity to overcome activation energy barriers associated with short-range chemical reactions. Absorption spectroscopy and electromagnetic full-wave simulations show that variations in nanogap spacing have a greater influence on optical response than variations in close-packed oligomer geometry. The EHD flow-anhydride cross-linking assembly method enables close-packed oligomers with uniform gap spacings that produce uniform SERS enhancement factors. These results demonstrate the efficacy of colloidal driving forces to selectively enable chemical reactions leading to future assembly platforms for large-area nanodevices.

Synthesis, optical properties and supramolecular order of π-conjugated 2,5-di(alcoxy)phenyleneethynylene oligomers

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Castruita, Griselda; Arias, Eduardo; Moggio, Ivana; Pérez, Fátima; Medellín, Diana; Torres, Román; Ziolo, Ronald; Olivas, Amelia; Giorgetti, Emilia; Muniz-Miranda, Maurizio

2009-11-01

Two series of 2,5-di(alkoxy)phenyleneethynylene oligomers were synthesized by Sonogashira-Heck coupling reaction. The chemical structure was corroborated by 1H, 13C, APT, DEPT-135 NMR, Raman, FTIR and MALDI-TOF mass spectrometry. The chemical structure of the molecules has been varied in order to study the effect on the physicochemical and optoelectronic properties of the different chain lengths of the lateral substituents (dodecanoxy and butoxy), of different terminal groups (H, Br and I), of different chain length (3, 5 and 7 repeat units in the main conjugated backbone). The thermal properties were analyzed by DSC, TGA and by temperature-dependent X-ray diffraction. The diffraction studies of the oligomers revealed a crystalline behavior for the butoxy series, while for the dodecanoxy series the X-ray patterns are consistent with a supramolecular organization formed of randomly distributed crystalline domains that exhibit a periodic structure at small angles, indicating the presence of a lamellar order. The optical properties can be modulated within a series by increasing the length of the conjugated oligomer chain. On the contrary, neither the length of the alkoxy substituents nor the terminal groups have effect on the shape of the absorption and emission spectra.

Oligomers and Polymers Based on Pentacene Building Blocks

Directory of Open Access Journals (Sweden)

Dan Lehnherr

2010-04-01

Full Text Available Functionalized pentacene derivatives continue to provide unique materials for organic semiconductor applications. Although oligomers and polymers based on pentacene building blocks remain quite rare, recent synthetic achievements have provided a number of examples with varied structural motifs. This review highlights recent work in this area and, when possible, contrasts the properties of defined-length pentacene oligomers to those of mono- and polymeric systems.

Amyloid oligomers and protofibrils, but not filaments, self-replicate from native lysozyme.

Science.gov (United States)

Mulaj, Mentor; Foley, Joseph; Muschol, Martin

2014-06-25

Self-assembly of amyloid fibrils is the molecular mechanism best known for its connection with debilitating human disorders such as Alzheimer's disease but is also associated with various functional cellular responses. There is increasing evidence that amyloid formation proceeds along two distinct assembly pathways involving either globular oligomers and protofibrils or rigid monomeric filaments. Oligomers, in particular, have been implicated as the dominant molecular species responsible for pathogenesis. Yet the molecular mechanisms regulating their self-assembly have remained elusive. Here we show that oligomers/protofibrils and monomeric filaments, formed along distinct assembly pathways, display critical differences in their ability to template amyloid growth at physiological vs denaturing temperatures. At physiological temperatures, amyloid filaments remained stable but could not seed growth of native monomers. In contrast, oligomers and protofibrils not only remained intact but were capable of self-replication using native monomers as the substrate. Kinetic data further suggested that this prion-like growth mode of oligomers/protofibrils involved two distinct activities operating orthogonal from each other: autocatalytic self-replication of oligomers from native monomers and nucleated polymerization of oligomers into protofibrils. The environmental changes to stability and templating competence of these different amyloid species in different environments are likely to be important for understanding the molecular mechanisms underlying both pathogenic and functional amyloid self-assembly.

Effects of lattice fluctuations on electronic transmission in metal/conjugated-oligomer/metal structures

International Nuclear Information System (INIS)

Yu, Z.G.; Smith, D.L.; Saxena, A.; Bishop, A.R.

1997-01-01

The electronic transmission across metal/conjugated-oligomer/metal structures in the presence of lattice fluctuations is studied for short oligomer chains. The lattice fluctuations are approximated by static white noise disorder. Resonant transmission occurs when the energy of an incoming electron coincides with a discrete electronic level of the oligomer. The corresponding transmission peak diminishes in intensity with increasing disorder strength. Because of disorder there is an enhancement of the electronic transmission for energies that lie within the electronic gap of the oligomer. If fluctuations are sufficiently strong, a transmission peak within the gap is found at the midgap energy E=0 for degenerate conjugated oligomers (e.g., trans-polyacetylene) and E≠0 for AB-type degenerate oligomers. These results can be interpreted in terms of soliton-antisoliton states created by lattice fluctuations. copyright 1997 The American Physical Society

Small angle X-ray scattering-based elucidation of the self-association mechanism of human insulin analogue lys(B29)(N(e)¿-carboxyheptadecanoyl) des(B30)

DEFF Research Database (Denmark)

Jensen, Malene Hillerup; Wahlund, Per-Olof; Toft, Katrine Nørgaard

2013-01-01

of biophysical and structural methods (field flow fractionation, dynamic and multiangle light scattering, circular dichroism, size exclusion chromatography, and crystallography), we propose a mechanism for the self-association expected to occur upon subcutaneous injection of this insulin analogue. SAXS data...... provide evidence of the in solution structure of the self-associated oligomer, which is a long straight rod composed of "tense" state insulin hexamers (T(6)-hexamers) as the smallest repeating unit. The smallest oligomer building block in the process is a T(6)T(6)-dihexamer. This tense dihexamer is formed...... by the allosteric change of the initial equilibrium between a proposed "relaxed" state R(6)-hexamer and an R(3)T(3)T(3)R(3)-dihexamer. The allosteric change from relaxed to tense is triggered by removal of phenol, mimicking subcutaneous injection. The data hence provide the first unequivocal evidence...

Interpenetrating polymer networks based on cyanate ester and fluorinated ethynyl-terminated imide oligomers

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Y. Wen

2017-12-01

Full Text Available Highly soluble fluorinated ethynyl-terminated imide (FETI oligomers were prepared via a conventional one-step method in m-cresol, using 4, 4′-(hexafluoroisopropylidene diphthalic anhydride and 2, 2′-bis(trifluoromethyl benzidine as the monomers, and ethynylphthalic anhydride as the end-capper; then interpenetrating polymer networks (IPN were formulated from FETI oligomers and bisphenol A dicyanate ester (BADCy through a solvent-free procedure, and their thermal, mechanical, and dielectric properties were fully characterized. The curing mechanism was studied by model reactions using nitrogen nuclear magnetic resonance. As evidenced by differential scanning calorimetry analysis and rheological measurements, the FETI/BADCy blends exhibited lower curing temperature and shorter gelation time in comparison with pure BADCy due to the catalytic effects of ethynyl and residue amic acid groups. The properties of IPNs were fully compared with those of polycyanurate, and the results revealed that the incorporation of FETI into cyanate ester resins could significantly improve the toughness, glass transition temperatures, mechanical and dielectric properties of the resultant IPNs.

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

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Jackson George R

2011-06-01

Full Text Available Abstract Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I, and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

Antioxidant Activity of Hispidin Oligomers from Medicinal Fungi: A DFT Study

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El Hassane Anouar

2014-03-01

Full Text Available Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biological activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and determine the favored mechanism involved in free radical scavenging, DFT calculations were carried out at the B3P86/6-31+G (d, p level of theory in gas and solvent. The results showed that bond dissociation enthalpies of OH groups of hispidin oligomers (ArOH and spin density delocalization of related radicals (ArO• are the appropriate parameters to clarify the differences between the observed antioxidant activities for the four oligomers. The effect of the number of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were determined. Thermodynamic and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin density distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.

Photo-electron spectroscopy study of energy levels in conjugated oligomers

NARCIS (Netherlands)

Veenstra, SC; Heeres, A; Stalmach, U; Wildeman, J; Hadziioannou, G; Sawatzky, GA; Jonkman, HT; Moss, SC

2002-01-01

We report on the valence orbital structure of poly(para-phenylenevinylene) (PPV)-like oligomers. We studied these molecules as isolated oligomers in the gas phase, as well as in thin films deposited on metal substrates. We use a simple model based on a previously reported Hamiltonian that accurately

Computer simulations and theoretical aspects of the depletion interaction in protein-oligomer mixtures.

Science.gov (United States)

Boncina, M; Rescic, J; Kalyuzhnyi, Yu V; Vlachy, V

2007-07-21

The depletion interaction between proteins caused by addition of either uncharged or partially charged oligomers was studied using the canonical Monte Carlo simulation technique and the integral equation theory. A protein molecule was modeled in two different ways: either as (i) a hard sphere of diameter 30.0 A with net charge 0, or +5, or (ii) as a hard sphere with discrete charges (depending on the pH of solution) of diameter 45.4 A. The oligomers were pictured as tangentially jointed, uncharged, or partially charged, hard spheres. The ions of a simple electrolyte present in solution were represented by charged hard spheres distributed in the dielectric continuum. In this study we were particularly interested in changes of the protein-protein pair-distribution function, caused by addition of the oligomer component. In agreement with previous studies we found that addition of a nonadsorbing oligomer reduces the phase stability of solution, which is reflected in the shape of the protein-protein pair-distribution function. The value of this function in protein-protein contact increases with increasing oligomer concentration, and is larger for charged oligomers. The range of the depletion interaction and its strength also depend on the length (number of monomer units) of the oligomer chain. The integral equation theory, based on the Wertheim Ornstein-Zernike approach applied in this study, was found to be in fair agreement with Monte Carlo results only for very short oligomers. The computer simulations for a model mimicking the lysozyme molecule (ii) are in qualitative agreement with small-angle neutron experiments for lysozyme-dextran mixtures.

Fundamental studies on the insulin receptor in rabbit erythrocytes

Energy Technology Data Exchange (ETDEWEB)

Shinomiya, Y; Kagawa, S; Konishi, Y; Morimoto, H; Tsumura, Y [Hyogo Medical Coll. (Japan)

1975-09-01

The authors studied the binding of insulin to rabbit erythrocytes as a mode case in the hope of characterizing the physiologic role of the binding of insulin to receptor in both normal adults and patients. Specific binding sites for insulin were detected in rabbit erythrocytes. The characteristics of the binding were similar to those observed in other target tissues. The specific binding of /sup 125/I-labeled insulin was competitively inhibited by a small amount of unlabeled insulin and was completely inhibited by 1,000 ng/ml of unlabeled insulin. Glucagon, however, had no effect on the insulin binding to fat cells or liver membranes nor had it any effect on the binding of insulin to rabbit erythrocytes. Scatchard analysis of this binding reaction indicated two different binding sites with Ksub(aff)=3.2 x 10/sup 8//M, Ksub(diss)=3.1 x 10/sup -9/M; Ksub(aff)=1.4 x 10/sup 8//M, Ksub(diss)=7.1 x 10/sup -9/M respectively, and the binding capacities of each site were estimated at 0.011 ng/4 x 10/sup 8/ cells and 0.138 ng/4 x 10/sup 8/ cells. The binding of /sup 125/I-insulin to rabbit erythrocytes was a saturable function of the insulin concentration and was a linear function of cell concentration. The pH optimum for the reaction was 7.4 at 0/sup 0/C, the amount of insulin binding increased continuously under the reaction and this binding reaction reached a steady state after 10 to 15hr. On the other hand, the specific binding of insulin at higher temperatures showed maximal amounts after 20 to 30 min. and subsequently fell off at later time points.

Applications of oligomers for nanostructured conducting polymers.

Science.gov (United States)

Wang, Yue; Tran, Henry D; Kaner, Richard B

2011-01-03

This Feature Article provides an overview of the distinctive nanostructures that aniline oligomers form and the applications of these oligomers for shaping the nanoscale morphologies and chirality of conducting polymers. We focus on the synthetic methods for achieving such goals and highlight the underlying mechanisms. The clear advantages of each method and their possible drawbacks are discussed. Assembly and applications of these novel organic (semi)conducting nanomaterials are also outlined. We conclude this article with our perspective on the main challenges, new opportunities, and future directions for this nascent yet vibrant field of research. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Donor-acceptor-donor thienyl/bithienyl-benzothiadiazole/quinoxaline model oligomers: experimental and theoretical studies.

Science.gov (United States)

Pina, João; de Melo, J Seixas; Breusov, D; Scherf, Ullrich

2013-09-28

A comprehensive spectral and photophysical investigation of four donor-acceptor-donor (DAD) oligomers consisting of electron-deficient 2,1,3-benzothiadiazole or quinoxaline moieties linked to electron-rich thienyl or bithienyl units has been undertaken. Additionally, a bis(dithienyl) substituted naphthalene was also investigated. The D-A-D nature of these oligomers resulted in the presence of an intramolecular charge transfer (ICT) state, which was further substantiated by solvatochromism studies (analysis with the Lippert-Mataga formalism). Hereby, significant differences have been obtained for the fluorescence quantum yields of the oligomers in the non-polar solvent methylcyclohexane vs. the polar ethanol. The study was further complemented with the determination of the optimized ground-state molecular geometries for the oligomers together with the prediction of the lowest vertical one-electron excitation energy and the relevant molecular orbital contours using DFT calculations. The electronic transitions show a clear HOMO to LUMO charge-transfer character. In contrast to the thiophene oligomers (the oligothiophenes with n = 1-7), where the intersystem crossing (ISC) yield decreases with n, the studied DAD oligomers were found to show an increase in the ISC efficiency with the number of (donor) thienyl units.

Laser-Induced Population Inversion in Rhodamine 6G for Lysozyme Oligomer Detection.

Science.gov (United States)

Hanczyc, Piotr; Sznitko, Lech

2017-06-06

Fluorescence spectroscopy is a common method for detecting amyloid fibrils in which organic fluorophores are used as markers that exhibit an increase in quantum yield upon binding. However, most of the dyes exhibit enhanced emission only when bound to mature fibrils, and significantly weaker signals are obtained in the presence of amyloid oligomers. In the concept of population inversion, a laser is used as an excitation source to keep the major fraction of molecules in the excited state to create the pathways for the occurrence of stimulated emission. In the case of the proteins, the conformational changes lead to the self-ordering and thus different light scattering conditions that can influence the optical signatures of the generated light. Using this methodology, we show it is possible to optically detect amyloid oligomers using commonly available staining dyes in which population inversion can be induced. The results indicate that rhodamine 6G molecules are complexed with oligomers, and using a laser-assisted methodology, weakly emissive states can be detected. Significant spectral red-shifting of rhodamine 6G dispersed with amyloid oligomers and a notable difference determined by comparison of spectra of the fibrils suggest the existence of specific dye aggregates around the oligomer binding sites. This approach can provide new insights into intermediate oligomer states that are believed to be responsible for toxic seeding in neurodegeneration diseases.

Solvent Free Low-Melt Viscosity Imide Oligomers And Thermosetting Polyimide Composites

Science.gov (United States)

Chuang, CHun-Hua (Inventor)

2006-01-01

This invention relates to the composition and a solvent-free process for preparing novel imide oligomers and polymers specifically formulated with effective amounts of a dianhydride such as 2,3,3',4-biphenyltetra carboxylic dianydride (a-BPDA), at least one aromatic diamine' and an endcapped of 4-phenylethynylphthalic anhydride (PEPA) or nadic anhydride to produce imide oligomers that possess a low-melt viscosity of 1-60 poise at 260-280" C. When the imide oligomer melt is cured at about 371 C. in a press or autoclave under 100-500 psi, the melt resulted in a thermoset polyimide having a glass transition temperature (T(sub g)) equal to and above 310 C. A novel feature of this process is that the monomers; namely the dianhydrides, diamines and the endcaps, are melt processable to form imide oligomers at temperatures ranging between 232-280 C. (450-535 F) without any solvent. These low-melt imide oligomers can be easily processed by resin transfer molding (RTM), vacuum-assisted resin transfer molding (VARTM) or the resin infusion process with fiber preforms e.g. carbon, glass or quartz preforms to produce polyimide matrix composites with 288-343C (550-650 F) high temperature performance capability.

Aniline oligomers versus polyaniline

Czech Academy of Sciences Publication Activity Database

Stejskal, Jaroslav; Trchová, Miroslava

2012-01-01

Roč. 61, č. 2 (2012), s. 240-251 ISSN 0959-8103 R&D Projects: GA AV ČR IAA400500905; GA AV ČR IAA100500902; GA ČR GA203/08/0686; GA ČR GA202/09/1626 Institutional research plan: CEZ:AV0Z40500505 Keywords : polyaniline * anilin e oligomers * anilin e Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.125, year: 2012

SYNTHESIS OF THE FULLY PROTECTED PHOSPHORAMIDITE OF THE BENZENE-DNA ADDUCT, N2- (4-HYDROXYPHENYL)-2'-DEOXYGUANOSINE AND INCORPORATION OF THE LATER INTO DNA OLIGOMERS

Energy Technology Data Exchange (ETDEWEB)

Chenna, Ahmed; Gupta, Ramesh C.; Bonala, Radha R.; Johnson, Francis; Huang, Bo

2008-06-09

N2-(4-Hydroxyphenyl)-2'-deoxyguanosine-5'-O-DMT-3'-phosphoramidite has been synthesized and used to incorporate the N2-(4-hydroxyphenyl)-2'-dG (N2-4-HOPh-dG) into DNA, using solid-state synthesis technology. The key step to obtaining the xenonucleoside is a palladium (Xantphos-chelated) catalyzed N2-arylation (Buchwald-Hartwig reaction) of a fully protected 2'-deoxyguanosine derivative by 4-isobutyryloxybromobenzene. The reaction proceeded in good yield and the adduct was converted to the required 5'-O-DMT-3'-O-phosphoramidite by standard methods. The latter was used to synthesize oligodeoxynucleotides in which the N2-4-HOPh-dG adduct was incorporated site-specifically. The oligomers were purified by reverse-phase HPLC. Enzymatic hydrolysis and HPLC analysis confirmed the presence of this adduct in the oligomers.

Pulse radiolysis study of zinc(II)-insulin

Energy Technology Data Exchange (ETDEWEB)

Elliot, A J; Wilkinson, F; Armstrong, D A [Calgary Univ., Alberta (Canada). Dept. of Chemistry

1980-07-01

Reactions of e/sup -/sub(aq) with zinc(II)-insulin at pH 6.6 and 9.0 yielded relatively low disulphide anion absorptions, suggesting e/sup -/sub(aq) reacts at other sites than S-S. A similar conclusion was reached for the reaction of COsub(./2) where an even lower yield of disulphide anion was found. However, here the disulphide anion yield increased with 'prepulsing'. Simultaneously the rate constant decreased, implying that a more reactive site was 'cleaned up'. While no reaction of Brsub(./2) with insulin was observed, both OH and Clsub(./2) reacted rapidly and predominantly at the tyrosine residues. The second order rate constants, calculated in terms of insulin monomer concentrations, are reported for e/sup -/sub(aq) COsub(./2) and Clsub(./2). The transient spectra qualitatively support evidence regarding the accessibility of S-S bonds and tyrosine residues in the various forms of insulin as predicted from earlier studies.

Chemical stability of insulin. 5. Isolation, characterization and identification of insulin transformation products.

Science.gov (United States)

Brange, J; Hallund, O; Sørensen, E

1992-01-01

During storage of insulin formulated for therapy, minor amounts of various degradation and covalent di- and polymerization products are formed [1-3]. The main chemical transformation products were isolated from aged preparations and characterized chemically and biologically. The most prominent products formed in neutral medium were identified as a mixture of deamidation products hydrolyzed at residue B3, namely isoAsp B3 and Asp B3 derivatives. A hydrolysis product formed only in crystals of insulin zinc suspensions containing a surplus of zinc ions in the supernatant was identified as an A8-A9 cleavage product. The small amounts of covalent insulin dimers (CID) formed in all formulations were shown to be a heterogenous mixture of 5-6 different CIDs with a composition dependent on the pharmaceutical formulation. The chemical characteristics of the CIDs indicate that they are formed through a transamidation reaction mainly between the B-chain N-terminal and one of the four amide side-chains of the A chain. GlnA15, AsnA18 and, in particular, AsnA21 participate in the formation of such isopeptide links between two insulin molecules. The covalent insulin-protamine products (CIPP) formed during storage of NPH preparations presumably originate from a similar reaction between the protamine N-terminal with an amide in insulin. Covalent polymerization products, mainly formed during storage of amorphously suspended insulin at higher temperature, were shown to be due to disulfide interactions. Biological in vivo potencies relative to native insulin were less than 2% for the split-(A8-A9)-product and for the covalent disulfide exchange polymers, 4% for the CIPP, approximately 15% for the CIDs, whereas the B3 derivatives exhibited full potency. Rabbit immunization experiments revealed that none of the insulin transformation products had significantly increased immunogenicity in rabbits.

Structural Investigations of on-pathway Oligomers of α-Synuclein

DEFF Research Database (Denmark)

Pedersen, Martin Nors; Horvath, Istvan; Weise, Christoph F.

Academy of Sciences of the United States of America 108(8): 3246-3251. Horvath, I., et al. (2012). "Mechanisms of protein oligomerization: In-hibitor of functional amyloids templates a-synuclein fibrilla-tion." Journal of the American Chemical Society. Spillantini, M. G., et al. (1997). "[alpha...... by decomposition of SAXS data from the evolving fibrillating solution (Giehm et al. 2011). NMR data have furthermore suggested that the C-terminal is exposed on oligomers obtained by incubation with the ligand FN075 (Horvath et al. 2012). In this study we aim at obtaining SAXS data from isolated stabilized...... oligomer (MAX-lab, May 2012); data analysis is in progress. ITC experiments are furthermore planned to more accurately determine the stoichiometry between α-synuclein and FN075. Horvath and co-workers have already shown that the FN075 stabilized oligomer is on pathway. We have shown that the in...

Characterization of methacrylate-based composites containing thio-urethane oligomers.

Science.gov (United States)

Bacchi, Atais; Nelson, Morgan; Pfeifer, Carmem S

2016-02-01

To evaluate the ability of thio-urethane oligomers to improve the properties of restorative composite resins. Oligomers were synthesized by combining 1,6-hexanediol-diissocyante (aliphatic) with pentaerythritol tetra-3-mercaptopropionate (PETMP) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (aromatic) with trimethylol-tris-3-mercaptopropionate (TMP), at 1:2 isocyanate:thiol, leaving pendant thiols. Oligomers were added at 0-20 wt% to BisGMA-TEGDMA (70-30 wt%). Silanated inorganic fillers were added (70 wt%). Materials were photoactivated at 800 mW/cm(2) filtered to 320-500 nm. Near-IR was used to follow degree of methacrylate conversion (DC). Mechanical properties were evaluated in three-point bending with 2 mm × 2 mm × 25 mm bars for flexural strength/modulus and toughness (FS/E, and T) according to ISO 4049, and 2 mm × 5 mm × 25 mm notched specimens for fracture toughness (KIC). Polymerization stress (PS) was measured on the Bioman. Results were analyzed with ANOVA/Tukey's test (α=5%). Significant increase in DC was observed in thio-urethane-containing materials especially for the group with 20 wt% of aliphatic version. Materials composed by oligomers also promoted higher FS, E, and KIC in comparison to controls irrespective of thio-urethane type. A significant increase in toughness was detected by ANOVA, but not distinguished in the groups. The PS was significantly reduced by the presence of thio-urethane for almost all groups. The use of thio-urethane oligomer to compose methacrylate-based restorative composite promote increase in DC, FS, E and KIC while significant reduces PS. A simple additive was shown to reduce stress while increasing convrersion and mechanical properties, mainly fracture toughness. This has he potential of increasing the service life of dental composites, without changing current operatory procedures. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Acrylate oligomers in ultraviolet cured PSA's glass transition, molecular weight versus peel strength

International Nuclear Information System (INIS)

Miller, H.C.

1999-01-01

Typically those not skilled in the art relate Glass Transition Temperature to Pressure Sensitive Adhesives. You need a low Tg material to prepare good pressure sensitive adhesives. This report deals with a wide range acrylate terminated oligomers in a standard formulation. Molecular weight, chemical structure variations are examined versus the Glass Transition of the oligomers and final peel strength. Each formulated adhesive will require unique oligomer properties to reach one hundred newtons per 100 millimeters (5.71 pounds per square inch) peel strength. Excellent peel strengths may be obtained with oligomer molecular weight ranging from six thousand to one thousand molecular weight and glass transition temperatures ranging from minus seventy four degrees centigrade up to thirteen degrees centigrade

On the labelling of insuline and insuline derivatives with tritium and carbon-14

International Nuclear Information System (INIS)

Uschkoreit, J.

1979-01-01

Two different labelling methods were investigated. By means of the Wilzbach labelling with diaminosuberoylinsuline the insuline is irreversibly altered. As a second method the reductive methylation was used, in doing so it was possible to distinguish between mono and dimethylated parts of the reaction product by using C-14 labelled formaldehyde. Furthermore four N,N-dimethylated insuline derivatives were isolated with yields of 25 until 35%. By using C-14 and h-3 labelled reagents insuline can be labelled doubly. Moreover N-terminal amino groups could be protected irreversibly with this method. Furthermore structure-function investigations and investigations concerning the insuline metabolism were done. (SPI) [de

Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent

Science.gov (United States)

Ibrahim, Khalid A.; El-Eswed, Bassam I.; Abu-Sbeih, Khaleel A.; Arafat, Tawfeeq A.; Al Omari, Mahmoud M. H.; Darras, Fouad H.; Badwan, Adnan A.

2016-01-01

An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers) in medicine and food fields because they are not only water-soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC/MS), and ninhydrin test. PMID:27455287

Thio-urethane oligomers improve the properties of light-cured resin cements.

Science.gov (United States)

Bacchi, Ataís; Consani, Rafael L; Martim, Gedalias C; Pfeifer, Carmem S

2015-05-01

Thio-urethanes were synthesized by combining 1,6-hexanediol-diissocyante (aliphatic) with pentaerythritol tetra-3-mercaptopropionate (PETMP) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (aromatic) with trimethylol-tris-3-mercaptopropionate (TMP), at 1:2 isocyanate:thiol, leaving pendant thiols. Oligomers were added at 10-30 phr to BisGMA-UDMA-TEGDMA (5:3:2, BUT). 25 wt% silanated inorganic fillers were added. Commercial cement (Relyx Veneer, 3M-ESPE) was also evaluated with 10-20 phr of aromatic oligomer. Near-IR was used to follow methacrylate conversion (DC) and rate of polymerization (Rpmax). Mechanical properties were evaluated in three-point bending (ISO 4049) for flexural strength/modulus (FS/FM, and toughness), and notched specimens (ASTM Standard E399-90) for fracture toughness (KIC). Polymerization stress (PS) was measured on the Bioman. Volumetric shrinkage (VS, %) was measured with the bonded disk technique. Results were analyzed with ANOVA/Tukey's test (α=5%). In general terms, for BUT cements, conversion and mechanical properties in flexure increased for selected groups with the addition of thio-urethane oligomers. The aromatic versions resulted in greater FS/FM than aliphatic. Fracture toughness increased by two-fold in the experimental groups (from 1.17 ± 0.36 MPam(1/2) to around 3.23 ± 0.22 MPam(1/2)). Rpmax decreased with the addition of thio-urethanes, though the vitrification point was not statistically different from the control. VS and PS decreased with both oligomers. For the commercial cement, 20 phr of oligomer increased DC, vitrification, reduced Rpmax and also significantly increased KIC, and reduced PS and FM. Thio-urethane oligomers were shown to favorably modify conventional dimethacrylate networks. Significant reductions in polymerization stress were achieved at the same time conversion and fracture toughness increased. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Multicolored, Low-Voltage-Driven, Flexible Organic Electrochromic Devices Based on Oligomers.

Science.gov (United States)

Wan, Zhijun; Zeng, Jinming; Li, Hui; Liu, Ping; Deng, Wenji

2018-04-20

In this study, a series of organic conjugated oligomers containing 3,4-ethylenedioxythiophene (EDOT) and aromatic groups are synthesized, which are as follows: 2,5-di(methyl benzoate)-3,4-ethylenedioxy-thiophene (1EDOT-2B-COOCH 3 ), 5,5'-di(methyl benzoate)-2,2'-bi(3,4-ethylenedioxythiophene) (2EDOT-2B-COOCH 3 ), 5,5″-di(methyl benzoate)-2,2':5',2″-ter(3,4-ethylenedioxythiophene) (3EDOT-2B-COOCH 3 ), and 5,5″'-di(methyl benzoate)-2,2':5',2″: 5″,2″'-quater(3,4-ethylenedioxythiophene) (4EDOT-2B-COOCH 3 ). Using these oligomers as active materials, flexible organic electrochromic devices are fabricated. The device structure is indium tin oxide-PET plastic slide (ITO-PET)/active layer/conducting gel/ITO-PET, and the electrochromic properties of oligomers are investigated. These oligomers exhibit reversible color changes upon electrochemical doping and dedoping. The highest optical contrast is exhibited by 4EDOT-2B-COOCH 3 , which is 75.2% at 700 nm. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Peptide oligomers for holographic data storage

DEFF Research Database (Denmark)

Berg, Rolf Henrik; Hvilsted, Søren; Ramanujam, P.S.

1996-01-01

SEVERAL classes of organic materials (such as photoanisotropic liquid-crystalline polymers(1-4) and photorefractive polymers(5-7)) are being investigated for the development of media for optical data storage. Here we describe a new family of organic materials-peptide oligomers containing azobenzene...

Self-assembly of aniline oligomers

Czech Academy of Sciences Publication Activity Database

Zhao, Y.; Tomšík, Elena; Wang, J.; Morávková, Zuzana; Zhigunov, Alexander; Stejskal, Jaroslav; Trchová, Miroslava

2013-01-01

Roč. 8, č. 1 (2013), s. 129-137 ISSN 1861-4728 R&D Projects: GA ČR GA202/09/1626; GA ČR GAP205/12/0911 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : morphology * oligoaniline * oligomers Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.935, year: 2013

Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

DEFF Research Database (Denmark)

Pedersen, Martin Nors; Foderà, Vito; Horvath, Istvan

2015-01-01

link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed......Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which...

Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent

Directory of Open Access Journals (Sweden)

Khalid A. Ibrahim

2016-07-01

Full Text Available An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers in medicine and food fields because they are not only water-soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC, liquid chromatography/mass spectroscopy (LC/MS, and ninhydrin test.

Determination of oligomers in virgin and recycled polyethylene terephthalate (PET) samples by UPLC-MS-QTOF.

Science.gov (United States)

Ubeda, Sara; Aznar, Margarita; Nerín, Cristina

2018-03-01

An oligomer is a molecule that consists of a few monomer units. It can be formed during polymer manufacturing and also due to polymer degradation processes or even during use conditions. Since oligomers are not included in chemical databases, their identification is a complex process. In this work, the oligomers present in 20 different PET pellet samples have been determined. Two different sample treatment procedures, solvent extraction and total dissolution, were applied in order to select the most efficient one. The analyses were carried out by UPLC-MS-QTOF. The use of high resolution mass spectrometry allowed the structural elucidation of these compounds and their correct identification. The main oligomers identified were cyclic as well as lineal from the first, second, and third series. All of them were composed of terephthalic acid (TPA), diethylene glycol (DEG), and ethylene glycol (EG). Quantitative values were very different in both procedures. In total dissolution of PET samples, the concentration of oligomers was always, at least, 10 times higher than in solvent extraction; some of the compounds were only detected when total dissolution was used. Results showed that the oligomers with the highest concentration values were dimers and trimers, cyclic, as well as lineal, from the first and second series. The oligomer with the maximum concentration value was TPA 2 -EG-DEG that was found in all the samples in a concentration range from 2493 to 19,290 ng/g PET. No differences between virgin and recycled PET were found. Migration experiments were performed in two PET bottles, and results showed the transference of most of these oligomers to a fat food simulant (ethanol 95%). Graphical abstract Graphical abstract of the two procedures developd and optimized for identifying oligomers in PET pellets and in migration form PET bottles.

Role of the reaction of stabilized Criegee intermediates with peroxy radicals in particle formation and growth in air.

Science.gov (United States)

Zhao, Yue; Wingen, Lisa M; Perraud, Véronique; Greaves, John; Finlayson-Pitts, Barbara J

2015-05-21

Ozonolysis of alkenes is an important source of secondary organic aerosol (SOA) in the atmosphere. However, the mechanisms by which stabilized Criegee intermediates (SCI) react to form and grow the particles, and in particular the contributions from oligomers, are not well understood. In this study, ozonolysis of trans-3-hexene (C6H12), as a proxy for small alkenes, was investigated with an emphasis on the mechanisms of particle formation and growth. Ozonolysis experiments were carried out both in static Teflon chambers (18-20 min reaction times) and in a glass flow reactor (24 s reaction time) in the absence and presence of OH or SCI scavengers, and under different relative humidity (RH) conditions. The chemical composition of polydisperse and size-selected SOA particles was probed using different mass spectrometric techniques and infrared spectroscopy. Oligomers having SCI as the chain unit are found to be the dominant components of such SOA particles. The formation mechanism for these oligomers suggested by our results follows the sequential addition of SCI to organic peroxy (RO2) radicals, in agreement with previous studies by Moortgat and coworkers. Smaller particles are shown to have a relatively greater contribution from longer oligomers. Higher O/C ratios are observed in smaller particles and are similar to those of oligomers resulting from RO2 + nSCI, supporting a significant role for longer oligomers in particle nucleation and early growth. Under atmospherically relevant RH of 30-80%, water vapor suppresses oligomer formation through scavenging SCI, but also enhances particle nucleation. Under humid conditions, or in the presence of formic or hydrochloric acid as SCI scavengers, peroxyhemiacetals are formed by the acid-catalyzed particle phase reaction between oligomers from RO2 + nSCI and a trans-3-hexene derived carbonyl product. In contrast to the ozonolysis of trans-3-hexene, oligomerization involving RO2 + nSCI does not appear to be prevalent in the

Overall and specific migration from multilayer high barrier food contact materials - kinetic study of cyclic polyester oligomers migration.

Science.gov (United States)

Úbeda, Sara; Aznar, Margarita; Vera, Paula; Nerín, Cristina; Henríquez, Luis; Taborda, Laura; Restrepo, Claudia

2017-10-01

Most multilayer high barrier materials used in food packaging have a polyurethane adhesive layer in their structures. In order to assess the safety of these materials, it is important to determine the compounds intentionally added to the adhesives (IAS) as well as those non-intentionally added substances (NIAS). During the manufacture of polyurethane adhesives, some by-products can be formed, such as cyclic polyester oligomers coming from the reaction between dicarboxylic acids and glycols. Since these compounds are not listed in the Regulation 10/2011/EU, they should not be found in migration above 0.01 mg/kg of simulant. In this study two flexible multilayer packaging materials were used and migration was evaluated in simulant A (ethanol 10% v/v), simulant B (acetic acid 3% w/v) and simulant ethanol 95% v/v during 10 days at 60ºC. Identification and quantification of non-volatile compounds was carried out by UPLC-MS-QTOF. Most of migrants were oligomers such as cyclic polyesters and caprolactam oligomers. Overall migration and specific migration of adipic acid-diethylene glycol and phthalic acid-diethylene glycol were monitored over time and analysed by UPLC-MS-TQ. In most cases, ethanol 95% v/v was the simulant with the highest concentration values. Overall migration kinetics followed a similar pattern than specific migration kinetics.

Separation of xylose oligomers using centrifugal partition chromatography with a butanol-methanol-water system.

Science.gov (United States)

Lau, Ching-Shuan; Clausen, Edgar C; Lay, Jackson O; Gidden, Jennifer; Carrier, Danielle Julie

2013-01-01

Xylose oligomers are the intermediate products of xylan depolymerization into xylose monomers. An understanding of xylan depolymerization kinetics is important to improve the conversion of xylan into monomeric xylose and to minimize the formation of inhibitory products, thereby reducing ethanol production costs. The study of xylan depolymerization requires copious amount of xylose oligomers, which are expensive if acquired commercially. Our approach consisted of producing in-house oligomer material. To this end, birchwood xylan was used as the starting material and hydrolyzed in hot water at 200 °C for 60 min with a 4 % solids loading. The mixture of xylose oligomers was subsequently fractionated by a centrifugal partition chromatography (CPC) with a solvent system of butanol:methanol:water in a 5:1:4 volumetric ratio. Operating in an ascending mode, the butanol-rich upper phase (the mobile phase) eluted xylose oligomers from the water-rich stationary phase at a 4.89 mL/min flow rate for a total fractionation time of 300 min. The elution of xylose oligomers occurred between 110 and 280 min. The yields and purities of xylobiose (DP 2), xylotriose (DP 3), xylotetraose (DP 4), and xylopentaose (DP 5) were 21, 10, 14, and 15 mg/g xylan and 95, 90, 89, and 68 %, respectively. The purities of xylose oligomers from this solvent system were higher than those reported previously using tetrahydrofuran:dimethyl sulfoxide:water in a 6:1:3 volumetric ratio. Moreover, the butanol-based solvent system improved overall procedures by facilitating the evaporation of the solvents from the CPC fractions, rendering the purification process more efficient.

Aβ42 oligomers selectively disrupt neuronal calcium release.

Science.gov (United States)

Lazzari, Cristian; Kipanyula, Maulilio J; Agostini, Mario; Pozzan, Tullio; Fasolato, Cristina

2015-02-01

Accumulation of amyloid-β (Aβ) peptides correlates with aging and progression of Alzheimer's disease (AD). Aβ peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca(2+) homeostasis. By cytosolic and endoplasmic reticulum Ca(2+) measurements, we here define the short-term effects of synthetic Aβ42 on neuronal Ca(2+) dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Aβ42 did not cause Ca(2+) release or Ca(2+) influx. Similarly, 1-hour treatment with Aβ42 modified neither the resting cytosolic Ca(2+) level nor the long-lasting Ca(2+) influx caused by KCl-induced depolarization. In contrast, Aβ42 oligomers, but not monomers, significantly altered Ca(2+) release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca(2+) mobilization without alteration of the total store Ca(2+) content. Ca(2+) dysregulation by Aβ42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca(2+) store dysfunction is directly involved in Aβ42 neurotoxicity and represents a potential therapeutic target in AD-like dementia. Copyright © 2015 Elsevier Inc. All rights reserved.

Template-directed synthesis of linear porphyrin oligomers: classical, Vernier and mutual Vernier† †Electronic supplementary information (ESI) available: Synthesis and characterization of new compounds, ladder complexes, UV-vis-NIR titrations and binding data for reference compounds and for the formation of linear oligomer complexes, calculation of effective molarities, analytical GPC calibration and molar absorption coefficients. See DOI: 10.1039/c6sc05355f Click here for additional data file.

Science.gov (United States)

Kamonsutthipaijit, Nuntaporn

2017-01-01

Three different types of template-directed syntheses of linear porphyrin oligomers are presented. In the classical approach the product has the same number of binding sites as the template, whereas in Vernier reactions the product has the lowest common multiple of the numbers of binding sites in the template and the building block. Mutual Vernier templating is like Vernier templating except that both strands of the Vernier complex undergo coupling simultaneously, so that it becomes impossible to say which is the ‘template’ and which is the ‘building block’. The template-directed synthesis of monodisperse linear oligomers is more difficult than that of cyclic oligomers, because the products of linear templating have reactive ends. All three types of templating are demonstrated here, and used to prepare a nickel(ii) porphyrin dodecamer with 4-pyridyl substituents on all twelve porphyrin units. The stabilities and cooperativities of the double-strand complexes involved in these reactions were investigated by UV-vis-NIR titration. The four-rung ladder duplex has a stability constant of about 2 × 1018 M–1 in dichloromethane at 298 K. PMID:28553508

Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo.

Science.gov (United States)

Rockenstein, Edward; Nuber, Silke; Overk, Cassia R; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H; Campioni, Silvia; Riek, Roland; Winkler, Jürgen; Gage, Fred H; Winner, Beate; Masliah, Eliezer

2014-05-01

In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the

Ultrafast Photoinduced Electron Transfer in a π-Conjugated Oligomer/Porphyrin Complex

KAUST Repository

Aly, Shawkat Mohammede

2014-10-02

Controlling charge transfer (CT), charge separation (CS), and charge recombination (CR) at the donor-acceptor interface is extremely important to optimize the conversion efficiency in solar cell devices. In general, ultrafast CT and slow CR are desirable for optimal device performance. In this Letter, the ultrafast excited-state CT between platinum oligomer (DPP-Pt(acac)) as a new electron donor and porphyrin as an electron acceptor is monitored for the first time using femtosecond (fs) transient absorption (TA) spectroscopy with broad-band capability and 120 fs temporal resolution. Turning the CT on/off has been shown to be possible either by switching from an organometallic oligomer to a metal-free oligomer or by controlling the charge density on the nitrogen atom of the porphyrin meso unit. Our time-resolved data show that the CT and CS between DPP-Pt(acac) and cationic porphyrin are ultrafast (approximately 1.5 ps), and the CR is slow (ns time scale), as inferred from the formation and the decay of the cationic and anionic species. We also found that the metallic center in the DPP-Pt(acac) oligomer and the positive charge on the porphyrin are the keys to switching on/off the ultrafast CT process.

Laccase-Catalyzed Synthesis of Low-Molecular-Weight Lignin-Like Oligomers and their Application as UV-Blocking Materials.

Science.gov (United States)

Lim, Jieyan; Sana, Barindra; Krishnan, Ranganathan; Seayad, Jayasree; Ghadessy, Farid J; Jana, Satyasankar; Ramalingam, Balamurugan

2018-02-02

The laccase-catalyzed oxidative polymerization of monomeric and dimeric lignin model compounds was carried out with oxygen as the oxidant in aqueous medium. The oligomers were characterized by using gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS) analysis. Oxidative polymerization led to the formation of oligomeric species with a number-average molecular weight (M n ) that ranged from 700 to 2300 Da with a low polydispersity index. Spectroscopic analysis provided insight into the possible modes of linkages present in the oligomers, and the oligomerization is likely to proceed through the formation of C-C linkages between phenolic aromatic rings. The oligomers were found to show good UV light absorption characteristics with high molar extinction coefficient (5000-38 000 m -1  cm -1 ) in the UV spectral region. The oligomers were blended independently with polyvinyl chloride (PVC) by using solution blending to evaluate the compatibility and UV protection ability of the oligomers. The UV/Vis transmittance spectra of the oligomer-embedded PVC films indicated that these lignin-like oligomers possessed a notable ability to block UV light. In particular, oligomers obtained from vanillyl alcohol and the dimeric lignin model were found to show good photostability in accelerated UV weathering experiments. The UV-blocking characteristics and photostability were finally compared with the commercial low-molecular-weight UV stabilizer 2,4-dihydroxybenzophenone. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination.

Directory of Open Access Journals (Sweden)

Antonia Nicole Klein

Full Text Available The aggregation of amyloid-β (Aβ is postulated to be the crucial event in Alzheimer's disease (AD. In particular, small neurotoxic Aβ oligomers are considered to be responsible for the development and progression of AD. Therefore, elimination of thesis oligomers represents a potential causal therapy of AD. Starting from the well-characterized d-enantiomeric peptide D3, we identified D3 derivatives that bind monomeric Aβ. The underlying hypothesis is that ligands bind monomeric Aβ and stabilize these species within the various equilibria with Aβ assemblies, leading ultimately to the elimination of Aβ oligomers. One of the hereby identified d-peptides, DB3, and a head-to-tail tandem of DB3, DB3DB3, were studied in detail. Both peptides were found to: (i inhibit the formation of Thioflavin T-positive fibrils; (ii bind to Aβ monomers with micromolar affinities; (iii eliminate Aβ oligomers; (iv reduce Aβ-induced cytotoxicity; and (v disassemble preformed Aβ aggregates. The beneficial effects of DB3 were improved by DB3DB3, which showed highly enhanced efficacy. Our approach yielded Aβ monomer-stabilizing ligands that can be investigated as a suitable therapeutic strategy against AD.

PrP(Sc-specific antibodies with the ability to immunodetect prion oligomers.

Directory of Open Access Journals (Sweden)

Mourad Tayebi

Full Text Available The development of antibodies with binding capacity towards soluble oligomeric forms of PrPSc recognised in the aggregation process in early stage of the disease would be of paramount importance in diagnosing prion diseases before extensive neuropathology has ensued. As blood transfusion appears to be efficient in the transmission of the infectious prion agent, there is an urgent need to develop reagents that would specifically recognize oligomeric forms of the abnormally folded prion protein, PrPSc.To that end, we show that anti-PrP monoclonal antibodies (called PRIOC mAbs derived from mice immunised with native PrP-coated microbeads are able to immunodetect oligomers/multimers of PrPSc. Oligomer-specific immunoreactivity displayed by these PRIOC mAbs was demonstrated as large aggregates of immunoreactive deposits in prion-permissive neuroblastoma cell lines but not in equivalent non-infected or prn-p(0/0 cell lines. In contrast, an anti-monomer PrP antibody displayed diffuse immunoreactivity restricted to the cell membrane. Furthermore, our PRIOC mAbs did not display any binding with monomeric recombinant and cellular prion proteins but strongly detected PrPSc oligomers as shown by a newly developed sensitive and specific ELISA. Finally, PrioC antibodies were also able to bind soluble oligomers formed of Aβ and α-synuclein. These findings demonstrate the potential use of anti-prion antibodies that bind PrPSc oligomers, recognised in early stage of the disease, for the diagnosis of prion diseases in blood and other body fluids.

Amyloid β oligomers induce interleukin-1β production in primary microglia in a cathepsin B- and reactive oxygen species-dependent manner

Energy Technology Data Exchange (ETDEWEB)

Taneo, Jun; Adachi, Takumi [Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501 (Japan); Yoshida, Aiko; Takayasu, Kunio [Responses to Environmental Signals and Stresses, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto, Kyoto 606-8501 (Japan); Takahara, Kazuhiko, E-mail: ktakahar@zoo.zool.kyoto-u.ac.jp [Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501 (Japan); Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0081 (Japan); Inaba, Kayo [Department of Animal Development and Physiology, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501 (Japan); Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo 102-0081 (Japan)

2015-03-13

Amyloid β (Aβ) peptide, a causative agent of Alzheimer's disease, forms two types of aggregates: oligomers and fibrils. These aggregates induce inflammatory responses, such as interleukin-1β (IL-1β) production by microglia, which are macrophage-like cells located in the brain. In this study, we examined the effect of the two forms of Aβ aggregates on IL-1β production in mouse primary microglia. We prepared Aβ oligomer and fibril from Aβ (1–42) peptide in vitro. We analyzed the characteristics of these oligomers and fibrils by electrophoresis and atomic force microscopy. Interestingly, Aβ oligomers but not Aβ monomers or fibrils induced robust IL-1β production in the presence of lipopolysaccharide. Moreover, Aβ oligomers induced endo/phagolysosome rupture, which released cathepsin B into the cytoplasm. Aβ oligomer-induced IL-1β production was inhibited not only by the cathepsin B inhibitor CA-074-Me but also by the reactive oxygen species (ROS) inhibitor N-acetylcysteine. Random chemical crosslinking abolished the ability of the oligomers to induce IL-1β. Thus, multimerization and fibrillization causes Aβ oligomers to lose the ability to induce IL-1β. These results indicate that Aβ oligomers, but not fibrils, induce IL-1β production in primary microglia in a cathepsin B- and ROS-dependent manner. - Highlights: • We prepared amyloid β (Aβ) fibrils with minimum contamination of Aβ oligomers. • Primary microglia (MG) produced IL-1β in response to Aβ oligomers, but not fibrils. • Only Aβ oligomers induced leakage of cathepsin B from endo/phagolysosomes. • IL-1β production in response to Aβ oligomers depended on both cathepsin B and ROS. • Crosslinking reduced the ability of the Aβ oligomers to induce IL-1β from MG.

Dynamics in coarse-grained models for oligomer-grafted silica nanoparticles

KAUST Repository

Hong, Bingbing

2012-01-01

Coarse-grained models of poly(ethylene oxide) oligomer-grafted nanoparticles are established by matching their structural distribution functions to atomistic simulation data. Coarse-grained force fields for bulk oligomer chains show excellent transferability with respect to chain lengths and temperature, but structure and dynamics of grafted nanoparticle systems exhibit a strong dependence on the core-core interactions. This leads to poor transferability of the core potential to conditions different from the state point at which the potential was optimized. Remarkably, coarse graining of grafted nanoparticles can either accelerate or slowdown the core motions, depending on the length of the grafted chains. This stands in sharp contrast to linear polymer systems, for which coarse graining always accelerates the dynamics. Diffusivity data suggest that the grafting topology is one cause of slower motions of the cores for short-chain oligomer-grafted nanoparticles; an estimation based on transition-state theory shows the coarse-grained core-core potential also has a slowing-down effect on the nanoparticle organic hybrid materials motions; both effects diminish as grafted chains become longer. © 2012 American Institute of Physics.

Interchain interactions in charged diacetylenic oligomers carrying bulk substituents revisited

International Nuclear Information System (INIS)

Ottonelli, M.; Izzo, G.M.M.; Comoretto, D.; Musso, G.F.; Dellepiane, G.

2006-01-01

We are studying how the electronic properties of an aggregate, built with conjugated oligomers carrying bulk substituents, are affected by intermolecular interactions. In this paper we apply the CEO (Collective Electronic Oscillator) method, on the basis of the semiempirical INDO/S Hamiltonian, to compute the electronic density matrix modifications following the photon absorption in a doubly charged cluster of two units of a fully carbazolyl-substituted oligodiacetylene tetramer, taken as a model system. The picture that had emerged from our previous calculations based on the less sophisticated CIS (Configuration Interaction including Singles) approach is seen to be confirmed. Despite the large separation between the backbones, a through-space charge transfer occurs between the two oligomers due to the fact that the excess charge, contrary to what is generally believed, is not localized on the conjugated backbone, but is spread out over the carbazolyl moieties of the charged molecule. Consideration of this kind of interaction improves the theoretical results obtained for the isolated charged oligomer chain, and aids in better explaining some features of the experimental photoinduced spectra of the corresponding polymer

Insulin and C-peptide in human brain neurons (insulin/C-peptide/brain peptides/immunohistochemistry/radioimmunoassay)

International Nuclear Information System (INIS)

Dorn, A.; Bernstein, H.G.; Rinne, A.; Hahn, H.J.; Ziegler, M.

1983-01-01

The regional distribution and cellular localization of insulin and C-peptide immunoreactivities were studied in human cadaver brains using the indirect immunofluorescence method, the peroxidase-antiperoxidase technique, and radioimmunoassay. Products of the immune reactions to both polypeptides were observed in most nerve cells in all areas of the brain examined. Immunostaining was mainly restricted to the cell soma and proximal dendrites. Radioimmunoassay revealed that human brain contains insulin and C-peptide in concentrations much higher than the blood, the highest being in the hypothalamus. These findings support the hypothesis that the 'brain insulin' is - at least in part - produced in the CNS. (author)

Chemical stability of insulin. 3. Influence of excipients, formulation, and pH.

Science.gov (United States)

Brange, J; Langkjaer, L

1992-01-01

The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.

Extended Ladder-Type Benzo[ k ]tetraphene-Derived Oligomers

Energy Technology Data Exchange (ETDEWEB)

Lee, Jongbok [Department of Chemistry, Texas A& M University, 3255 TAMU College Station TX 77843-3255 USA; Li, Huanbin [MOE Key Laboratory of Macromolecular Synthesis and Functionalization, State Key Laboratory of Silicon Materials, Department of Polymer Science and Engineering, Zhejiang University, 38 Zheda Rd Hangzhou 310027 China; Kalin, Alexander J. [Department of Chemistry, Texas A& M University, 3255 TAMU College Station TX 77843-3255 USA; Yuan, Tianyu [Department of Materials Science and Engineering, Texas A& M University, 3003 TAMU College Station TX 77843-3003 USA; Wang, Chenxu [Department of Materials Science and Engineering, Texas A& M University, 3003 TAMU College Station TX 77843-3003 USA; Olson, Troy [Department of Chemistry, Texas A& M University, 3255 TAMU College Station TX 77843-3255 USA; Li, Hanying [MOE Key Laboratory of Macromolecular Synthesis and Functionalization, State Key Laboratory of Silicon Materials, Department of Polymer Science and Engineering, Zhejiang University, 38 Zheda Rd Hangzhou 310027 China; Fang, Lei [Department of Chemistry, Texas A& M University, 3255 TAMU College Station TX 77843-3255 USA; Department of Materials Science and Engineering, Texas A& M University, 3003 TAMU College Station TX 77843-3003 USA

2017-10-02

Well-defined, fused-ring aromatic oligomers represent promising candidates for the fundamental understanding and application of advanced carbon-rich materials, though bottom-up synthesis and structure–property correlation of these compounds remain challenging. In this work, an efficient synthetic route was employed to construct extended benzo[k]tetraphene-derived oligomers with up to 13 fused rings. The molecular and electronic structures of these compounds were clearly elucidated. Precise correlation of molecular sizes and crystallization dynamics was established, thus demonstrating the pivotal balance between intermolecular interaction and molecular mobility for optimized processing of highly ordered solids of these extended conjugated molecules.

Excitations and optical properties of phenylene-based conjugated polymers and oligomers

Science.gov (United States)

Brazovskii, S.; Kirova, N.; Bishop, A. R.; Klimov, V.; McBranch, D.; Barashkov, N. N.; Ferraris, J. P.

1998-01-01

We present a combined experimental and theoretical study of the ground and photoexcited optical properties of a model oligomer of PPV, MEH-DSB. Our theoretical picture is based upon a band description of electronic states of PPV oligomers, while invoking corrections from Coulomb interactions. The necessary discrete energy levels at low and intermediate energies appear naturally, in addition to the lower energy delocalized states. On this basis we identify the most important features in direct optical absorption for both high (4-6 eV) and low (2-4 eV) photon energies as well as in photoinduced absorption (PA) and stimulated photoemissions (SE) in MEH-DSB solutions, which represent the limit of noninteracting oligomers. While in agreement with previous interpretations for three absorption peaks (2.74, 4.46 and 6.2 eV), we give a new assignment for the most disputed 3.62 eV one as well as for the two PA peaks.

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

Science.gov (United States)

De Haan, David O; Tapavicza, Enrico; Riva, Matthieu; Cui, Tianqu; Surratt, Jason D; Smith, Adam C; Jordan, Mary-Caitlin; Nilakantan, Shiva; Almodovar, Marisol; Stewart, Tiffany N; de Loera, Alexia; De Haan, Audrey C; Cazaunau, Mathieu; Gratien, Aline; Pangui, Edouard; Doussin, Jean-François

2018-04-03

Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS 2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light-absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ∼80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CH 3 CO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events.

Structure–property relationships of synthetic organophosphorus flame retardant oligomers by thermal analysis

International Nuclear Information System (INIS)

Bai, Zhiman; Wang, Xin; Tang, Gang; Song, Lei; Hu, Yuan; Yuen, Richard K.K.

2013-01-01

Highlights: • Oligomers with different chemical components in molecular chains were synthesized. • FP-3 containing three IFR components possessed high thermal stability. • FP-3 possessed lowest flammability. • FP-3 exhibited a synergistic interaction between gas and condensed phase. - Abstract: A series of flame retardant oligomers with different chemical components in molecular chains, designated as FP-1, FP-2 and FP-3, respectively, were successfully synthesized using solution polycondensation and well characterized. The thermal properties and flammability of these oligomers were investigated by thermogravimetric analysis (TGA) and microscale combustion calorimeter (MCC). The results demonstrated that FP-3 had the lowest flammability in terms of the lowest maximum mass loss rate, and FP-1 possessed the highest thermal stability and char yield, due to its higher stable hexatomic ring structure of piperazine compared with the linear alkane chain structure of neopentyl glycol. The gases evolved during decomposition were analyzed using Fourier transform infrared coupled with the thermogravimetric analyzer (TG–IR) technique. The char residues of the flame retardant oligomers were investigated by scanning electron microscopy (SEM) and Raman spectroscopy. The results demonstrated that FP-3 exhibited a synergistic interaction between the gas phase and condensation phase, increasing its flame retardancy

Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

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Sara Sanz-Blasco

Full Text Available Dysregulation of intracellular Ca(2+ homeostasis may underlie amyloid beta peptide (Abeta toxicity in Alzheimer's Disease (AD but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+ in neurons and promote mitochondrial Ca(2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+ overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i mitochondrial Ca(2+ overload underlies the neurotoxicity induced by Abeta oligomers and ii inhibition of mitochondrial Ca(2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

Science.gov (United States)

Sanz-Blasco, Sara; Valero, Ruth A; Rodríguez-Crespo, Ignacio; Villalobos, Carlos; Núñez, Lucía

2008-07-23

Dysregulation of intracellular Ca(2+) homeostasis may underlie amyloid beta peptide (Abeta) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42) oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+) in neurons and promote mitochondrial Ca(2+) overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+) overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+) overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i) mitochondrial Ca(2+) overload underlies the neurotoxicity induced by Abeta oligomers and ii) inhibition of mitochondrial Ca(2+) overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

A monomeric variant of insulin degrading enzyme (IDE loses its regulatory properties.

Directory of Open Access Journals (Sweden)

Eun Suk Song

2010-03-01

Full Text Available Insulin degrading enzyme (IDE is a key enzyme in the metabolism of both insulin and amyloid beta peptides. IDE is unique in that it is subject to allosteric activation which is hypothesized to occur through an oligomeric structure.IDE is known to exist as an equilibrium mixture of monomers, dimers, and higher oligomers, with the dimer being the predominant form. Based on the crystal structure of IDE we deleted the putative dimer interface in the C-terminal region, which resulted in a monomeric variant. Monomeric IDE retained enzymatic activity, however instead of the allosteric behavior seen with wild type enzyme it displayed Michaelis-Menten kinetic behavior. With the substrate Abz-GGFLRKHGQ-EDDnp, monomeric IDE retained approximately 25% of the wild type activity. In contrast with the larger peptide substrates beta-endorphin and amyloid beta peptide 1-40, monomeric IDE retained only 1 to 0.25% of wild type activity. Unlike wild type IDE neither bradykinin nor dynorphin B-9 activated the monomeric variant of the enzyme. Similarly, monomeric IDE was not activated by polyphosphates under conditions in which the activity of wild type enzyme was increased more than 50 fold.These findings serve to establish the dimer interface in IDE and demonstrate the requirement for an oligomeric form of the enzyme for its regulatory properties. The data support a mechanism where the binding of activators to oligomeric IDE induces a conformational change that cannot occur in the monomeric variant. Since a conformational change from a closed to a more open structure is likely the rate-determining step in the IDE reaction, the subunit induced conformational change likely shifts the structure of the oligomeric enzyme to a more open conformation.

Enthalpies of solvation of ethylene oxide oligomers CH{sub 3}O(CH{sub 2}CH{sub 2}O){sub n}CH{sub 3} (n = 1 to 4) in different H-bonding solvents: Methanol, chloroform, and water. Group contribution method as applied to the polar oligomers

Energy Technology Data Exchange (ETDEWEB)

Barannikov, Vladimir P., E-mail: vpb@isc-ras.ru [Institute of Solution Chemistry, Russian Academy of Sciences, Academicheskaya Str. 1, Ivanovo 153045 (Russian Federation); Guseynov, Sabir S.; Vyugin, Anatoliy I. [Institute of Solution Chemistry, Russian Academy of Sciences, Academicheskaya Str. 1, Ivanovo 153045 (Russian Federation)

2011-12-15

Highlights: > Solvation enthalpy is found for ethylene oxide oligomers in chloroform and methanol. > Coefficients of solute-solute interaction are determined for oligomers in methanol. > Enthalpies of hydrogen bonding of oligomers with chloroform and water are estimated. > Additivity scheme is developed for describing enthalpies of solvation of oligomers. - Abstract: The enthalpies of solution and solvation of ethylene oxide oligomers CH{sub 3}O(CH{sub 2}CH{sub 2}O){sub n}CH{sub 3} (n = 1 to 4) in methanol and chloroform have been determined from calorimetric measurements at T = 298.15 K. The enthalpic coefficients of pairwise solute-solute interaction for methanol solutions have been calculated. The enthalpic characteristics of the oligomers in methanol, chloroform, water and tetrachloromethane have been compared. The hydrogen bonding of the oligomers with chloroform and water molecules is exhibited in the values of solvation enthalpy and coefficient of solute-solute interaction. This effect is not observed for methanol solvent. The thermochemical data evidence an existence of multi-centred hydrogen bonds in associates of polyethers with the solvent molecules. Enthalpies of hydrogen bonding of the oligomers with chloroform and water have been estimated. The additivity scheme has been developed to describe the enthalpies of solvation of ethylene oxide oligomers, unbranched monoethers and n-alkanes in chloroform, methanol, water, and tetrachloromethane. The correction parameters for contribution of repeated polar groups and correction term for methoxy-compounds have been introduced. The obtained group contributions permit to describe the enthalpies of solvation of unbranched monoethers and ethylene oxide oligomers in the solvents with standard deviation up to 0.6 kJ . mol{sup -1}. The values of group contributions and corrections are strongly influenced by solvent properties.

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

Directory of Open Access Journals (Sweden)

Langen Ralf

2008-10-01

Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

Effect of Conjugation Length on Photoinduced Charge-Transfer in π-Conjugated Oligomer-Acceptor Dyads

KAUST Repository

Jiang, Junlin

2017-05-25

A series of -conjugated oligomer-acceptor dyads were synthesized that feature oligo(phenylene ethynylene) (OPE) conjugated backbones end-capped with a naphthalene diimide (NDI) acceptor. The OPE segments vary in length from 4 to 8 phenylene ethynene units (PEn-NDI, where n = 4, 6 and 8). Fluorescence and transient absorption spectroscopy reveals that intramolecular OPE NDI charge transfer dominates the deactivation of excited states of the PEn-NDI oligomers. Both charge separation (CS) and charge recombination (CR) are strongly exothermic (G0CS ~ -1.1 and G0CR ~ -2.0 eV), and the driving forces do not vary much across the series because the oxidation and reduction potentials and singlet energies of the OPEs do not vary much with their length. Bimolecular photoinduced charge transfer between model OPEs that do not contain the NDI acceptors with methyl viologen was studied, and the results reveal that the absorption of the cation radical state (OPE+•) remains approximately constant ( ~ 575 nm) regardless of oligomer length. This finding suggests that the cation radical (polaron) of the OPE is relatively localized, effectively occupying a confined segment of n 4 repeat units in the longer oligomers. Photoinduced intramolecular electron transfer dynamics in the PEn-NDI series was investigated by UV-visible femtosecond transient absorption spectroscopy with visible and mid-infrared probes. Charge separation occurs on the 1 – 10 ps timescale, with the rates decreasing slightly with increased oligomer length (βCS ~ 0.15 Å-1). The rate for charge-recombination decreases in the sequence PE4-NDI > PE6-NDI ~ PE8-NDI. The discontinuous distance dependence in the rate for charge recombination may be related to the spatial localization of the positive polaron state in the longer oligomers.

Effect of Conjugation Length on Photoinduced Charge-Transfer in π-Conjugated Oligomer-Acceptor Dyads

KAUST Repository

Jiang, Junlin; Alsam, Amani Abdu; Wang, Shanshan; Aly, Shawkat Mohammede; Pan, Zhenxing; Mohammed, Omar F.; Schanze, Kirk S.

2017-01-01

A series of -conjugated oligomer-acceptor dyads were synthesized that feature oligo(phenylene ethynylene) (OPE) conjugated backbones end-capped with a naphthalene diimide (NDI) acceptor. The OPE segments vary in length from 4 to 8 phenylene ethynene units (PEn-NDI, where n = 4, 6 and 8). Fluorescence and transient absorption spectroscopy reveals that intramolecular OPE NDI charge transfer dominates the deactivation of excited states of the PEn-NDI oligomers. Both charge separation (CS) and charge recombination (CR) are strongly exothermic (G0CS ~ -1.1 and G0CR ~ -2.0 eV), and the driving forces do not vary much across the series because the oxidation and reduction potentials and singlet energies of the OPEs do not vary much with their length. Bimolecular photoinduced charge transfer between model OPEs that do not contain the NDI acceptors with methyl viologen was studied, and the results reveal that the absorption of the cation radical state (OPE+•) remains approximately constant ( ~ 575 nm) regardless of oligomer length. This finding suggests that the cation radical (polaron) of the OPE is relatively localized, effectively occupying a confined segment of n 4 repeat units in the longer oligomers. Photoinduced intramolecular electron transfer dynamics in the PEn-NDI series was investigated by UV-visible femtosecond transient absorption spectroscopy with visible and mid-infrared probes. Charge separation occurs on the 1 – 10 ps timescale, with the rates decreasing slightly with increased oligomer length (βCS ~ 0.15 Å-1). The rate for charge-recombination decreases in the sequence PE4-NDI > PE6-NDI ~ PE8-NDI. The discontinuous distance dependence in the rate for charge recombination may be related to the spatial localization of the positive polaron state in the longer oligomers.

α-Synuclein oligomers and clinical implications for Parkinson disease

Science.gov (United States)

Kalia, Lorraine V.; Kalia, Suneil K.; McLean, Pamela J.; Lozano, Andres M.; Lang, Anthony E.

2012-01-01

Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long-held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent suggesting another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α-synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α-synuclein also forms oligomeric species with certain conformations being toxic to cells. The mechanisms by which these α-synuclein oligomers cause cell death are being actively investigated as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α-synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications. PMID:23225525

Studies on Oligomer Metal Complexes Derived from Bisamic Acid of Pyromellitic Dianhydride and 4-Bromoaniline.

Science.gov (United States)

Patel, Yogesh S

2014-01-01

Novel oligomer metal complexes (2a-f) of the ligand 2,5-bis((4-bromophenyl)carbamoyl) terephthalic acid (1) were prepared using transition metal salts and characterized by various spectroscopic techniques. The geometry of oligomer metal complexes was carried out by electronic spectral analysis and magnetic measurement studies. Polymeric properties have also been carried out. Ligand was synthesized using pyromellitic dianhydride and 4-bromoaniline. It was duly characterized. All novel synthesized compounds 1 and 2a-f were evaluated for their antibacterial and antifungal activity. The results showed significantly higher antibacterial and antifungal activity of oligomer metal complexes compared to the ligand.

Studies on insulin receptor, 1

International Nuclear Information System (INIS)

Sakai, Yukio

1979-01-01

The present study was designed for the purpose of establishing a method of insulin radioreceptor assay using plasma membranes of guinea pigs as receptor sites. The results obtained are as follows: 1) Insulin receptor in the renal plasma membranes of guinea pigs showed a significantly high affinity to porcine insulin compared with that in the plasma membranes of guinea pig liver or rat kidney and liver. 2) In the insulin radioreceptor assay, an optimum condition was observed by the incubation at 4 0 C for 24 - 48 hours with 100 μg membrane protein of guinea pig kidney and 0.08 ng of 125 I-insulin. This assay method was specific for insulin and showed an accurate biological activity of insulin. 3) The recovery rate of insulin radioreceptor assay was 98.4% and dilution check up to 16 times did not influence on the result. An average of coefficient variation was 3.92% within assay. All of these results indicated the method to be satisfactory. 4) Glucose induced insulin release by perfusion method in isolated Langerhans islets of rats showed an identical pattern of reaction curves between radioreceptor assay and radioimmunoassay, although the values of radioreceptor assay was slightly low. 5) Insulin free serum produced by ultra filtration method was added to the standard assay medium. By this procedure, direct measurement of human serum by radioreceptor assay became possible. 6) The value of human serum insulin receptor binding activity by the radioreceptor assay showed a high correlation with that of insulin radioimmunoassay in sera of normal, borderline or diabetic type defined by glucose tolerance test. (author)

Organic heterostructures based on arylenevinylene oligomers deposited by MAPLE

Czech Academy of Sciences Publication Activity Database

Socol, M.; Preda, N.; Vacareanu, L.; Grigoras, M.; Socol, G.; Mihailescu, I. N.; Stanculescu, F.; Jelínek, Miroslav; Stanculescu, A.; Stoicanescu, M.

2014-01-01

Roč. 302, May (2014), s. 216-222 ISSN 0169-4332 Institutional support: RVO:68378271 Keywords : organic heterostructures * MAPLE * oligomer * optoelectronica Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.711, year: 2014

Combined HILIC-ELSD/ESI-MS(n) enables the separation, identification and quantification of sugar beet pectin derived oligomers.

Science.gov (United States)

Remoroza, C; Cord-Landwehr, S; Leijdekkers, A G M; Moerschbacher, B M; Schols, H A; Gruppen, H

2012-09-01

The combined action of endo-polygalacturonase (endo-PGII), pectin lyase (PL), pectin methyl esterase (fungal PME) and RG-I degrading enzymes enabled the extended degradation of methylesterified and acetylated sugar beet pectins (SBPs). The released oligomers were separated, identified and quantified using hydrophilic interaction liquid chromatography (HILIC) with online electrospray ionization ion trap mass spectrometry (ESI-IT-MS(n)) and evaporative light scattering detection (ELSD). By MS(n), the structures of galacturonic acid (GalA) oligomers having an acetyl group in the O-2 and/or O-3 positions eluting from the HILIC column were elucidated. The presence of methylesterified and/or acetylated galacturonic acid units within an oligomer reduced the interaction with the HILIC column significantly compared to the unsubstituted GalA oligomers. The HILIC column enables a good separation of most oligomers present in the digest. The use of ELSD to quantify oligogalacturonides was validated using pure GalA standards and the signal was found to be independent of the chemical structure of the oligomer being detected. The combination of chromatographic and enzymatic strategies enables to distinguish SBPs having different methylesters and acetyl group distribution. Copyright © 2012 Elsevier Ltd. All rights reserved.

Insulin resistance in therapeutic clinic

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Anna V. Pashentseva

2017-09-01

Full Text Available Today an obesity became the global epidemic striking both children, and adults and represents one of the most important problems of health care worldwide. Excess accumulation of fatty tissue is resulted by insulin resistance and a compensatory hyperinsulinaemia which are the main predictors of development of a diabetes mellitus type 2. Insulin resistance is also one of key links of a pathogenesis of such diseases as cardiovascular pathology, not-alcoholic fatty liver disease, a polycystic ovary syndrome, gestational diabetes and many others. Depression of sensitivity of tissues to insulin can be physiological reaction of an organism to stress factors and pathological process. The endogenic reasons also take part in development of insulin resistance besides factors of the external environment. The role of genetic predisposition, a subclinical inflammation of fatty tissue, thyroid hormones, adipokines and vitamin D in formation of this pathological process is studied. As insulin resistance takes part in a pathogenesis of various diseases, methods of its diagnostics and correction are of great importance in therapeutic practice. At purpose of treatment it is worth giving preference to the drugs which are positively influencing sensitivity of tissues to insulin.

New strategy for stable-isotope-aided, multidimensional NMR spectroscopy of DNA oligomers

Energy Technology Data Exchange (ETDEWEB)

Ono, Okira; Tate, Shin-Ichi; Kainosho, Masatsune [Tokyo Metropolitan Univ., Tokyo (Japan)

1994-12-01

Nuclear Magnetic Resonance (NMR) is the most efficient method for determining the solution structures of biomolecules. By applying multidimensional heteronuclear NMR techniques to {sup 13}C/{sup 15}N-labeled proteins, we can determine the solution structures of proteins with molecular mass of 20 to 30kDa at an accuracy similar to that of x-ray crystallography. Improvements in NMR instrumentation and techniques as well as the development of protein engineering methods for labeling proteins have rapidly advanced multidimensional heteronuclear NMR of proteins. In contrast, multidimensional heteronuclear NMR studies of nucleic acids is less advanced because there were no efficient methods for preparing large amounts of labeled DNA/RNA oligomers. In this report, we focused on the chemical synthesis of DNA oligomers labeled at specific residue(s). RNA oligomers with specific labels, which are difficult to synthesize by the enzyme method, can be synthesized by the chemical method. The specific labels are useful for conformational analysis of larger molecules such as protein-nucleic acid complexes.

Toxic prefibrillar α-synuclein amyloid oligomers adopt a distinctive antiparallel β-sheet structure.

Science.gov (United States)

Celej, María Soledad; Sarroukh, Rabia; Goormaghtigh, Erik; Fidelio, Gerardo D; Ruysschaert, Jean-Marie; Raussens, Vincent

2012-05-01

Parkinson's disease is an age-related movement disorder characterized by the presence in the mid-brain of amyloid deposits of the 140-amino-acid protein AS (α-synuclein). AS fibrillation follows a nucleation polymerization pathway involving diverse transient prefibrillar species varying in size and morphology. Similar to other neurodegenerative diseases, cytotoxicity is currently attributed to these prefibrillar species rather than to the insoluble aggregates. Nevertheless, the underlying molecular mechanisms responsible for cytotoxicity remain elusive and structural studies may contribute to the understanding of both the amyloid aggregation mechanism and oligomer-induced toxicity. It is already recognized that soluble oligomeric AS species adopt β-sheet structures that differ from those characterizing the fibrillar structure. In the present study we used ATR (attenuated total reflection)-FTIR (Fourier-transform infrared) spectroscopy, a technique especially sensitive to β-sheet structure, to get a deeper insight into the β-sheet organization within oligomers and fibrils. Careful spectral analysis revealed that AS oligomers adopt an antiparallel β-sheet structure, whereas fibrils adopt a parallel arrangement. The results are discussed in terms of regions of the protein involved in the early β-sheet interactions and the implications of such conformational arrangement for the pathogenicity associated with AS oligomers.

Diffusivities and Viscosities of Poly(ethylene oxide) Oligomers †

KAUST Repository

Hong, Bingbing; Escobedo, Fernando; Panagiotopoulos, Athanassios Z.

2010-01-01

Diffusivities and viscosities of poly(ethylene oxide) (PEO) oligomer melts with 1 to 12 repeat units have been obtained from equilibrium molecular dynamics simulations using the TraPPE-UA force field. The simulations generated diffusion coefficients

Synthesis and Electronic Properties of Length-Defined 9,10-Anthrylene-Butadiynylene Oligomers.

Science.gov (United States)

Nagaoka, Maiko; Tsurumaki, Eiji; Nishiuchi, Mai; Iwanaga, Tetsuo; Toyota, Shinji

2018-05-18

Linear π-conjugated oligomers consisting of anthracene and diacetylene units were readily synthesized by a one-pot process that involved desilylation and oxidative coupling from appropriate building units. We were able to isolate length-defined oligomers ranging from 2-mer to 6-mer as stable and soluble solids. The bathochromic shifts in the UV-vis spectra suggested that the π-conjugation was extended with elongation of the linear chain. Cyclic voltammetric measurements showed characteristic reversible oxidation waves that were dependent on the number of anthracene units.

Size-Dependent Affinity of Glycine and Its Short Oligomers to Pyrite Surface: A Model for Prebiotic Accumulation of Amino Acid Oligomers on a Mineral Surface

Science.gov (United States)

Afrin, Rehana; Ganbaatar, Narangerel; Aono, Masashi; Cleaves, H. James; Yano, Taka-aki; Hara, Masahiko

2018-01-01

The interaction strength of progressively longer oligomers of glycine, (Gly), di-Gly, tri-Gly, and penta-Gly, with a natural pyrite surface was directly measured using the force mode of an atomic force microscope (AFM). In recent years, selective activation of abiotically formed amino acids on mineral surfaces, especially that of pyrite, has been proposed as an important step in many origins of life scenarios. To investigate such notions, we used AFM-based force measurements to probe possible non-covalent interactions between pyrite and amino acids, starting from the simplest amino acid, Gly. Although Gly itself interacted with the pyrite surface only weakly, progressively larger unbinding forces and binding frequencies were obtained using oligomers from di-Gly to penta-Gly. In addition to an expected increase of the configurational entropy and size-dependent van der Waals force, the increasing number of polar peptide bonds, among others, may be responsible for this observation. The effect of chain length was also investigated by performing similar experiments using l-lysine vs. poly-l-lysine (PLL), and l-glutamic acid vs. poly-l-glutamic acid. The results suggest that longer oligomers/polymers of amino acids can be preferentially adsorbed on pyrite surfaces. PMID:29370126

Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis.

Science.gov (United States)

Yuan, Zhen; Yang, Lifeng; Chen, Baian; Zhu, Ting; Hassan, Mohammad Farooque; Yin, Xiaomin; Zhou, Xiangmei; Zhao, Deming

2015-06-01

The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into β-state oligomers. Herein, we demonstrate that β-state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP-induced neurotoxicity. We have characterized protein misfolding cyclic amplification-induced monomer-to-oligomer conversion of PrP from three species using western blotting, circular dichroism, size-exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting β-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3 in both wild-type and PrP(-/-) cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain. We found that β-state oligomeric PrPs can be generated through protein misfolding cyclic amplification (PMCA) from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP. β-oligomers are toxic to primary mouse cortical neurons independent of the presence of PrP(C) in the neurons, while the corresponding monomeric PrPs were not toxic. This toxicity is the result of oligomers-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3. These results may contribute to our understanding of prion transformation within the brain. © 2015 International Society for Neurochemistry.

Actinic radiation-curable formulations from the reaction product of organic isocyanate, poly(alkylene oxide) polyol and an unsaturated addition-polymerizable monomeric compound having a single isocyanate-reactive hydrogen group

International Nuclear Information System (INIS)

Howard, D.D.

1979-01-01

Energy-curable compositions which can be cured in the presence of air by exposure to actinic radiation contain at least one unsaturated urethane oligomer. The oligomer comprises the reaction product of at least one poly(alkylene oxide) polyol, at least one polyisocyanate, and at least one unsaturated active hydrogen-containing compound

Charge transfer in conjugated oligomers encapsulated into carbon nanotubes

Energy Technology Data Exchange (ETDEWEB)

Almadori, Y.; Alvarez, L.; Michel, T.; Le Parc, R.; Bantignies, J.L.; Hermet, P.; Sauvajol, J.L. [Laboratoire Charles Coulomb UMR 5521, Universite Montpellier 2, 34095 Montpellier (France); Laboratoire Charles Coulomb UMR 5521, CNRS, 34095 Montpellier (France); Arenal, R. [Laboratoire d' Etude des Microstructures, CNRS-ONERA, 92322 Chatillon (France); Laboratorio de Microscopias Avanzadas, Instituto de Nanociencia de Aragon, U. Zaragoza, 50018 Zaragoza (Spain); Babaa, R. [Laboratoire de Chimie des Surfaces et Interfaces, CEA, IRAMIS, SPCSI, 91191 Gif-sur-Yvette Cedex (France); Chemical Engineering Department, University of Technology PETRONAS, UTP, Ipoh-Perak (Malaysia); Jouselme, B.; Palacin, S. [Laboratoire de Chimie des Surfaces et Interfaces, CEA, IRAMIS, SPCSI, 91191 Gif-sur-Yvette Cedex (France)

2011-11-15

This study deals with a hybrid system consisting in quaterthiophene derivative encapsulated inside single-walled and multi-walled carbon nanotubes. Investigations of the encapsulation step are performed by transmission electron microscopy. Raman spectroscopy data point out different behaviors depending on the laser excitation energy with respect to the optical absorption of quaterthiophene. At low excitation energy (far from the oligomer resonance window) there is no significant modification of the Raman spectra before and after encapsulation. By contrast, at high excitation energy (close to the oligomer resonance window), Raman spectra exhibit a G-band shift together with an important RBM intensity loss, suggesting a significant charge transfer between the inserted molecule and the host nanotubes. Those results suggest a photo induced process leading to a significant charge transfer. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

Structure and properties of binary mixtures polystyrene-epoxyacrylic oligomers irradiated by electrons

International Nuclear Information System (INIS)

Lomonosova, N.V.

1995-01-01

Using the methods of birefringence, isometrical heating, IR-dichroism and thermal optical analysis change in structure of oriented polymer-oligomer systems on the base of PS (M>10 6 ) and epoxyacrylic (EA) oligomers of aliphatic and aromatic structure is studied during the process of irradiation by fast electrons. Their mechanical properties are studied and it is established that introduction of aliphatic epoxyacrylate to PS and subsequent irradiation allow to obtain composite materials with higher values of strength, modulus of elasticity and softening temperature in isotropic and oriented states. 6 refs., 2 figs., 3 tabs

Selective amyloid β oligomer assay based on abasic site-containing molecular beacon and enzyme-free amplification.

Science.gov (United States)

Zhu, Linling; Zhang, Junying; Wang, Fengyang; Wang, Ya; Lu, Linlin; Feng, Chongchong; Xu, Zhiai; Zhang, Wen

2016-04-15

Amyloid-beta (Aβ) oligomers are highly toxic species in the process of Aβ aggregation and are regarded as potent therapeutic targets and diagnostic markers for Alzheimer's disease (AD). Herein, a label-free molecular beacon (MB) system integrated with enzyme-free amplification strategy was developed for simple and highly selective assay of Aβ oligomers. The MB system was constructed with abasic site (AP site)-containing stem-loop DNA and a fluorescent ligand 2-amino-5,6,7-trimethyl-1,8-naphyridine (ATMND), of which the fluorescence was quenched upon binding to the AP site in DNA stem. Enzyme-free amplification was realized by target-triggered continuous opening of two delicately designed MBs (MB1 and MB2). Target DNA hybridization with MB1 and then MB2 resulted in the release of two ATMND molecules in one binding event. Subsequent target recycling could greatly amplify the detection sensitivity due to the greatly enhanced turn-on emission of ATMND fluorescence. Combining with Aβ oligomers aptamers, the strategy was applied to analyze Aβ oligomers and the results showed that it could quantify Aβ oligomers with high selectivity and monitor the Aβ aggregation process. This novel method may be conducive to improve the diagnosis and pathogenic study of Alzheimer's disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Flame retardant cotton fabrics by electron beam-induced polymerization of vinyl phosphonate oligomer

International Nuclear Information System (INIS)

Sawai, Takeshi; Ametani, Kazuo; Enomoto, Ichiro

1988-01-01

Vinyl phosphonate oligomer is presently used commercially as a cellulosic flame retardant in conjugation with N-methylol acrylamide, using a persulfate catalyst and a thermal cure. This combination can also be cured at room temperature with electron beams, as can the vinyl phosphonate alone. For the textile application, fixation of flame retardants by electron beams with low energy is one of the most promising applications. For the purpose of preparing flame resistant cotton fabrics such as bed sheets and pajamas, flame retardant curing of vinyl phosphonate oligomer on cotton fabrics was examined using electron beams from a self-sealed electron beam processor and gamma rays from a 60 Co source. A joint investigation was undertaken by the Tokyo Metropolitan Textile Research Institute and Tokyo Metropolitan Isotope Research Center to determine the feasibility of curing vinyl phosphonate oligomer on the cotton fabrics for textile finishing. (author)

Conjugated Polymers and Oligomers: Structural and Soft Matter Aspects

DEFF Research Database (Denmark)

This book identifies modern topics and current trends of structural and soft matter aspects of conjugated polymers and oligomers. Each chapter recognizes an active research line where structural perspective dominates research and therefore the book covers fundamental aspects of persistent...

Effect of phenolic oligomer on adhesion of poly (ethylene terephthalate) film laminated steel sheets by Electron Beam Curing method

International Nuclear Information System (INIS)

Masuhara, Kenichi; Mori, Koji; Koshiishi, Kenji; Sasaki, Takashi.

1995-01-01

Adhesion of poly (ethylene terephthalate) film by Electron Beam Curing (EBC) method which can be thought as an energy-saving process was studied for the purpose of bestowing economically design and distinctness of image on thermosetting high molecular weight polyester precoated steel sheets. Adhesion of EB curable resins onto metal is generally poor. In this report, addition of EB curable phenolic resole oligomer with bifunctional acrylates to the top coat used for precoated steel was studied in order to increase the adhesion of an EB curable adhesive, and it was found that the phenolic oligomer is tremendously effective for the improvement of adhesion. The reasons why the phenolic oligomer provides excellent adhesion were 1) elongation at break of the top coat to which the phenolic oligomer is added is little decreased by EB irradiation, and the formability does not reduce. 2) As the phenolic oligomer is unevenly distributed to the surface layer of the top coat, it is suggested that the contact frequency of the phenolic oligomer to the EB curable adhesive is so high that graft polymerization between them is liable to occur. (author)

Unraveling the Role of Π - Conjugation in Thiophene Oligomers for Optoelectronic Properties by DFT/TDDFT Approach

Directory of Open Access Journals (Sweden)

Gajalakshmi

Full Text Available ABSTRACT Thiophene oligomer has been investigated using DFT/TDDFT calculations with an aim to check its suitability for opto electronic applications and also to analyse the influence of π-bridge. Our results revealed that thiophene oligomers have excellent π-conjugation throughout. FMO analysis give an estimate of band gap of thiophene oligomer and further revealed HOMO are localized on π - bridge, donor group and LUMO are localized on π - bridge and acceptor group. A TDDFT calculation has been performed to understand the absorption properties of them in gas phase and solvent phase. PCM calculations convey that absorption maxima show positive solvatochromism. Among the designed candidates, the one with more π - bridge show higher wavelength of absorption maxima and would be a choice for better optoelectronic materials. NBO analysis provides support for complete delocalization in these systems. It is interesting to note that oligomer with more π-bridge display an enhanced optoelectronic properties than with less π - bridge.

A simple procedure for preparing chitin oligomers through acetone precipitation after hydrolysis in concentrated hydrochloric acid.

Science.gov (United States)

Kazami, Nao; Sakaguchi, Masayoshi; Mizutani, Daisuke; Masuda, Tatsuhiko; Wakita, Satoshi; Oyama, Fumitaka; Kawakita, Masao; Sugahara, Yasusato

2015-11-05

Chitin oligomers are of interest because of their numerous biologically relevant properties. To prepare chitin oligomers containing 4-6 GlcNAc units [(GlcNAc)4-6], α- and β-chitin were hydrolyzed with concentrated hydrochloric acid at 40 °C. The reactant was mixed with acetone to recover the acetone-insoluble material, and (GlcNAc)4-6 was efficiently recovered after subsequent water extraction. Composition analysis using gel permeation chromatography and MALDI-TOF mass spectrometry indicated that (GlcNAc)4-6 could be isolated from the acetone-insoluble material with recoveries of approximately 17% and 21% from the starting α-chitin and β-chitin, respectively. The acetone precipitation method is highly useful for recovering chitin oligomers from the acid hydrolysate of chitin. The changes in the molecular size and higher-order structure of chitin during the course of hydrolysis were also analyzed, and a model that explains the process of oligomer accumulation is proposed. Copyright © 2015 Elsevier Ltd. All rights reserved.

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification.

Science.gov (United States)

Kotler, Samuel A; Brender, Jeffrey R; Vivekanandan, Subramanian; Suzuki, Yuta; Yamamoto, Kazutoshi; Monette, Martine; Krishnamoorthy, Janarthanan; Walsh, Patrick; Cauble, Meagan; Holl, Mark M Banaszak; Marsh, E Neil G; Ramamoorthy, Ayyalusamy

2015-07-03

Alzheimer's disease is characterized by the misfolding and self-assembly of the amyloidogenic protein amyloid-β (Aβ). The aggregation of Aβ leads to diverse oligomeric states, each of which may be potential targets for intervention. Obtaining insight into Aβ oligomers at the atomic level has been a major challenge to most techniques. Here, we use magic angle spinning recoupling (1)H-(1)H NMR experiments to overcome many of these limitations. Using (1)H-(1)H dipolar couplings as a NMR spectral filter to remove both high and low molecular weight species, we provide atomic-level characterization of a non-fibrillar aggregation product of the Aβ1-40 peptide using non-frozen samples without isotopic labeling. Importantly, this spectral filter allows the detection of the specific oligomer signal without a separate purification procedure. In comparison to other solid-state NMR techniques, the experiment is extraordinarily selective and sensitive. A resolved 2D spectra could be acquired of a small population of oligomers (6 micrograms, 7% of the total) amongst a much larger population of monomers and fibers (93% of the total). By coupling real-time (1)H-(1)H NMR experiments with other biophysical measurements, we show that a stable, primarily disordered Aβ1-40 oligomer 5-15 nm in diameter can form and coexist in parallel with the well-known cross-β-sheet fibrils.

High-capacity conductive nanocellulose paper sheets for electrochemically controlled extraction of DNA oligomers.

Directory of Open Access Journals (Sweden)

Aamir Razaq

Full Text Available Highly porous polypyrrole (PPy-nanocellulose paper sheets have been evaluated as inexpensive and disposable electrochemically controlled three-dimensional solid phase extraction materials. The composites, which had a total anion exchange capacity of about 1.1 mol kg(-1, were used for extraction and subsequent release of negatively charged fluorophore tagged DNA oligomers via galvanostatic oxidation and reduction of a 30-50 nm conformal PPy layer on the cellulose substrate. The ion exchange capacity, which was, at least, two orders of magnitude higher than those previously reached in electrochemically controlled extraction, originated from the high surface area (i.e. 80 m(2 g(-1 of the porous composites and the thin PPy layer which ensured excellent access to the ion exchange material. This enabled the extractions to be carried out faster and with better control of the PPy charge than with previously employed approaches. Experiments in equimolar mixtures of (dT(6, (dT(20, and (dT(40 DNA oligomers showed that all oligomers could be extracted, and that the smallest oligomer was preferentially released with an efficiency of up to 40% during the reduction of the PPy layer. These results indicate that the present material is very promising for the development of inexpensive and efficient electrochemically controlled ion-exchange membranes for batch-wise extraction of biomolecules.

Computational Design of High-χ Block Oligomers for Accessing 1 nm Domains.

Science.gov (United States)

Chen, Qile P; Barreda, Leonel; Oquendo, Luis E; Hillmyer, Marc A; Lodge, Timothy P; Siepmann, J Ilja

2018-05-22

Molecular dynamics simulations are used to design a series of high-χ block oligomers (HCBOs) that can self-assemble into a variety of mesophases with domain sizes as small as 1 nm. The exploration of these oligomers with various chain lengths, volume fractions, and chain architectures at multiple temperatures reveals the presence of ordered lamellae, perforated lamellae, and hexagonally packed cylinders. The achieved periods are as small as 3.0 and 2.1 nm for lamellae and cylinders, respectively, which correspond to polar domains of approximately 1 nm. Interestingly, the detailed phase behavior of these oligomers is distinct from that of either solvent-free surfactants or block polymers. The simulations reveal that the behavior of these HCBOs is a product of an interplay between both "surfactant factors" (headgroup interactions, chain flexibility, and interfacial curvature) and "block polymer factors" (χ, chain length N, and volume fraction f). This insight promotes the understanding of molecular features pivotal for mesophase formation at the sub-5 nm length scale, which facilitates the design of HCBOs tailored toward particular desired morphologies.

Backbone conformation affects duplex initiation and duplex propagation in hybridisation of synthetic H-bonding oligomers.

Science.gov (United States)

Iadevaia, Giulia; Núñez-Villanueva, Diego; Stross, Alexander E; Hunter, Christopher A

2018-06-06

Synthetic oligomers equipped with complementary H-bond donor and acceptor side chains form multiply H-bonded duplexes in organic solvents. Comparison of the duplex forming properties of four families of oligomers with different backbones shows that formation of an extended duplex with three or four inter-strand H-bonds is more challenging than formation of complexes that make only two H-bonds. The stabilities of 1 : 1 complexes formed between length complementary homo-oligomers equipped with either phosphine oxide or phenol recognition modules were measured in toluene. When the backbone is very flexible (pentane-1,5-diyl thioether), the stability increases uniformly by an order of magnitude for each additional base-pair added to the duplex: the effective molarities for formation of the first intramolecular H-bond (duplex initiation) and subsequent intramolecular H-bonds (duplex propagation) are similar. This flexible system is compared with three more rigid backbones that are isomeric combinations of an aromatic ring and methylene groups. One of the rigid systems behaves in exactly the same way as the flexible backbone, but the other two do not. For these systems, the effective molarity for formation of the first intramolecular H-bond is the same as that found for the other two backbones, but additional H-bonds are not formed between the longer oligomers. The effective molarities are too low for duplex propagation in these systems, because the oligomer backbones cannot adopt conformations compatible with formation of an extended duplex.

Alzheimer's-associated Aβ oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal

International Nuclear Information System (INIS)

Pitt, Jason; Roth, William; Lacor, Pascale; Smith, Amos B.; Blankenship, Matthew; Velasco, Pauline; De Felice, Fernanda; Breslin, Paul; Klein, William L.

2009-01-01

It now appears likely that soluble oligomers of amyloid-β 1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Aβ oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturally-occurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Aβ species, when assayed with both sequence- and conformation-specific Aβ antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Aβ-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.

Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level

Directory of Open Access Journals (Sweden)

Nübling Georg

2012-07-01

Full Text Available Abstract Background Fibrillar amyloid-like deposits and co-deposits of tau and α-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and α-synuclein are not well understood. Results We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with α-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3β exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of α-synuclein in pre-formed tau oligomers. Conclusions Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration.

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice

Directory of Open Access Journals (Sweden)

Liping Chen

2017-11-01

Full Text Available Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio, an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5 and glycogen synthase kinase-3β (GSK3β, two pharmacological targets of Alzheimer's disease (AD. In this study, we have discovered that 2.3–23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6 and tumor necrosis factor-α (TNF-α. Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD with hyper-phosphorylated tau (pTau, glial fibrillary acidic protein (GFAP and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.

Charge transport and dielectric relaxation processes in anilin-based oligomers

Czech Academy of Sciences Publication Activity Database

Mrlík, M.; Moučka, R.; Ilčíková, M.; Bober, Patrycja; Kazantseva, N.; Špitálský, Z.; Trchová, Miroslava; Stejskal, Jaroslav

2014-01-01

Roč. 192, June (2014), s. 37-42 ISSN 0379-6779 Institutional support: RVO:61389013 Keywords : aniline-based oligomers * conductivity * dielectric properties Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.252, year: 2014

Photopolymerizable silicone monomers, oligomers, and resins

International Nuclear Information System (INIS)

Jacobine, A.F.; Nakos, S.T.

1992-01-01

The purpose of this chapter is to acquaint the general photopolymer researcher with the historical development of the chemistry and technology of photopolymerizable silicone monomers, fluids, and resins. The current status of research in these areas is assessed. The focus of this chapter is not only on the polymer chemistry and application of this technology, but also on important aspects of the synthetic chemistry involved in the preparation of UV-curable silicone monomers, oligomers, and resins. 236 refs., 6 tabs

Theory of microphase separation in homopolymer-oligomer mixtures

Energy Technology Data Exchange (ETDEWEB)

Olemskoi, Alexander [Department of Physical Electronics, Sumy State University, Rimskii-Korsakov St. 2, 40007 Sumy (Ukraine)]. E-mail: alex@ufn.ru; Savelyev, Alexey [Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290 (United States)]. E-mail: alexsav@unc.edu

2005-11-01

This work starts with the review of theoretical methods proposed, during past decades, for description of phase behavior in different polymer systems, involving variety of linear polymers (regular and polydisperse block (co)polymers, random polymers) and the polymer systems with non-covalent bonds of different strength. Microphase separation (MS) into different ordered mesophases is known to be the principal property of such systems. It is shown that most of the theoretical approaches proposed for description of the MS are based on the simple random phase approximation (RPA). It turns out, however, that mean field RPA method applied to description of the systems with non-covalent bonds does not provide the whole picture of MS. We show that the problem here arises when one treats both Flory-Huggins non-associated interactions and non-covalent bonds (hydrogen, ionic) within the unified RPA scheme, which is obviously rough for description of the latter type of interactions. Such a theory was developed in a few recent papers for the systems involving weak hydrogen bonds between homopolymer chains and the low molecular weight oligomers (surfactants). However, it leaves some experimental data unaccounted. The purpose of this review is to consider more detailed theory which is able to explain not only all the experimental data for the above systems but also to take into account the strength variation of non-bonding interactions. In particular, we consider the strong ionic interactions, weak hydrogen bonding, and the interactions of intermediate strength between polymer chain and short oligomers within our unifying theory. To develop such a description in a self-consistent way we propose to use a general field theory of stochastic systems. The mesoscopic (lamellar) structure of the periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for the systems with both strong (ionic) and weak (hydrogen

Theory of microphase separation in homopolymer-oligomer mixtures

International Nuclear Information System (INIS)

Olemskoi, Alexander; Savelyev, Alexey

2005-01-01

This work starts with the review of theoretical methods proposed, during past decades, for description of phase behavior in different polymer systems, involving variety of linear polymers (regular and polydisperse block (co)polymers, random polymers) and the polymer systems with non-covalent bonds of different strength. Microphase separation (MS) into different ordered mesophases is known to be the principal property of such systems. It is shown that most of the theoretical approaches proposed for description of the MS are based on the simple random phase approximation (RPA). It turns out, however, that mean field RPA method applied to description of the systems with non-covalent bonds does not provide the whole picture of MS. We show that the problem here arises when one treats both Flory-Huggins non-associated interactions and non-covalent bonds (hydrogen, ionic) within the unified RPA scheme, which is obviously rough for description of the latter type of interactions. Such a theory was developed in a few recent papers for the systems involving weak hydrogen bonds between homopolymer chains and the low molecular weight oligomers (surfactants). However, it leaves some experimental data unaccounted. The purpose of this review is to consider more detailed theory which is able to explain not only all the experimental data for the above systems but also to take into account the strength variation of non-bonding interactions. In particular, we consider the strong ionic interactions, weak hydrogen bonding, and the interactions of intermediate strength between polymer chain and short oligomers within our unifying theory. To develop such a description in a self-consistent way we propose to use a general field theory of stochastic systems. The mesoscopic (lamellar) structure of the periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for the systems with both strong (ionic) and weak (hydrogen

NEXAFS characterization of DNA components and molecular-orientation of surface-bound DNA oligomers

International Nuclear Information System (INIS)

Samuel, Newton T.; Lee, C.-Y.; Gamble, Lara J.; Fischer, Daniel A.; Castner, David G.

2006-01-01

Single stranded DNA oligomers (ssDNA) immobilized onto solid surfaces forms the basis for several biotechnological applications such as DNA microarrays, affinity separations, and biosensors. Surface structure of Surface-bound oligomers is expected to significantly influence their biological activity and interactions with the environment. In this study near-edge X-ray absorption fine structure spectroscopy (NEXAFS) is used to characterize the components of DNA (nucleobases, nucleotides and nucleosides) and the orientation information of surface-bound ssDNA. The K-edges of carbon, nitrogen and oxygen have spectra with features that are characteristic of the different chemical species present in the nucleobases of DNA. The effect of addition of the DNA sugar and phosphate components on the NEXAFS K-edge spectra was also investigated. The polarization-dependent nitrogen K-edge NEXAFS data show significant changes for different orientations of surface bound ssDNA. These results establish NEXAFS as a powerful technique for chemical and structural characterization of surface-bound DNA oligomers

Genotoxicity of styrene oligomers extracted from polystyrene intended for use in contact with food

Directory of Open Access Journals (Sweden)

Makoto Nakai

2014-01-01

Full Text Available Here, we conducted in vitro genotoxicity tests to evaluate the genotoxicity of styrene oligomers extracted from polystyrene intended for use in contact with food. Styrene oligomers were extracted with acetone and the extract was subjected to the Ames test (OECD test guideline No. 471 and the in vitro chromosomal aberration test (OECD test guideline No. 473 under good laboratory practice conditions. The concentrations of styrene dimers and trimers in the concentrated extract were 540 and 13,431 ppm, respectively. Extraction with acetone provided markedly higher concentrations of styrene oligomers compared with extraction with 50% ethanol aqueous solution, which is the food simulant currently recommended for use in safety assessments of polystyrene by both the United States Food and Drug Administration and the European Food Safety Authority. And these high concentrations of styrene dimers and trimers were utilized for the evaluation of genotoxicity in vitro. Ames tests using five bacterial tester strains were negative both in the presence or absence of metabolic activation. The in vitro chromosomal aberration test using Chinese hamster lung cells (CHL/IU was also negative. Together, these results suggest that the risk of the genotoxicity of styrene oligomers that migrate from polystyrene food packaging into food is very low.

Synthesis of alginate oligomers by gamma irradiation and to investigate its antioxidant and prebiotic activity

International Nuclear Information System (INIS)

Bhoir, S.A.; Chawla, S.P.

2016-01-01

Alginate oligomers formed by alginate lyase have been reported to possess antioxidant activity as well as prebiotic activity. Hence, utility of gamma radiation to depolymerise alginate in its aqueous solution was investigated and its antioxidant and prebiotic activities were screened. 1% aqueous solution of sodium alginate was subjected to gamma irradiation and it's reducing power and ability to scavenge DPPH". and O_2"."."-, chelate iron and prevent heat induced β-carotene bleaching was determined. Prebiotic activity was determined by using alginate oligomers to promote prebiotic activity of Lactobacillus plantarum against E coli. Gamma radiation induced depolymerisation of alginate resulted in formation of oligomers with antioxidant and prebiotic activity. These polymers are potential candidates for utilization as natural preservatives and functional foods

Characterizing the Dynamics of α-Synuclein Oligomers Using Hydrogen/Deuterium Exchange Monitored by Mass Spectrometry

DEFF Research Database (Denmark)

Mysling, Simon; Betzer, Cristine; Jensen, Poul Henning

2013-01-01

Soluble oligomers formed by α-synuclein (αSN) are suspected to play a central role in neuronal cell death during Parkinson's disease. While studies have probed the surface structure of these oligomers, little is known about the backbone dynamics of αSN when they form soluble oligomers. Using...... analyses performed on αSN fibrils and indicated a possible zipperlike maturation mechanism for αSN aggregates. We find the protected N-terminus (residues 4-17) to be of particular interest, as this region has previously been observed to be highly dynamic for both monomeric and fibrillar αSN. This region...... has mainly been described in relation to membrane binding of αSN, and structuring may be important in relation to disease....

Aerosol-Forming Reactions of Glyoxal, Methylglyoxal and Amino Acids in Clouds

Science.gov (United States)

de Haan, D. O.; Smith, K. W.; Stroik, D. R.; Corrigan, A. L.; Lee, F. E.; Phan, J. T.; Conley, A. C.

2008-12-01

Glyoxal and methylglyoxal are two common aldehydes present in fog and cloud water. Amino acids are present in clouds at similar concentrations. Here we present bulk and aerosol mass spectroscopic data demonstrating that irreversible reactions between glyoxal and amino acids, triggered by droplet evaporation, produce N-derivatized imidazole compounds along with deeply colored Maillard reaction products. These reactions can occur in the dark and in the absence of oxidants. Reactions between methylglyoxal and amino acids produce analogous methylated products plus oligomers with masses up to m/z = 1000. These reactions, which go to completion on the 10-min-timescale of cloud processing, could be significant sources of secondary organic aerosol and humic-like substances (HULIS or brown carbon).

Structures of Metalloporphyrin-Oligomer Multianions: Cofacial versus Coplanar Motifs as Resolved by Ion Mobility Spectrometry.

Science.gov (United States)

Brendle, Katrina; Schwarz, Ulrike; Jäger, Patrick; Weis, Patrick; Kappes, Manfred

2016-11-03

We have combined ion mobility mass spectrometry with quantum chemical calculations to investigate the gas-phase structures of multiply negatively charged oligomers of meso-tetra(4-sulfonatophenyl)metalloporphyrins comprising the divalent metal centers Zn II , Cu II , and Pd II . Sets of candidate structures were obtained by geometry optimizations based on calculations at both the semiempirical PM7 and density functional theory (DFT) levels. The corresponding theoretical cross sections were calculated with the projection approximation and also with the trajectory method. By comparing these collision cross sections with the respective experimental values we were able to assign oligomer structures up to the tetramer. In most cases the cross sections of the lowest energy isomers predicted by theory were found to agree with the measurements to within the experimental uncertainty (2%). Specifically, we find that for a given oligomer size the structures are independent of the metal center but depend strongly on the charge state. Oligomers in low charge states with a correspondingly larger number of sodium counterions tend to form stacked, cofacial structures reminiscent of H-aggregate motifs observed in solution. By contrast, in higher charge states, the stack opens to form coplanar structures.

A nonsense mutation causing decreased levels of insulin receptor mRNA: Detection by a simplified technique for direct sequencing of genomic DNA amplified by the polymerase chain reaction

International Nuclear Information System (INIS)

Kadowaki, T.; Kadowaki, H.; Taylor, S.I.

1990-01-01

Mutations in the insulin receptor gene can render the cell resistant to the biological action of insulin. The authors have studied a patient with leprechaunism (leprechaun/Minn-1), a genetic syndrome associated with intrauterine growth retardation and extreme insulin resistance. Genomic DNA from the patient was amplified by the polymerase chain reaction catalyzed by Thermus aquaticus (Taq) DNA polymerase, and the amplified DNA was directly sequenced. A nonsense mutations was identified at codon 897 in exon 14 in the paternal allele of the patient's insulin receptor gene. Levels of insulin receptor mRNA are decreased to <10% of normal in Epstein-Barr virus-transformed lymphoblasts and cultured skin fibroblasts from this patient. Thus, this nonsense mutation appears to cause a decrease in the levels of insulin receptor mRNA. In addition, they have obtained indirect evidence that the patient's maternal allele of the insulin receptor gene contains a cis-acting dominant mutation that also decreases the level of mRNA, but by a different mechanism. The nucleotide sequence of the entire protein-coding domain and the sequences of the intron-exon boundaries for all 22 exons of the maternal allele were normal. Presumably, the mutation in the maternal allele maps elsewhere in the insulin receptor gene. Thus, they conclude that the patient is a compound heterozygote for two cis-acting dominant mutations in the insulin receptor gene: (i) a nonsense mutation in the paternal allel that reduces the level of insulin receptor mRNA and (ii) an as yet unidentified mutation in the maternal allele that either decreases the rate of transcription or decreases the stability of the mRNA

Molecular Mechanisms of Insulin Resistance in Chronic Kidney Disease

Science.gov (United States)

Thomas, Sandhya S.; Zhang, Liping; Mitch, William E.

2015-01-01

Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identifies the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to activation of different, E3 ubiquitin ligases which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID:26444029

Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice.

Science.gov (United States)

Kittelberger, Kara A; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G

2012-01-01

Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

Science.gov (United States)

Kittelberger, Kara A.; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G.

2012-01-01

Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID:22238679

Coronavirus nucleocapsid proteins assemble constitutively in high molecular oligomers

NARCIS (Netherlands)

Cong, Yingying; Kriegenburg, Franziska; de Haan, Cornelis A. M.; Reggiori, Fulvio

2017-01-01

Coronaviruses (CoV) are enveloped viruses and rely on their nucleocapsid N protein to incorporate the positive-stranded genomic RNA into the virions. CoV N proteins form oligomers but the mechanism and relevance underlying their multimerization remain to be fully understood. Using in vitro pull-down

Solid state properties of oligomers containing dithienothiophene or fluorene residues suitable for field effect transistor devices

International Nuclear Information System (INIS)

Porzio, William; Destri, Silvia; Giovanella, Umberto; Pasini, Mariacecilia; Marin, Luminita; Iosip, Mariana Dana; Campione, Marcello

2007-01-01

A series of three thiophene based oligomers has been extensively characterized. The chemical design has been addressed to obtain ionization potential (IP) and electronic affinity (EA) values matching the work function of commonly used electrode materials. Such IP and EA values were tested by cyclovoltammetry. In order to tune electron-donation and drawing strength the sequence of the molecule subunits in the oligomer has been varied. The thermal properties with particular reference to their stability during preparation and operation were checked by using differential scanning calorimetry, polarised light microscopy and thermogravimetric analysis techniques. Prototypes of thin film field effect transistor, based on this series of oligomers have been electrically and structurally characterized. The long axes of the molecules are oriented nearly perpendicular to the gate insulator, in agreement with both highly sensitive X-ray diffraction and atomic force microscopy. From powder diffraction data the structure of oligomer I was solved. A general relation is envisaged between charge mobility and packing closeness in the series. For the most promising molecule a study of mobility/temperature behaviour was performed yielding interesting results

Thermodynamically stable amyloid-β monomers have much lower membrane affinity than the small oligomers

Directory of Open Access Journals (Sweden)

Bidyut eSarkar

2013-04-01

Full Text Available Amyloid beta (Aβ is an extracellular 39-43 residue long peptide present in the mammalian cerebrospinal fluid, whose aggregation is associated with Alzheimer’s disease. Small oligomers of Aβ are currently thought to be the key to toxicity. However, it is not clear why the monomers of Aβ are non-toxic, and at what stage of aggregation toxicity emerges. Interactions of Aβ with cell membranes is thought to be the initiator of toxicity, but membrane-binding studies with different preparations of monomers and oligomers have not settled this issue. We have earlier found that thermodynamically stable Aβ monomers emerge spontaneously from oligomeric mixtures upon long term incubation in physiological solutions (Nag et al, JBC, 2011. Here we show that the membrane-affinity of these stable Aβ monomers is much lower than that of a mixture of small oligomers (containing dimers to decamers, providing a clue to the emergence of toxicity. Fluorescently labeled Aβ40 monomers show negligible binding to cell membranes of a neuronal cell line (RN46A at physiological concentrations (250 nM, while oligomers at the same concentrations show strong binding within 30 minutes of incubation. The increased affinity most likely does not require any specific neuronal receptor, since this difference in membrane-affinity was also observed in a somatic cell-line (HEK 293T. Similar results are also obtained for Aβ42 monomers and oligomers. Minimal amount of cell death is observed at these concentrations even after 36 hours of incubation. It is likely that membrane binding precedes subsequent slower toxic events induced by Aβ. Our results a provide an explanation for the non-toxic nature of Aβ monomers, b suggest that Aβ toxicity emerges at the initial oligomeric phase, and c provide a quick assay for monitoring the benign-to-toxic transformation of Aβ.

Distinct Internalization Pathways of Human Amylin Monomers and Its Cytotoxic Oligomers in Pancreatic Cells

Science.gov (United States)

Trikha, Saurabh; Jeremic, Aleksandar M.

2013-01-01

Toxic human amylin oligomers and aggregates are implicated in the pathogenesis of type 2 diabetes mellitus (TTDM). Although recent studies have shown that pancreatic cells can recycle amylin monomers and toxic oligomers, the exact uptake mechanism and trafficking routes of these molecular forms and their significance for amylin toxicity are yet to be determined. Using pancreatic rat insulinoma (RIN-m5F) beta (β)-cells and human islets as model systems we show that monomers and oligomers cross the plasma membrane (PM) through both endocytotic and non-endocytotic (translocation) mechanisms, the predominance of which is dependent on amylin concentrations and incubation times. At low (≤100 nM) concentrations, internalization of amylin monomers in pancreatic cells is completely blocked by the selective amylin-receptor (AM-R) antagonist, AC-187, indicating an AM-R dependent mechanism. In contrast at cytotoxic (µM) concentrations monomers initially (1 hour) enter pancreatic cells by two distinct mechanisms: translocation and macropinocytosis. However, during the late stage (24 hours) monomers internalize by a clathrin-dependent but AM-R and macropinocytotic independent pathway. Like monomers a small fraction of the oligomers initially enter cells by a non-endocytotic mechanism. In contrast a majority of the oligomers at both early (1 hour) and late times (24 hours) traffic with a fluid-phase marker, dextran, to the same endocytotic compartments, the uptake of which is blocked by potent macropinocytotic inhibitors. This led to a significant increase in extra-cellular PM accumulation, in turn potentiating amylin toxicity in pancreatic cells. Our studies suggest that macropinocytosis is a major but not the only clearance mechanism for both amylin’s molecular forms, thereby serving a cyto-protective role in these cells. PMID:24019897

Benzothienobenzothiophene-based conjugated oligomers as semiconductors for stable organic thin-film transistors.

Science.gov (United States)

Yu, Han; Li, Weili; Tian, Hongkun; Wang, Haibo; Yan, Donghang; Zhang, Jingping; Geng, Yanhou; Wang, Fosong

2014-04-09

Two benzothienobenzothiophene (BTBT)-based conjugated oligomers, i.e., 2,2'-bi[1]benzothieno[3,2-b][1]benzothiophene (1) and 5,5'-bis([1]benzothieno[3,2-b][1]benzothiophen-2-yl)-2,2'-bithiophene (2), were prepared and characterized. Both oligomers exhibit excellent thermal stability, with 5% weight-loss temperatures (T(L)) above 370 °C; no phase transition was observed before decomposition. The highest occupied molecular orbital (HOMO) levels of 1 and 2 are -5.3 and -4.9 eV, respectively, as measured by ultraviolet photoelectron spectroscopy. Thin-film X-ray diffraction and atomic force microscopy characterizations indicate that both oligomers form highly crystalline films with large domain sizes on octadecyltrimethoxysilane-modified substrates. Organic thin-film transistors with top-contact and bottom-gate geometry based on 1 and 2 exhibited mobilities up to 2.12 cm(2)/V·s for 1 and 1.39 cm(2)/V·s for 2 in an ambient atmosphere. 1-based devices exhibited great air and thermal stabilities, as evidenced by the slight performance degradation after 2 months of storage under ambient conditions and after thermal annealing at temperatures below 250 °C.

Rapamycin-induced oligomer formation system of FRB-FKBP fusion proteins.

Science.gov (United States)

Inobe, Tomonao; Nukina, Nobuyuki

2016-07-01

Most proteins form larger protein complexes and perform multiple functions in the cell. Thus, artificial regulation of protein complex formation controls the cellular functions that involve protein complexes. Although several artificial dimerization systems have already been used for numerous applications in biomedical research, cellular protein complexes form not only simple dimers but also larger oligomers. In this study, we showed that fusion proteins comprising the induced heterodimer formation proteins FRB and FKBP formed various oligomers upon addition of rapamycin. By adjusting the configuration of fusion proteins, we succeeded in generating an inducible tetramer formation system. Proteins of interest also formed tetramers by fusing to the inducible tetramer formation system, which exhibits its utility in a broad range of biological applications. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Studies on Oligomer Metal Complexes Derived from Bisamic Acid of Pyromellitic Dianhydride and 4-Bromoaniline

OpenAIRE

Patel, Yogesh S.

2014-01-01

Novel oligomer metal complexes (2a–f) of the ligand 2,5-bis((4-bromophenyl)carbamoyl) terephthalic acid (1) were prepared using transition metal salts and characterized by various spectroscopic techniques. The geometry of oligomer metal complexes was carried out by electronic spectral analysis and magnetic measurement studies. Polymeric properties have also been carried out. Ligand was synthesized using pyromellitic dianhydride and 4-bromoaniline. It was duly characterized. All novel synthesi...

Differentiation of human-induced pluripotent stem cells into insulin-producing clusters.

Science.gov (United States)

Shaer, Anahita; Azarpira, Negar; Vahdati, Akbar; Karimi, Mohammad Hosein; Shariati, Mehrdad

2015-02-01

In diabetes mellitus type 1, beta cells are mostly destroyed; while in diabetes mellitus type 2, beta cells are reduced by 40% to 60%. We hope that soon, stem cells can be used in diabetes therapy via pancreatic beta cell replacement. Induced pluripotent stem cells are a kind of stem cell taken from an adult somatic cell by "stimulating" certain genes. These induced pluripotent stem cells may be a promising source of cell therapy. This study sought to produce isletlike clusters of insulin-producing cells taken from induced pluripotent stem cells. A human-induced pluripotent stem cell line was induced into isletlike clusters via a 4-step protocol, by adding insulin, transferrin, and selenium (ITS), N2, B27, fibroblast growth factor, and nicotinamide. During differentiation, expression of pancreatic β-cell genes was evaluated by reverse transcriptase-polymerase chain reaction; the morphologic changes of induced pluripotent stem cells toward isletlike clusters were observed by a light microscope. Dithizone staining was used to stain these isletlike clusters. Insulin produced by these clusters was evaluated by radio immunosorbent assay, and the secretion capacity was analyzed with a glucose challenge test. Differentiation was evaluated by analyzing the morphology, dithizone staining, real-time quantitative polymerase chain reaction, and immunocytochemistry. Gene expression of insulin, glucagon, PDX1, NGN3, PAX4, PAX6, NKX6.1, KIR6.2, and GLUT2 were documented by analyzing real-time quantitative polymerase chain reaction. Dithizone-stained cellular clusters were observed after 23 days. The isletlike clusters significantly produced insulin. The isletlike clusters could increase insulin secretion after a glucose challenge test. This work provides a model for studying the differentiation of human-induced pluripotent stem cells to insulin-producing cells.

Structure and properties of binary polystyrene-epoxy acrylate oligomer mixtures irradiated by electron beams

International Nuclear Information System (INIS)

Lomonosova, N.V.

1995-01-01

The change in the structure of oriented polymer-oligomer systems based on polystyrene (PS) with M > 10 6 and epoxy acrylate oligomers (aliphatic and aromatic) under irradiation by accelerated electrons was studied using birefringence, isometric heating, IR dichroism, and thermooptical analysis. Mechanical properties of these systems were investigated. It was found that, by adding aliphatic epoxy acrylate to PS and further irradiating this mixture, one can obtain both isotropic and oriented composites with higher strengths, elasticity moduli, and glass transition temperatures

Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice.

Directory of Open Access Journals (Sweden)

Kara A Kittelberger

Full Text Available Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD. It has been proposed that soluble amyloid-beta (Abeta oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

Charge-carrier selective electrodes for organic bulk heterojunction solar cell by contact-printed siloxane oligomers

International Nuclear Information System (INIS)

Hwang, Hyun-Sik; Khang, Dahl-Young

2015-01-01

‘Smart’ (or selective) electrode for charge carriers, both electrons and holes, in organic bulk-heterojunction (BHJ) solar cells using insertion layers made of hydrophobically-recovered and contact-printed siloxane oligomers between electrodes and active material has been demonstrated. The siloxane oligomer insertion layer has been formed at a given interface simply by conformally-contacting a cured slab of polydimethylsiloxane stamp for less than 100 s. All the devices, either siloxane oligomer printed at one interface only or printed at both interfaces, showed efficiency enhancement when compared to non-printed ones. The possible mechanism that is responsible for the observed efficiency enhancement has been discussed based on the point of optimum symmetry and photocurrent analysis. Besides its simplicity and large-area applicability, the demonstrated contact-printing technique does not involve any vacuum or wet processing steps and thus can be very useful for the roll-based, continuous production scheme for organic BHJ solar cells. - Highlights: • Carrier-selective insertion layer in organic bulk heterojunction solar cells • Simple contact-printing of siloxane oligomers improves cell efficiency. • Printed siloxane layer reduces carrier recombination at electrode surfaces. • Siloxane insertion layer works equally well at both electrode surfaces. • Patterned PDMS stamp shortens the printing time within 100 s

[Solid state isotope hydrogen exchange for deuterium and tritium in human gene-engineered insulin].

Science.gov (United States)

Zolotarev, Yu A; Dadayan, A K; Kozik, V S; Gasanov, E V; Nazimov, I V; Ziganshin, R Kh; Vaskovsky, B V; Murashov, A N; Ksenofontov, A L; Haribin, O N; Nikolaev, E N; Myasoedov, N F

2014-01-01

The reaction of high temperature solid state catalytic isotope exchange in peptides and proteins under the action of catalyst-activated spillover hydrogen was studied. The reaction of human gene-engineered insulin with deuterium and tritium was conducted at 120-140° C to produce insulin samples containing 2-6 hydrogen isotope atoms. To determine the distribution of the isotope label over tritium-labeled insulin's amino acid residues, oxidation of the S-S bonds of insulin by performic acid was performed and polypeptide chains isolated; then their acid hydrolysis, amino acid analysis and liquid scintillation counts of tritium in the amino acids were conducted. The isotope label was shown to be incorporated in all amino acids of the protein, with the peptide fragment FVNQHLCGSHLVE of the insulin β-chain showing the largest incorporation. About 45% of the total protein isotope label was incorporated in His5 and His10 of this fragment. For the analysis of isotope label distribution in labeled insulin's peptide fragments, the recovery of the S-S bonds by mercaptoethanol, the enzymatic hydrolysis by glutamyl endopeptidase from Bacillus intermedius and HPLC division of the resulting peptides were carried out. Attribution of the peptide fragments formed due to hydrolysis at the Glu-X bond in the β-chain was accomplished by mass spectrometry. Mass spectrometry analysis data of the deuterium-labeled insulin samples' isotopomeric composition showed that the studied solid state isotope exchange reaction equally involved all the protein molecules. Biological studying of tritium-labeled insulin showed its physiological activity to be completely retained.

Enzymatic radioiodination of insulin for radioimmunoassay use

Energy Technology Data Exchange (ETDEWEB)

Awh, O D; Kim, J R [Korea Atomic Energy Research Inst., Seoul (Republic of Korea)

1980-06-01

Insulin was labelled with /sup 125/I using lactoperoxidase as an oxidizing agent. The reaction product was purified via two stages; a starch gel electrophoresis(SGE) and a Sephadex gel filtration(SF). Upon comparison of the labelling yields and the bindabilities of the labelled insulin to its antibody, it has been found that the enzyme method shows higher yields (50%) and the better bindability to its antibody than the conventional chloramine-T method (35%). By checking the insulin blank labelling mixture with a SGE, a paper chromatography, and a radioautography technique, a by-product in the lactoperoxidase method has been identified. The separated fractions in SGE and SF were also analyzed and discussed.

Atomistic simulation of CO 2 solubility in poly(ethylene oxide) oligomers

KAUST Repository

Hong, Bingbing; Panagiotopoulos, Athanassios Z.

2013-01-01

We have performed atomistic molecular dynamics simulations coupled with thermodynamic integration to obtain the excess chemical potential and pressure-composition phase diagrams for CO2 in poly(ethylene oxide) oligomers. Poly(ethylene oxide

Macrocyclic 2,7-Anthrylene Oligomers.

Science.gov (United States)

Yamamoto, Yuta; Wakamatsu, Kan; Iwanaga, Tetsuo; Sato, Hiroyasu; Toyota, Shinji

2016-05-06

A macrocyclic compound consisting of six 2,7-anthrylene units was successfully synthesized by Ni-mediated coupling of the corresponding dibromo precursor as a novel π-conjugated compound. This compound was sufficiently stable and soluble in organic solvents due to the presence of mesityl groups. X-ray analysis showed that the molecule had a nonplanar and hexagonal wheel-shaped framework of approximately S6 symmetry. The dynamic process between two S6 structures was observed by using the dynamic NMR technique, the barrier being 58 kJ mol(-1) . The spectroscopic properties of the hexamer were compared with those of analogous linear oligomers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Science.gov (United States)

Swanson, Eric; Breckenridge, Leigham; McMahon, Lloyd; Som, Sreemoyee; McConnell, Ian; Bloom, George S.

2017-01-01

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. PMID:28482642

Chemistry of Furan Conversion into Aromatics and Olefins over HZSM-5: A Model Biomass Conversion Reaction

Energy Technology Data Exchange (ETDEWEB)

Cheng, Yu-Ting; Huber, George W.

2011-06-03

The conversion of furan (a model of cellulosic biomass) over HZSM-5 was investigated in a thermogravimetric analysis–mass spectrometry system, in situ Fourier transform infrared analysis, and in a continuous-flow fixed-bed reactor. Furan adsorbed as oligomers at room temperature with a 1.73 of adsorbed furan/Al ratio. These oligomers were polycyclic aromatic compounds that were converted to CO, CO₂, aromatics, and olefins at temperatures from 400 to 600 °C. Aromatics (e.g., benzene, toluene, and naphthalene), oligomer isomers (e.g., benzofuran, 2,2-methylenebisfuran, and benzodioxane), and heavy oxygenates (C₁₂{sub +} oligomers) were identified as intermediates formed inside HZSM-5 at different reaction temperatures. During furan conversion, graphite-type coke formed on the catalyst surface, which caused the aromatics and olefins formation to deactivate within the first 30 min of time on-stream. We have measured the effects of space velocity and temperature for furan conversion to help us understand the chemistry of biomass conversion inside zeolite catalysts. The major products for furan conversion included CO, CO₂, allene, C₂–C₆ olefins, benzene, toluene, styrene, benzofuran, indene, and naphthalene. The aromatics (benzene and toluene) and olefins (ethylene and propylene) selectivity decreased with increasing space velocity. Unsaturated hydrocarbons such as allene, cyclopentadiene, and aromatics selectivity increased with increasing space velocity. The product distribution was selective to olefins and CO at high temperatures (650 °C) but was selective to aromatics (benzene and toluene) at intermediate temperatures (450–600 °C). At low temperatures (450 °C), benzofuran and coke contributed 60% of the carbon selectivity. Several different reactions were occurring for furan conversion over zeolites. Some important reactions that we have identified in this study include Diels–Alder condensation (e.g., two furans form benzofuran and water

Alpha-synuclein oligomers - neurotoxic molecules in Parkinson’s disease and other Lewy body disorders

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Martin Ingelsson

2016-09-01

Full Text Available Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson’s disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson’s disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.

Targeting α-synuclein oligomers

DEFF Research Database (Denmark)

van Diggelen, Femke

Parkinson’s Disease (PD) is a complex disease, characterised by degeneration of neocortical, limbic and nigrostriatal neurons. It is unknown what initiates neurodegeneration, but soluble oligomers of the protein α-synuclein (αSn) seem to be particularly toxic, compared to insoluble fibrils...... unique characteristics, e.g. they were recognized by different conformational antibodies and DHA–αSOs also formed a second elongated species in addition to the dominant spherical species. Although further functional testing is needed, this suggests that each species has its own distinct toxic mechanism......+/K+ ATPase, V-type ATPase, VDAC, CaMKII and Rab-3A. The identification of these targets is a first step towards unravelling the toxic pathways which are activated upon synaptic binding of extracellularly added αSOs, and hopefully will contribute to the discovery of new disease modifying compounds, which can...

Molecular Mechanisms of Insulin Resistance Development

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Vsevolod Arsen'evich Tkachuk

2014-05-01

Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

Salicylamide and salicylglycine oxidovanadium complexes with insulin-mimetic properties.

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Nilsson, Jessica; Shteinman, Albert A; Degerman, Eva; Enyedy, Eva A; Kiss, Tamás; Behrens, Ulrich; Rehder, Dieter; Nordlander, Ebbe

2011-12-01

Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular size evolution of oligomers in organic aerosols collected in urban atmospheres and generated in a smog chamber.

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Kalberer, Markus; Sax, Mirjam; Samburova, Vera

2006-10-01

Only a minor fraction of the total organic aerosol mass can be resolved on a molecular level. High molecular weight compounds in organic aerosols have recently gained much attention because this class of compound potentially explains a major fraction of the unexplained organic aerosol mass. These compounds have been identified with different mass spectrometric methods, and compounds with molecular masses up to 1000 Da are found in secondary organic aerosols (SOA) generated from aromatic and terpene precursors in smog chamber experiments. Here, we apply matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to SOA particles from two biogenic precursors, alpha-pinene and isoprene. Similar oligomer patterns are found in these two SOA systems, but also in SOA from trimethylbenzene, an anthropogenic SOA precursor. However, different maxima molecular sizes were measured for these three SOA systems. While oligomers in alpha-pinene and isoprene have sizes mostly below 600-700 Da, they grow up to about 1000 Da in trimethylbenzene-SOA. The final molecular size of the oligomers is reached early during the particle aging process, whereas other particle properties related to aging, such as the overall acid concentration or the oligomer concentration, increase continuously over a much longer time scale. This kinetic behavior of the oligomer molecular size growth can be explained by a chain growth kinetic regime. Similar oligomer mass patterns were measured in aqueous extracts of ambient aerosol samples (measured with the same technique). Distinct differences between summer and winter were observed. In summer a few single mass peaks were measured with much higher intensity than in winter, pointing to a possible difference in the formation processes of these compounds in winter and summer.

Isolation and Quantification of Polyamide Cyclic Oligomers in Kitchen Utensils and Their Migration into Various Food Simulants.

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Abe, Yutaka; Mutsuga, Motoh; Ohno, Hiroyuki; Kawamura, Yoko; Akiyama, Hiroshi

2016-01-01

Small amounts of cyclic monomers and oligomers are present in polyamide (PA)-based kitchen utensils. In this study, we isolated eight PA-based cyclic monomers and oligomers from kitchen utensils made from PA6 (a polymer of ε-caprolactam) and PA66 (a polymer of 1,6-diaminohexane and adipic acid). Their structures were identified using high-resolution mass spectrometry and 1H- and 13C-nuclear magnetic resonance spectroscopy, and their residual levels in PA-based kitchen utensils and degree of migration into food simulants were quantified by high-performance liquid chromatography/mass spectrometry using purchased PA6 monomer and isolated PA66 monomers, and isolated PA6 and PA66 oligomers as calibration standards. Their total residual levels among 23 PA-based kitchen utensils made from PA6, PA66, and copolymers of PA6 and PA66 (PA6/66) ranged from 7.8 to 20 mg/g. Using water, 20% ethanol, and olive oil as food simulants, the total migration levels of the PA monomers and oligomers ranged from 0.66 to 100 μg/cm2 under most examined conditions. However, the total migration levels of the PA66 monomer and oligomers from PA66 and PA6/66 kitchen utensils into 20% ethanol at 95°C were very high (1,700 and 2,200 μg/cm2, respectively) due to swelling by high-temperature ethanol.

Isolation and Quantification of Polyamide Cyclic Oligomers in Kitchen Utensils and Their Migration into Various Food Simulants.

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Yutaka Abe

Full Text Available Small amounts of cyclic monomers and oligomers are present in polyamide (PA-based kitchen utensils. In this study, we isolated eight PA-based cyclic monomers and oligomers from kitchen utensils made from PA6 (a polymer of ε-caprolactam and PA66 (a polymer of 1,6-diaminohexane and adipic acid. Their structures were identified using high-resolution mass spectrometry and 1H- and 13C-nuclear magnetic resonance spectroscopy, and their residual levels in PA-based kitchen utensils and degree of migration into food simulants were quantified by high-performance liquid chromatography/mass spectrometry using purchased PA6 monomer and isolated PA66 monomers, and isolated PA6 and PA66 oligomers as calibration standards. Their total residual levels among 23 PA-based kitchen utensils made from PA6, PA66, and copolymers of PA6 and PA66 (PA6/66 ranged from 7.8 to 20 mg/g. Using water, 20% ethanol, and olive oil as food simulants, the total migration levels of the PA monomers and oligomers ranged from 0.66 to 100 μg/cm2 under most examined conditions. However, the total migration levels of the PA66 monomer and oligomers from PA66 and PA6/66 kitchen utensils into 20% ethanol at 95°C were very high (1,700 and 2,200 μg/cm2, respectively due to swelling by high-temperature ethanol.

A combined semiempirical-DFT study of oligomers within the finite-chain approximation, evolution from oligomers to polymers.

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Derosa, Pedro A

2009-06-01

A computationally cheap approach combining time-independent density functional theory (TIDFT) and semiempirical methods with an appropriate extrapolation procedure is proposed to accurately estimate geometrical and electronic properties of conjugated polymers using just a small set of oligomers. The highest occupied molecular orbital-lowest unoccupied molecular orbital gap (HLG) obtained at a TIDFT level (B3PW91) for two polymers, trans-polyacetylene--the simplest conjugated polymer, and a much larger poly(2-methoxy-5-(2,9-ethyl-hexyloxy)-1,4-phenylenevinylene (MEH-PPV) polymer converge to virtually the same asymptotic value than the excitation energy obtained with time-dependent DFT (TDDFT) calculations using the same functional. For TIDFT geometries, the HLG is found to converge to a value within the experimentally accepted range for the band gap of these polymers, when an exponential extrapolation is used; however if semiempirical geometries are used, a linear fit of the HLG versus 1/n is found to produce the best results. Geometrical parameters are observed to reach a saturation value in good agreement with experimental information, within the length of oligomers calculated here and no extrapolation was considered necessary. Finally, the performance of three different semiempirical methods (AM1, PM3, and MNDO) and for the TIDFT calculations, the performance of 7 different full electron basis sets (6-311+G**, 6-31+ +G**, 6-311+ +G**, 6-31+G**, 6-31G**, 6-31+G*, and 6-31G) is compared and it is determined that the choice of semiempirical method or the basis set does not significantly affect the results. 2008 Wiley Periodicals, Inc.

Detection of the electronic structure of iron-(iii)-oxo oligomers forming in aqueous solutions.

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Seidel, Robert; Kraffert, Katrin; Kabelitz, Anke; Pohl, Marvin N; Kraehnert, Ralph; Emmerling, Franziska; Winter, Bernd

2017-12-13

The nature of the small iron-oxo oligomers in iron-(iii) aqueous solutions has a determining effect on the chemical processes that govern the formation of nanoparticles in aqueous phase. Here we report on a liquid-jet photoelectron-spectroscopy experiment for the investigation of the electronic structure of the occurring iron-oxo oligomers in FeCl 3 aqueous solutions. The only iron species in the as-prepared 0.75 M solution are Fe 3+ monomers. Addition of NaOH initiates Fe 3+ hydrolysis which is followed by the formation of iron-oxo oligomers. At small enough NaOH concentrations, corresponding to approximately [OH]/[Fe] = 0.2-0.25 ratio, the iron oligomers can be stabilized for several hours without engaging in further aggregation. Here, we apply a combination of non-resonant as well as iron 2p and oxygen 1s resonant photoelectron spectroscopy from a liquid microjet to detect the electronic structure of the occurring species. Specifically, the oxygen 1s partial electron yield X-ray absorption (PEY-XA) spectra are found to exhibit a peak well below the onset of liquid water and OH - (aq) absorption. The iron 2p absorption gives rise to signal centered between the main absorption bands typical for aqueous Fe 3+ . Absorption bands in both PEY-XA spectra are found to correlate with an enhanced photoelectron peak near 20 eV binding energy, which demonstrates the sensitivity of resonant photoelectron (RPE) spectroscopy to mixing between iron and ligand orbitals. These various signals from the iron-oxo oligomers exhibit maximum intensity at [OH]/[Fe] = 0.25 ratio. For the same ratio, we observe changes in the pH as well as in complementary Raman spectra, which can be assigned to the transition from monomeric to oligomeric species. At approximately [OH]/[Fe] = 0.3 we begin to observe particles larger than 1 nm in radius, detected by small-angle X-ray scattering.

Protein Self-Assembly and Protein-Induced DNA Morphologies

Science.gov (United States)

Mawhinney, Matthew T.

The ability of biomolecules to associate into various structural configurations has a substantial impact on human physiology. The synthesis of protein polypeptide chains using the information encoded by DNA is mediated through the use of regulatory proteins, known as transcription factors. Some transcription factors perform function by inducing local curvature in deoxyribonucleic acid (DNA) strands, the mechanisms of which are not entirely known. An important architectural protein, eleven zinc finger CTCF (11 ZF CTCF) is involved in genome organization and hypothesized to mediate DNA loop formation. Direct evidence for these CTCF-induced DNA loops has yet to be observed. In this thesis, the effect of 11 ZF CTCF on DNA morphology is examined using atomic force microscopy, a powerful technique for visualizing biomolecules with nanometer resolution. The presence of CTCF is revealed to induce a variety of morphologies deviating from the relaxed state of control DNA samples, including compact circular complexes, meshes, and networks. Images reveal quasi-circular DNA/CTCF complexes consistent with a single DNA molecule twice wrapped around the protein. The structures of DNA and proteins are highly important for operations in the cell. Structural irregularities may lead to a variety of issues, including more than twenty human pathologies resulting from aberrant protein misfolding into amyloid aggregates of elongated fibrils. Insulin deficiency and resistance characterizing type 2 diabetes often requires administration of insulin. Injectable and inhalable delivery methods have been documented to result in the deposition of amyloid fibrils. Oligomers, soluble multiprotein assemblies, are believed to play an important role in this process. Insulin aggregation under physiological conditions is not well understood and oligomers have not yet been fully characterized. In this thesis, in vitro insulin aggregation at acidic and neutral pH is explored using a variety of techniques

SAXS and stability studies of iron-induced oligomers of bacterial frataxin CyaY.

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Mostafa Fekry

Full Text Available Frataxin is a highly conserved protein found in both prokaryotes and eukaryotes. It is involved in several central functions in cells, which include iron delivery to biochemical processes, such as heme synthesis, assembly of iron-sulfur clusters (ISC, storage of surplus iron in conditions of iron overload, and repair of ISC in aconitase. Frataxin from different organisms has been shown to undergo iron-dependent oligomerization. At least two different classes of oligomers, with different modes of oligomer packing and stabilization, have been identified. Here, we continue our efforts to explore the factors that control the oligomerization of frataxin from different organisms, and focus on E. coli frataxin CyaY. Using small-angle X-ray scattering (SAXS, we show that higher iron-to-protein ratios lead to larger oligomeric species, and that oligomerization proceeds in a linear fashion as a results of iron oxidation. Native mass spectrometry and online size-exclusion chromatography combined with SAXS show that a dimer is the most common form of CyaY in the presence of iron at atmospheric conditions. Modeling of the dimer using the SAXS data confirms the earlier proposed head-to-tail packing arrangement of monomers. This packing mode brings several conserved acidic residues into close proximity to each other, creating an environment for metal ion binding and possibly even mineralization. Together with negative-stain electron microscopy, the experiments also show that trimers, tetramers, pentamers, and presumably higher-order oligomers may exist in solution. Nano-differential scanning fluorimetry shows that the oligomers have limited stability and may easily dissociate at elevated temperatures. The factors affecting the possible oligomerization mode are discussed.

Length dependence of rectification in organic co-oligomer spin rectifiers

International Nuclear Information System (INIS)

Hu Gui-Chao; Zhang Zhao; Li Ying; Ren Jun-Feng; Wang Chuan-Kui

2016-01-01

The rectification ratio of organic magnetic co-oligomer diodes is investigated theoretically by changing the molecular length. The results reveal two distinct length dependences of the rectification ratio: for a short molecular diode, the charge-current rectification changes little with the increase of molecular length, while the spin-current rectification is weakened sharply by the length; for a long molecular diode, both the charge-current and spin-current rectification ratios increase quickly with the length. The two kinds of dependence switch at a specific length accompanied with an inversion of the rectifying direction. The molecular ortibals and spin-resolved transmission analysis indicate that the dominant mechanism of rectification suffers a change at this specific length, that is, from asymmetric shift of molecular eigenlevels to asymmetric spatial localization of wave functions upon the reversal of bias. This work demonstrates a feasible way to control the rectification in organic co-oligomer spin diodes by adjusting the molecular length. (paper)

Targeted selected reaction monitoring mass spectrometric immunoassay for insulin-like growth factor 1.

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Eric E Niederkofler

Full Text Available Insulin-like growth factor 1 (IGF1 is an important biomarker of human growth disorders that is routinely analyzed in clinical laboratories. Mass spectrometry-based workflows offer a viable alternative to standard IGF1 immunoassays, which utilize various pre-analytical preparation strategies. In this work we developed an assay that incorporates a novel sample preparation method for dissociating IGF1 from its binding proteins. The workflow also includes an immunoaffinity step using antibody-derivatized pipette tips, followed by elution, trypsin digestion, and LC-MS/MS separation and detection of the signature peptides in a selected reaction monitoring (SRM mode. The resulting quantitative mass spectrometric immunoassay (MSIA exhibited good linearity in the range of 1 to 1,500 ng/mL IGF1, intra- and inter-assay precision with CVs of less than 10%, and lowest limits of detection of 1 ng/mL. The linearity and recovery characteristics of the assay were also established, and the new method compared to a commercially available immunoassay using a large cohort of human serum samples. The IGF1 SRM MSIA is well suited for use in clinical laboratories.

Tumor delivery of antisense oligomer using trastuzumab within a streptavidin nanoparticle

Energy Technology Data Exchange (ETDEWEB)

Wang, Yi [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Yale University, Yale PET Center, Department of Diagnostic Radiology, New Haven, CT (United States); Liu, Xinrong; Chen, Ling; Cheng, Dengfeng; Rusckowski, Mary [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Hnatowich, Donald J. [University of Massachusetts Medical School, Division of Nuclear Medicine, Department of Radiology, Worcester, MA (United States); Umass Medical School, Department of Radiology, Worcester, MA (United States)

2009-12-15

Trastuzumab (Herceptin trademark) is often internalized following binding to Her2+ tumor cells. The objective of this study was to investigate whether trastuzumab can be used as a specific carrier to deliver antisense oligomers into Her2+ tumor cells both in vitro and in vivo. A biotinylated MORF oligomer antisense to RhoC mRNA and its biotinylated sense control were labeled with either lissamine for fluorescence detection or {sup 99m}Tc for radioactivity detection and were linked to biotinylated trastuzumab via streptavidin. The nanoparticles were studied in SUM190 (RhoC+, Her2+) study and SUM149 (RhoC+, Her2-) control cells in culture and as xenografts in mice. As evidence of unimpaired Her2+ binding of trastuzumab within the nanoparticle, accumulations were clearly higher in SUM190 compared to SUM149 cells and, by whole-body imaging, targeting of SUM190 tumor was similar to that expected for a radiolabeled trastuzumab. As evidence of internalization, fluorescence microscopy images of cells grown in culture and obtained from xenografts showed uniform cytoplasm distribution of the lissamine-MORF. An invasion assay showed decreased RhoC expression in SUM190 cells when incubated with the antisense MORF nanoparticles at only 100 nM. Both in cell culture and in animals, the nanoparticle with trastuzumab as specific carrier greatly improved tumor delivery of the antisense oligomer against RhoC mRNA into tumor cells overexpressing Her2 and may be of general utility. (orig.)

Chemical and Biological Significance of Oenothein B and Related Ellagitannin Oligomers with Macrocyclic Structure

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Takashi Yoshida

2018-03-01

Full Text Available In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae. Among notable in vitro and in vivo biological activities reported for oenothein B are antioxidant, anti-inflammatory, enzyme inhibitory, antitumor, antimicrobial, and immunomodulatory activities. Oenothein B and related oligomers, and/or plant extracts containing them have thus attracted increasing interest as promising targets for the development of chemopreventive agents of life-related diseases associated with oxygen stress in human health. In order to better understand the significance of this type of ellagitannin in medicinal plants, this review summarizes (1 the structural characteristics of oenothein B and related dimers; (2 the oxidative metabolites of oenothein B up to heptameric oligomers; (3 the distribution of oenotheins and other macrocyclic analogs in the plant kingdom; and (4 the pharmacological activities hitherto documented for oenothein B, including those recently found by our laboratory.

Co-existence of two different α-synuclein oligomers with different core structures determined by hydrogen/deuterium exchange mass spectrometry

DEFF Research Database (Denmark)

Paslawski, Wojciech; Mysling, Simon; Thomsen, Karen

2014-01-01

Neurodegenerative disorders are characterized by the formation of protein oligomers and amyloid fibrils, which in the case of Parkinson's disease involves the protein α-synuclein (αSN). Cytotoxicity is mainly associated with the oligomeric species, but we still know little about their assembly...... are protected from exchange with D2 O until they dissociate into monomeric αSN by EX1 exchange kinetics. Fewer residues are protected against exchange in oligomer type II, but this type does not revert to αSN monomers. Both oligomers are protected in the core sequence Y39-A89. Based on incubation studies...

Organization of the resting TCR in nanoscale oligomers.

Science.gov (United States)

Schamel, Wolfgang W A; Alarcón, Balbino

2013-01-01

Despite the low affinity of the T-cell antigen receptor (TCR) for its peptide/major histocompatibility complex (pMHC) ligand, T cells are very sensitive to their antigens. This paradox can be resolved if we consider that the TCR may be organized into pre-existing oligomers or nanoclusters. Such structures could improve antigen recognition by increasing the functional affinity (avidity) of the TCR-pMHC interaction and by allowing cooperativity between individual TCRs. Up to approximately 20 TCRs become tightly apposed in these nanoclusters, often in a linear manner, and such structures could reflect a relatively generalized phenomenon: the non-random concentration of membrane receptors in specific areas of the plasma membrane known as protein islands. The association of TCRs into nanoclusters can explain the enhanced kinetics of the pMHC-TCR interaction in two dimensional versus three dimensional systems, but also their existence calls for a revision of the TCR triggering models based on pMHC-induced TCR clustering. Interestingly, the B-cell receptor and the FcεRI have also been shown to form nanoclusters, suggesting that the formation of pre-existing receptor oligomers could be widely used in the immune system. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Concentrated insulins: the new basal insulins

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Lamos EM

2016-03-01

Full Text Available Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Introduction: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered: This review highlights the published reports of the pharmacokinetic (PK and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion: Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration

Single-molecule studies of oligomer extraction and uptake of dyes in poly(dimethylsiloxane) films.

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Lange, Jeffrey J; Collinson, Maryanne M; Culbertson, Christopher T; Higgins, Daniel A

2009-12-15

Single-molecule microscopic methods were used to probe the uptake, mobility, and entrapment of dye molecules in cured poly(dimethylsiloxane) (PDMS) films as a function of oligomer extraction. The results are relevant to the use of PDMS in microfluidic separations, pervaporation, solid-phase microextraction, and nanofiltration. PDMS films were prepared by spin-casting dilute solutions of Sylgard 184 onto glass coverslips, yielding approximately 1.4 microm thick films after curing. Residual oligomers were subsequently extracted from the films by "spin extraction". In this procedure, 200 microL aliquots of isopropyl alcohol were repeatedly dropped onto the film surface and spun off at 2000 rpm. Samples extracted 5, 10, 20, and 40 times were investigated. Dye molecules were loaded into these films by spin-casting nanomolar dye solutions onto the films. Both neutral perylene diimide (N,N'-bis(butoxypropyl)perylene-3,4,9,10-tetracarboxylic diimide) and cationic rhodamine 6G (R6G) dyes were employed. The films were imaged by confocal fluorescence microscopy. The images obtained depict nonzero populations of fixed and mobile molecules in all films. Cross-correlation methods were used to quantitatively determine the population of fixed molecules in a given region, while a Bayesian burst analysis was used to obtain the total population of molecules. The results show that the total amount of dye loaded increases with increased oligomer extraction, while the relative populations of fixed and mobile molecules decrease and increase, respectively. Bulk R6G data also show greater dye loading with increased oligomer extraction.

Programmable Oligomers Targeting 5′-GGGG-3′ in the Minor Groove of DNA and NF-κB Binding Inhibition

Science.gov (United States)

Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B.

2009-01-01

A series of hairpin oligomers containing benzimidazole (Bi) and imidazopyridine (Ip) rings were synthesized and screened to target 5′-WGGGGW-3′, a core sequence in the DNA binding site of NF-κB, a prolific transcription factor important in biology and disease. Five Bi and Ip containing oligomers bound to the 5′-WGGGGW-3′ site with high affinity. One of the oligomers (Im-Im-Im-Im-γ-PyBi-PyBi-β-Dp) was able to inhibit DNA binding by the transcription factor NF-κB. PMID:17095230

Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

Science.gov (United States)

Talbot, Konrad; Wang, Hoau-Yan; Kazi, Hala; Han, Li-Ying; Bakshi, Kalindi P.; Stucky, Andres; Fuino, Robert L.; Kawaguchi, Krista R.; Samoyedny, Andrew J.; Wilson, Robert S.; Arvanitakis, Zoe; Schneider, Julie A.; Wolf, Bryan A.; Bennett, David A.; Trojanowski, John Q.; Arnold, Steven E.

2012-01-01

While a potential causal factor in Alzheimer’s disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS616) and IRS-1 pS636/639. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS616 and IRS-1 pS636/639 and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology. PMID:22476197

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth.

Science.gov (United States)

Foley, Joseph; Hill, Shannon E; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

2013-09-28

Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

Science.gov (United States)

Foley, Joseph; Hill, Shannon E.; Miti, Tatiana; Mulaj, Mentor; Ciesla, Marissa; Robeel, Rhonda; Persichilli, Christopher; Raynes, Rachel; Westerheide, Sandy; Muschol, Martin

2013-09-01

Deposits of fibrils formed by disease-specific proteins are the molecular hallmark of such diverse human disorders as Alzheimer's disease, type II diabetes, or rheumatoid arthritis. Amyloid fibril formation by structurally and functionally unrelated proteins exhibits many generic characteristics, most prominently the cross β-sheet structure of their mature fibrils. At the same time, amyloid formation tends to proceed along one of two separate assembly pathways yielding either stiff monomeric filaments or globular oligomers and curvilinear protofibrils. Given the focus on oligomers as major toxic species, the very existence of an oligomer-free assembly pathway is significant. Little is known, though, about the structure of the various intermediates emerging along different pathways and whether the pathways converge towards a common or distinct fibril structures. Using infrared spectroscopy we probed the structural evolution of intermediates and late-stage fibrils formed during in vitro lysozyme amyloid assembly along an oligomeric and oligomer-free pathway. Infrared spectroscopy confirmed that both pathways produced amyloid-specific β-sheet peaks, but at pathway-specific wavenumbers. We further found that the amyloid-specific dye thioflavin T responded to all intermediates along either pathway. The relative amplitudes of thioflavin T fluorescence responses displayed pathway-specific differences and could be utilized for monitoring the structural evolution of intermediates. Pathway-specific structural features obtained from infrared spectroscopy and Thioflavin T responses were identical for fibrils grown at highly acidic or at physiological pH values and showed no discernible effects of protein hydrolysis. Our results suggest that late-stage fibrils formed along either pathway are amyloidogenic in nature, but have distinguishable structural fingerprints. These pathway-specific fingerprints emerge during the earliest aggregation events and persist throughout the

Significance of grafting in radiation curing reactions. Comparison of ionising radiation and UV systems

International Nuclear Information System (INIS)

Zilic, E.; Ng, L.; Viengkhou, V.; Garnett, J.L.

1998-01-01

Full text: Radiation curing is now an accepted commercial technology where both ionising radiation (electron beam) and ultra violet light (UV) sources are used. Grafting is essentially the copolymerisation of a monomer/oligomer to a backbone polymer whereas curing is the rapid polymerisation of a monomer/oligomer mixture onto the surface of the substrate. There is no time scale theoretically associated with grafting processes which can occur in minutes or hours whereas curing reactions are usually very rapid, occurring within a fraction of a second. An important difference between grafting and curing is the nature of the bonding occurring in each process. In grafting covalent carbon-carbon bonds are formed, whereas in curing, bonding usually involves weaker Van der Waals or London dispersion forces. The bonding properties of the systems are important in determining their use commercially. Thus the possibility that concurrent grafting during curing could occur in a system is important since if present, grafting would not only minimise delamination of the coated product but could also, in some circumstances, render difficulties recycling of the finished product especially if it were cellulosic. Hence the conditions for observing the occurrence of concurrent grafting during radiation curing are important. In the present paper, this problem has been studied by examining the effect that the components used in radiation curing exert on a typical reaction. Instead of electron beam sources, the spent fuel element facility at Lucas Heights is used to simulate such ionising radiation sources. The model system utilised is the grafting of a typical methacrylate to cellulose. This is the generic chemistry used in curing systems. The effect of typical additives from curing systems including polyfunctional monomer and oligomers in the grafting reactions have been studied. The ionising radiation results have been compared with analogous data from UV experiments. The significance

"Nail" and "comb" effects of cholesterol modified NIPAm oligomers on cancer targeting liposomes

KAUST Repository

Li, Wengang; Deng, Lin; Moosa, Basem; Wang, Guangchao; Mashat, Afnan; Khashab, Niveen M.

2014-01-01

Thermosensitive liposomes are a promising approach to controlled release and reduced drug cytotoxicity. Low molecular weight N-isopropylacrylamide (NIPAm) oligomers (NOs) with different architectures (main chain NOs (MCNOs) and side chain NOs (SCNOs)) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and radical polymerization and then separately used to prepare thermosensitive liposomes. A more controlled and enhanced release was observed for both NO liposomes compared to pristine ones. Two release mechanisms depending on the oligomer architecture, namely "nail" for MCNOs and "comb" for SCNOs, are proposed. In addition to thermosensitivity, the cancer targeting property of NO liposomes was achieved by further biotinylation of the delivery system. © The Royal Society of Chemistry.

Liquid Crystalline Thermosets from Ester, Ester-imide, and Ester-amide Oligomers

Science.gov (United States)

Dingemans, Theodorus J. (Inventor); Weiser, Erik S. (Inventor); St. Clair, Terry L. (Inventor)

2009-01-01

Main chain thermotropic liquid crystal esters, ester-imides, and ester-amides were prepared from AA, BB, and AB type monomeric materials and end-capped with phenylacetylene, phenylmaleimide, or nadimide reactive end-groups. The end-capped liquid crystal oligomers are thermotropic and have, preferably, molecular weights in the range of approximately 1000-15,000 grams per mole. The end-capped liquid crystaloligomers have broad liquid crystalline melting ranges and exhibit high melt stability and very low melt viscosities at accessible temperatures. The end-capped liquid crystal oli-gomers are stable forup to an hour in the melt phase. They are highly processable by a variety of melt process shape forming and blending techniques. Once processed and shaped, the end-capped liquid crystal oigomers were heated to further polymerize and form liquid crystalline thermosets (LCT). The fully cured products are rubbers above their glass transition temperatures.

Amyloid oligomer structure characterization from simulations: A general method

Energy Technology Data Exchange (ETDEWEB)

Nguyen, Phuong H., E-mail: phuong.nguyen@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Li, Mai Suan [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland); Derreumaux, Philippe, E-mail: philippe.derreumaux@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Institut Universitaire de France, 103 Bvd Saint-Germain, 75005 Paris (France)

2014-03-07

Amyloid oligomers and plaques are composed of multiple chemically identical proteins. Therefore, one of the first fundamental problems in the characterization of structures from simulations is the treatment of the degeneracy, i.e., the permutation of the molecules. Second, the intramolecular and intermolecular degrees of freedom of the various molecules must be taken into account. Currently, the well-known dihedral principal component analysis method only considers the intramolecular degrees of freedom, and other methods employing collective variables can only describe intermolecular degrees of freedom at the global level. With this in mind, we propose a general method that identifies all the structures accurately. The basis idea is that the intramolecular and intermolecular states are described in terms of combinations of single-molecule and double-molecule states, respectively, and the overall structures of oligomers are the product basis of the intramolecular and intermolecular states. This way, the degeneracy is automatically avoided. The method is illustrated on the conformational ensemble of the tetramer of the Alzheimer's peptide Aβ{sub 9−40}, resulting from two atomistic molecular dynamics simulations in explicit solvent, each of 200 ns, starting from two distinct structures.

Theoretical study of stability geometrical and electronic structure of (BeHsub(2))sub(n) oligomers

Energy Technology Data Exchange (ETDEWEB)

Sukhanov, L P; Boldyrev, A I; Charkin, O P [AN SSSR, Moscow. Inst. Novykh Khimicheskikh Problem

1983-01-01

The Hartree-Fock-Ruthane method with the Roos-Siegbahn two-exponent basis is used to calculate stability, geometrical and electronic structures of (BeHsub(2))sub(n) oligomers, where n=1, 2, 3, 4 and 6. It is shown that with the growth of oligomerization degree n stability of linear band structure is increased as compared with other configurations including high-coordination volumetric ones. Tendencies in formation with n growth of geometrical, energetic characteristics, electronic structure of (BeHsub(2))sub(n) oligomers of band type are analysed.

Viscosity of nanoconfined polyamide-6,6 oligomers: atomistic reverse nonequilibrium molecular dynamics simulation.

Science.gov (United States)

Eslami, Hossein; Müller-Plathe, Florian

2010-01-14

Our new simulation scheme in isosurface-isothermal-isobaric ensemble [Eslami, H.; Mozaffari, F.; Moghadasi, J.; Müller-Plathe, F. J. Chem. Phys. 2008, 129, 194702], developed to simulate confined fluids in equilibrium with bulk, is applied to simulate polyamide-6,6 oligomers confined between graphite surfaces. The reverse nonequilibrium molecular dynamics simulation technique is employed to shear the graphite surfaces. In this work, six confined systems, with different surface separations, as well as the bulk fluid are simulated. Our results show a viscosity increase with respect to the bulk fluid, with decreasing distance between surfaces. Also, the calculated viscosities of the confined systems show an oscillatory behavior with maxima corresponding to well-formed layers between the surfaces. We observe a substantial slip at the surfaces, with the slip length depending on the shear rate and on the slit width. The slip length and the slip velocity show oscillatory behavior with out-of-phase oscillations with respect to the solvation force oscillations. Moreover, the temperature difference between coldest and hottest parts of the simulation box depends on the shear rate and on the layering effect (solvation force oscillations). An analysis of oligomer deformation under flow shows preferential alignment of oligomers parallel to the surfaces with increasing shear rate.

NMR studies of DNA oligomers and their interactions with minor groove binding ligands

Energy Technology Data Exchange (ETDEWEB)

Fagan, Patricia A. [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

1996-05-01

The cationic peptide ligands distamycin and netropsin bind noncovalently to the minor groove of DNA. The binding site, orientation, stoichiometry, and qualitative affinity of distamycin binding to several short DNA oligomers were investigated by NMR spectroscopy. The oligomers studied contain A,T-rich or I,C-rich binding sites, where I = 2-desaminodeoxyguanosine. I•C base pairs are functional analogs of A•T base pairs in the minor groove. The different behaviors exhibited by distamycin and netropsin binding to various DNA sequences suggested that these ligands are sensitive probes of DNA structure. For sites of five or more base pairs, distamycin can form 1:1 or 2:1 ligand:DNA complexes. Cooperativity in distamycin binding is low in sites such as AAAAA which has narrow minor grooves, and is higher in sites with wider minor grooves such as ATATAT. The distamycin binding and base pair opening lifetimes of I,C-containing DNA oligomers suggest that the I,C minor groove is structurally different from the A,T minor groove. Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. The author studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity of the reactive agent.

Formation of a stable oligomer of beta-2 microglobulin requires only transient encounter with Cu(II).

Science.gov (United States)

Calabrese, Matthew F; Miranker, Andrew D

2007-03-16

Beta-2 Microglobulin (beta2m) is a small, globular protein, with high solubility under conditions comparable to human serum. A complication of hemodialysis in renal failure patients is the deposition of unmodified beta2m as amyloid fibers. In vitro, exposure of beta2m to equimolar Cu(2+) under near-physiological conditions can result in self-association leading to amyloid fiber formation. Previously, we have shown that the early steps in this process involve a catalyzed structural rearrangement followed by formation of discrete oligomers. These oligomers, however, have a continued requirement for Cu(2+) while mature fibers are resistant to addition of metal chelate. Here, we report that the transition from Cu(2+) dependent to chelate resistant states occurs in the context of small oligomers, dimeric to hexameric in size. These species require Cu(2+) to form, but once generated, do not need metal cation for stability. Importantly, this transition occurs gradually over several days and the resulting oligomers are isolatable and kinetically stable on timescales exceeding weeks. In addition, formation is enhanced by levels of urea similar to those found in hemodialysis patients. Our results are consistent with our hypothesis that transient encounter of full-length wild-type beta2m with transition metal cation at the dialysis membrane interface is causal to dialysis related amyloidosis.

Some biological actions of PEG-conjugated RNase A oligomers

Czech Academy of Sciences Publication Activity Database

Poučková, P.; Škvor, J.; Gotte, G.; Vottariello, F.; Slavík, Tomáš; Matoušek, Josef; Laurents, D. V.; Libonati, M.; Souček, J.

2006-01-01

Roč. 53, č. 1 (2006), s. 79-85 ISSN 0028-2685 R&D Projects: GA ČR GA523/04/0755; GA MZd NR8233 Grant - others:Spanish Ministerio de Ciencia y Technologia BQU2003-05227 Institutional research plan: CEZ:AV0Z50450515 Keywords : RNase A oligomers * polyethylene glycol conjugates * anti-tumour activity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.247, year: 2006

Mass Spectrometric Characterization of Oligomers in Pseudomonas aeruginosa Azurin Solutions

Czech Academy of Sciences Publication Activity Database

Sokolová, L.; Williamson, H.; Sýkora, Jan; Hof, Martin; Gray, H. B.; Brutschy, B.; Vlček, Antonín

2011-01-01

Roč. 115, č. 16 (2011), s. 4790-4800 ISSN 1520-6106 R&D Projects: GA MŠk(CZ) ME10124; GA MŠk(CZ) LC06063 Institutional research plan: CEZ:AV0Z40400503 Keywords : mass spectrometry * oligomers * pseudomonas aeruginosa azurin solutions Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.696, year: 2011

Humans Can Taste Glucose Oligomers Independent of the hT1R2/hT1R3 Sweet Taste Receptor.

Science.gov (United States)

Lapis, Trina J; Penner, Michael H; Lim, Juyun

2016-08-23

It is widely accepted that humans can taste mono- and disaccharides as sweet substances, but they cannot taste longer chain oligo- and polysaccharides. From the evolutionary standpoint, the ability to taste starch or its oligomeric hydrolysis products would be highly adaptive, given their nutritional value. Here, we report that humans can taste glucose oligomer preparations (average degree of polymerization 7 and 14) without any other sensorial cues. The same human subjects could not taste the corresponding glucose polymer preparation (average degree of polymerization 44). When the sweet taste receptor was blocked by lactisole, a known sweet inhibitor, subjects could not detect sweet substances (glucose, maltose, and sucralose), but they could still detect the glucose oligomers. This suggests that glucose oligomer detection is independent of the hT1R2/hT1R3 sweet taste receptor. Human subjects described the taste of glucose oligomers as "starchy," while they describe sugars as "sweet." The dose-response function of glucose oligomer was also found to be indistinguishable from that of glucose on a molar basis. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

GalaxyHomomer: a web server for protein homo-oligomer structure prediction from a monomer sequence or structure.

Science.gov (United States)

Baek, Minkyung; Park, Taeyong; Heo, Lim; Park, Chiwook; Seok, Chaok

2017-07-03

Homo-oligomerization of proteins is abundant in nature, and is often intimately related with the physiological functions of proteins, such as in metabolism, signal transduction or immunity. Information on the homo-oligomer structure is therefore important to obtain a molecular-level understanding of protein functions and their regulation. Currently available web servers predict protein homo-oligomer structures either by template-based modeling using homo-oligomer templates selected from the protein structure database or by ab initio docking of monomer structures resolved by experiment or predicted by computation. The GalaxyHomomer server, freely accessible at http://galaxy.seoklab.org/homomer, carries out template-based modeling, ab initio docking or both depending on the availability of proper oligomer templates. It also incorporates recently developed model refinement methods that can consistently improve model quality. Moreover, the server provides additional options that can be chosen by the user depending on the availability of information on the monomer structure, oligomeric state and locations of unreliable/flexible loops or termini. The performance of the server was better than or comparable to that of other available methods when tested on benchmark sets and in a recent CASP performed in a blind fashion. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Nanoparticle for delivery of antisense γPNA oligomers targeting CCR5.

Science.gov (United States)

Bahal, Raman; McNeer, Nicole Ali; Ly, Danith H; Saltzman, W Mark; Glazer, Peter M

2013-01-01

The development of a new class of peptide nucleic acids (PNAs), i.e., gamma PNAs (γPNAs), creates the need for a general and effective method for its delivery into cells for regulating gene expression in mammalian cells. Here we report the antisense activity of a recently developed hydrophilic and biocompatible diethylene glycol (miniPEG)-based gamma peptide nucleic acid called MPγPNAs via its delivery by poly(lactide-co-glycolide) (PLGA)-based nanoparticle system. We show that MPγPNA oligomers designed to bind to the selective region of chemokine receptor 5 (CC R5) transcript, induce potent and sequence-specific antisense effects as compared with regular PNA oligomers. In addition, PLGA nanoparticle delivery of MPγPNAs is not toxic to the cells. The findings reported in this study provide a combination of γPNA technology and PLGA-based nanoparticle delivery method for regulating gene expression in live cells via the antisense mechanism.

Organization in sol-gel polymerization of methacrylate co-oligomers containing trimethoxysilylpropyl methacrylate

Czech Academy of Sciences Publication Activity Database

Vraštil, J.; Matějka, Libor; Špaček, V.; Večeřa, M.; Prokůpek, L.

2005-01-01

Roč. 46, č. 25 (2005), s. 11232-11240 ISSN 0032-3861 Institutional research plan: CEZ:AV0Z40500505 Keywords : organic-inorganic hybrid * sol-gel process * oligomers Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.849, year: 2005

Chemical stability of insulin. 4. Mechanisms and kinetics of chemical transformations in pharmaceutical formulation.

Science.gov (United States)

Brange, J

1992-01-01

Insulin decomposes by a multitude of chemical reactions [1-3]. It deamidates at two different residues by entirely different mechanisms. In acid, deamidation at AsnA21 is intramolecularly catalyzed by the protonated C-terminal, whereas above pH 6 an intermediate imide formation at residue AsnB3 leads to isoAsp and Asp derivatives. The imide formation requires a large rotation around the alpha-carbon/peptide carbonyl carbon bond at B3, corresponding to a 10 A movement of the B-chain N-terminal. The main determinant for the rate of B3 deamidation, as well as for the ratio between the two products formed, is the local conformational structure, which is highly influenced by various excipients and the physical state of the insulin. An amazing thermolysin-like, autoproteolytic cleavage of the A-chain takes place in rhombohedral insulin crystals, mediated by a concerted catalytic action by several, inter-hexameric functional groups and Zn2+. Intermolecular, covalent cross-linking of insulin molecules occurs via several mechanisms. The most prominent type of mechanism is aminolysis by the N-terminals, leading to isopeptide linkages with the A-chain side-chain amides of residues GlnA15, AsnA18 and AsnA21. The same type of reaction also leads to covalent cross-linking of the N-terminal in protamine with insulin. Disulfide exchange reactions, initiated by lysis of the A7-B7 disulfide bridge, lead mainly to formation of covalent oligo- and polymers. Activation energy (Ea) for the neutral deamidation and the aminolysis reactions was found to be 80 and 119 KJ/mol, respectively.

Mechanisms leading to oligomers and SOA through aqueous photooxidation: insights from OH radical oxidation of acetic acid and methylglyoxal

Directory of Open Access Journals (Sweden)

Y. Tan

2012-01-01

Full Text Available Previous experiments have demonstrated that the aqueous OH radical oxidation of methylglyoxal produces low volatility products including pyruvate, oxalate and oligomers. These products are found predominantly in the particle phase in the atmosphere, suggesting that methylglyoxal is a precursor of secondary organic aerosol (SOA. Acetic acid plays a central role in the aqueous oxidation of methylglyoxal and it is a ubiquitous product of gas phase photochemistry, making it a potential "aqueous" SOA precursor in its own right. However, the fate of acetic acid upon aqueous-phase oxidation is not well understood. In this research, acetic acid (20 μM–10 mM was oxidized by OH radicals, and pyruvic acid and methylglyoxal experimental samples were analyzed using new analytical methods, in order to better understand the formation of SOA from acetic acid and methylglyoxal. Glyoxylic, glycolic, and oxalic acids formed from acetic acid and OH radicals. In contrast to the aqueous OH radical oxidation of methylglyoxal, the aqueous OH radical oxidation of acetic acid did not produce succinic acid and oligomers. This suggests that the methylgloxal-derived oligomers do not form through the acid catalyzed esterification pathway proposed previously. Using results from these experiments, radical mechanisms responsible for oligomer formation from methylglyoxal oxidation in clouds and wet aerosols are proposed. The importance of acetic acid/acetate as an SOA precursor is also discussed. We hypothesize that this and similar chemistry is central to the daytime formation of oligomers in wet aerosols.

A Fluorescent Oligothiophene-Bis-Triazine ligand interacts with PrP fibrils and detects SDS-resistant oligomers in human prion diseases.

Science.gov (United States)

Imberdis, Thibaut; Ayrolles-Torro, Adeline; Duarte Rodrigues, Alysson; Torrent, Joan; Alvarez-Martinez, Maria Teresa; Kovacs, Gabor G; Verdier, Jean-Michel; Robitzer, Mike; Perrier, Véronique

2016-01-26

Prion diseases are characterized by the accumulation in the central nervous system of an abnormally folded isoform of the prion protein, named PrP(Sc). Aggregation of PrP(Sc) into oligomers and fibrils is critically involved in the pathogenesis of prion diseases. Oligomers are supposed to be the key neurotoxic agents in prion disease, so modulation of prion aggregation pathways with small molecules can be a valuable strategy for studying prion pathogenicity and for developing new diagnostic and therapeutic approaches. We previously identified thienyl pyrimidine compounds that induce SDS-resistant PrP(Sc) (rSDS-PrP(Sc)) oligomers in prion-infected samples. Due to the low effective doses of the thienyl pyrimidine hits, we synthesized a quaterthiophene-bis-triazine compound, called MR100 to better evaluate their diagnostic and therapeutic potentials. This molecule exhibits a powerful activity inducing rSDS-PrP(Sc) oligomers at nanomolar concentrations in prion-infected cells. Fluorescence interaction studies of MR100 with mouse PrP fibrils showed substantial modification of the spectrum, and the interaction was confirmed in vitro by production of rSDS-oligomer species upon incubation of MR100 with fibrils in SDS-PAGE gel. We further explored whether MR100 compound has a potential to be used in the diagnosis of prion diseases. Our results showed that: (i) MR100 can detect rSDS-oligomers in prion-infected brain homogenates of various species, including human samples from CJD patients; (ii) A protocol, called "Rapid Centrifugation Assay" (RCA), was developed based on MR100 property of inducing rSDS-PrP(Sc) oligomers only in prion-infected samples, and avoiding the protease digestion step. RCA allows the detection of both PK-sensitive and PK-resistant PrP(Sc) species in rodents samples but also from patients with different CJD forms (sporadic and new variant); (iii) A correlation could be established between the amount of rSDS-PrP(Sc) oligomers revealed by MR100 and the

Cholesterol facilitates interactions between α-synuclein oligomers and charge-neutral membranes

DEFF Research Database (Denmark)

van Maarschalkerweerd, Andreas; Vetri, Valeria; Vestergaard, Bente

2015-01-01

composed of anionic lipids, while the more physiologically relevant zwitterionic lipids remain intact. We present experimental evidence for significant morphological changes in zwitterionic membranes containing cholesterol, induced by α-synuclein oligomers. Depending on the lipid composition, model...... of cholesterol for mediating interactions between physiologically relevant membranes and α-synuclein....

The insulin radioimmunoassay kit prepared by IPEN-CNEN/SP - Brazil

International Nuclear Information System (INIS)

Mesquita, C.H. de; Silva, C.P.G. da; Hamada, M.M.

1985-11-01

The specification and methodological aspects of the insulin radioimmunoassay kit produced by IPEN-CNEN/SP - Brazil are described. The limitations taking care and the following quality control parameters or procedures are discussed: specific radioactivity, comparison between two insulin - 125 I purification procedures, affinity constant 'K' of the antigen - antibody reaction, minimal detectable dose (MDD), kinetics degradation of the radioinsulin, radioassay imprecision profile, radioassay performance temperature dependence and normal values histogram. (Author) [pt

Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model.

Science.gov (United States)

Kim, YoungDoo; Choi, Hyunwoo; Lee, WonJae; Park, Hyejin; Kam, Tae-In; Hong, Se-Hoon; Nah, Jihoon; Jung, Sunmin; Shin, Bora; Lee, Huikyong; Choi, Tae-Yong; Choo, Hyosun; Kim, Kyung-Keun; Choi, Se-Young; Kayed, Rakez; Jung, Yong-Keun

2016-03-01

In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v. injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro, and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates. Copyright © 2015 Elsevier Inc. All rights reserved.

Studies on radioimmunoassay of peptide hormone using polyethyleneglycol. I. Insulin

Energy Technology Data Exchange (ETDEWEB)

Kihara, A; Kikuchi, A; Yaegashi, T; Ohhara, H [Sapporo Medical Coll. (Japan)

1975-06-01

Radioimmunoassay (RIA) of insulin using polyethyleneglycol (PEG) was examined for measurement conditions such as the concentration, reaction time, temperature, and amount of serum to be added in order to allow uniform separations of free insulin and bound insulin. The standard curve of the present method was in good agreement with that of the two antibody method, and the two methods showed a highly significant correlation (r=0.98, p<0.001). The reproducibility showed only the fluctuations ranging from 0.9 to 4.9%, and the recovery rate was between 70 and 100%. Since the insulin RIA by PEG is convenient and economical and yields more stable results than those obtained by the two antibody method, it is possible to use it for RIA of other peptide hormones such as glucagon.

Rational steering of insulin binding specificity by intra-chain chemical crosslinking

Science.gov (United States)

Viková, Jitka; Collinsová, Michaela; Kletvíková, Emília; Buděšínský, Miloš; Kaplan, Vojtěch; Žáková, Lenka; Veverka, Václav; Hexnerová, Rozálie; Aviñó, Roberto J. Tarazona; Straková, Jana; Selicharová, Irena; Vaněk, Václav; Wright, Daniel W.; Watson, Christopher J.; Turkenburg, Johan P.; Brzozowski, Andrzej M.; Jiráček, Jiří

2016-01-01

Insulin is a key hormone of human metabolism with major therapeutic importance for both types of diabetes. New insulin analogues with more physiological profiles and better glycemic control are needed, especially analogues that preferentially bind to the metabolic B-isoform of insulin receptor (IR-B). Here, we aimed to stabilize and modulate the receptor-compatible conformation of insulin by covalent intra-chain crosslinking within its B22-B30 segment, using the CuI-catalyzed Huisgen 1,3-dipolar cycloaddition reaction of azides and alkynes. This approach resulted in 14 new, systematically crosslinked insulin analogues whose structures and functions were extensively characterized and correlated. One of the analogues, containing a B26-B29 triazole bridge, was highly active in binding to both IR isoforms, with a significant preference for IR-B. Our results demonstrate the potential of chemistry-driven modulation of insulin function, also shedding new light on the functional importance of hormone’s B-chain C-terminus for its IR-B specificity.

Effect of Side Chains on Molecular Conformation of Anthracene-Ethynylene-Phenylene-Vinylene Oligomers: A Comparative Density Functional Study With and Without Dispersion Interaction.

Science.gov (United States)

Dong, Chuanding; Hoppe, Harald; Beenken, Wichard J D

2016-06-02

Using density functional calculations with and without dispersion interaction, we studied the effects of linear octyl and branched 2-ethylhexyl side chains on the oligomer conformation of the conjugated copolymer poly(p-anthracene-ethynylene)-alt-poly(p-phenylene-vinylene). With dispersion included, the branched side chains can cause significant bending of the oligomer backbone, while without dispersion they induce mainly torsional disorder. The oligomers with mainly linear side chains keep good planarity when optimized with and without dispersion. Despite their dramatically different conformations, the calculated absorption spectra of the oligomers with various side chain combinations are very similar, indicating that the conformation of the copolymer is not the main reason for the experimentally observed different spectra of ordered and disordered phases.

Supersymmetry theory of microphase separation in homopolymer-oligomer mixtures

International Nuclear Information System (INIS)

Olemskoi, Alexander; Krakovsky, Ivan; Savelyev, Alexey

2004-01-01

The mesoscopic structure of periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for systems with both strong (ionic) and weak (hydrogen) interactions. We focus on the consideration of the distribution of oligomers along the homopolymer chains that is described by the effective equation of motion with the segment number playing the role of imaginary time. The supersymmetry technique is developed to consider associative hydrogen bonding, self-action effects, inhomogeneity, and temperature fluctuations in the oligomer distribution. Making use of the self-consistent approach allows one to explain experimentally observed temperature dependence of the structure period and the order-disorder transition temperature and period as functions of the oligomeric fraction for systems with different bonding strengths. A whole set of parameters of the model used is found for strong, intermediate, and weak coupled systems being Poly (4-vinyl pyridine)-dodecyl benzene sulfonic acid [P4VP-(DBSA) x ], P4VP-[Zn(DBS) 2 ] x , and P4VP- 3-pentadecyl Phenol x , respectively. A passage from the former two to the latter is shown to cause a crucial decrease in the magnitude of both parameters of hydrogen bonding and self-action, as well as the order-disorder transition temperature

Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

Science.gov (United States)

Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

2011-01-01

The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

International Nuclear Information System (INIS)

Naidoo, C.

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

Energy Technology Data Exchange (ETDEWEB)

Naidoo, C

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, /sup 125/I-insulin binding to the solubilized erythrocyte membrane receptor and /sup 125/I-insulin binding to fibroblasts in culture.

Radioiodine labelling of insulin using dimethylsulfoxide as a labelling-aid

Energy Technology Data Exchange (ETDEWEB)

Kim, J; Kim, Y H [Korea Atomic Energy Research Inst., Seoul, (Republic of Korea)

1977-12-01

Using dimethylsulfoxide (DMSO) as a labelling aid, insulin /sup 126/I of radioimmunoassay use has been effectively prepared. A small amount of DMSO was added to usual labelling mixture and the reaction time was controlled. The labelled insulin obtained in such a way showed improved bindabilities to the antibody and thus expressed larger dose-gradients in the plots of standard dose-response curves even though the labelling rate was decreased to some extent. However, by extending the reaction time to about 1 min, average labelling yield of 30% could be obtained. The average increase of bindability (B/F) in definite antiserum dilution was 2.5 compared with 1.5 obtained in the absence of DMSO. Thus, the net bindability increase was 70% of those obtained in the absence of DMSO. By means of NMR spectrometry, it has been confirmed that the DMSO in the labelling mixture is converted to dimethylsulfone by chloramine-T. The results, generally agreed with the Stagg's postulation, were discussed in view of a competitive oxidation of DMSO with disulfide linkages of the insulin molecule by the chloramine-T.

Rheological and mechanical properties and interfacial stress development of composite cements modified with thio-urethane oligomers.

Science.gov (United States)

Bacchi, Ataís; Pfeifer, Carmem S

2016-08-01

Thio-urethane oligomers have been shown to reduce stress and increase toughness in highly filled composite materials. This study evaluated the influence of thio-urethane backbone structure on rheological and mechanical properties of resin cements modified with a fixed concentration of the oligomers. Thio-urethane oligomers (TU) were synthesized by combining thiols - pentaerythritol tetra-3-mercaptopropionate (PETMP) or trimethylol-tris-3-mercaptopropionate (TMP) - with isocyanates - 1,6-hexanediol-diissocyante (HDDI) (aliphatic) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (BDI) (aromatic) or dicyclohexylmethane 4,4'-diisocyanate (HMDI) (cyclic), at 1:2 isocyanate:thiol, leaving pendant thiols. 20wt% TU were added to BisGMA-UDMA-TEGDMA (5:3:2). 60wt% silanated inorganic fillers were added. Near-IR was used to follow methacrylate conversion and rate of polymerization ( [Formula: see text] ). Mechanical properties were evaluated in three-point bending (ISO 4049) for flexural strength/modulus (FS/FM, and toughness), and notched specimens (ASTM Standard E399-90) for fracture toughness (KIC). PS was measured on the Bioman. Viscosity (V) and gel-points (defined as the crossover between storage and loss shear moduli (G'/G″)) were obtained with rheometry. Glass transition temperature (Tg), cross-link density and homogeneity of the network were obtained with dynamic mechanical analysis. Film-thickness was evaluated according to ISO 4049. DC and mechanical properties increased and [Formula: see text] and PS decreased with the addition of TUs. Gelation (G'/G″) was delayed and DC at G'/G″ increased in TU groups. Tg and cross-link density dropped in TU groups, while oligomers let to more homogenous networks. An increase in V was observed, with no effect on film-thickness. Significant reductions in PS were achieved at the same time conversion and mechanical properties increased. The addition of thio-urethane oligomers proved successful in improving several key properties

Structure of human insulin monomer in water/acetonitrile solution

International Nuclear Information System (INIS)

Bocian, Wojciech; Sitkowski, Jerzy; Bednarek, Elzbieta; Tarnowska, Anna; Kawecki, Robert; Kozerski, Lech

2008-01-01

Here we present evidence that in water/acetonitrile solvent detailed structural and dynamic information can be obtained for important proteins that are naturally present as oligomers under native conditions. An NMR-derived human insulin monomer structure in H 2 O/CD 3 CN, 65/35 vol%, pH 3.6 is presented and compared with the available X-ray structure of a monomer that forms part of a hexamer (Acta Crystallogr. 2003 Sec. D59, 474) and with NMR structures in water and organic cosolvent. Detailed analysis using PFGSE NMR, temperature-dependent NMR, dilution experiments and CSI proves that the structure is monomeric in the concentration and temperature ranges 0.1-3 mM and 10-30 deg. C, respectively. The presence of long-range interstrand NOEs, as found in the crystal structure of the monomer, provides the evidence for conservation of the tertiary structure. Starting from structures calculated by the program CYANA, two different molecular dynamics simulated annealing refinement protocols were applied, either using the program AMBER in vacuum (AMBER V C), or including a generalized Born solvent model (AMBER G B)

Towards directional assembly of hierarchical structures: aniline oligomers as the model precursors

Czech Academy of Sciences Publication Activity Database

Zhao, Y.; Stejskal, Jaroslav; Wang, J.

2013-01-01

Roč. 5, č. 7 (2013), s. 2620-2626 ISSN 2040-3364 R&D Projects: GA ČR GAP205/12/0911 Institutional support: RVO:61389013 Keywords : aniline oligomers * hierarchical nanostructures * microflowers Subject RIV: CD - Macromolecular Chemistry Impact factor: 6.739, year: 2013

Side-chain degradation of ultrapure π-conjugated oligomers: implications for organic electronics

NARCIS (Netherlands)

Abbel, R.J.; Wolffs, M.; Bovee, R.A.A.; Dongen, van J.L.J.; Lou, X.W.; Henze, O.; Feast, W.J.; Meijer, E.W.; Schenning, A.P.H.J.

2009-01-01

The degrdn. of two defect-free pi-conjugated oligomers and the participation of their solubilizing side chains in the process are studied in unprecedented detail. The detected intermediate products reveal a mechanism of successive shortening of alkyl and oligo(ethylene glycol) substituents.

Amplified release through the stimulus triggered degradation of self-immolative oligomers, dendrimers, and linear polymers.

Science.gov (United States)

Wong, Andrew D; DeWit, Matthew A; Gillies, Elizabeth R

2012-08-01

In recent years, numerous delivery systems based on polymers, dendrimers, and nano-scale assemblies have been developed to improve the properties of drug molecules. In general, for the drug molecules to be active, they must be released from these delivery systems, ideally in a selective manner at the therapeutic target. As the changes in physiological conditions are relatively subtle from one tissue to another and the concentrations of specific enzymes are often quite low, a release strategy involving the amplification of a biological signal is particularly attractive. This article describes the development of oligomers, dendrimers, and linear polymers based on self-immolative spacers. This new class of molecules is designed to undergo a cascade of intramolecular reactions in response to the cleavage of a trigger moiety, resulting in molecular fragmentation and the release of multiple reporter or drug molecules. Progress in the development of these materials as drug delivery vehicles and sensors will be highlighted. Copyright © 2011 Elsevier B.V. All rights reserved.

Isolation and Quantification of Polyamide Cyclic Oligomers in Kitchen Utensils and Their Migration into Various Food Simulants

OpenAIRE

Abe, Yutaka; Mutsuga, Motoh; Ohno, Hiroyuki; Kawamura, Yoko; Akiyama, Hiroshi

2016-01-01

Small amounts of cyclic monomers and oligomers are present in polyamide (PA)-based kitchen utensils. In this study, we isolated eight PA-based cyclic monomers and oligomers from kitchen utensils made from PA6 (a polymer of ε-caprolactam) and PA66 (a polymer of 1,6-diaminohexane and adipic acid). Their structures were identified using high-resolution mass spectrometry and 1H- and 13C-nuclear magnetic resonance spectroscopy, and their residual levels in PA-based kitchen utensils and degree of m...

Combining Orthogonal Chain-End Deprotections and Thiol-Maleimide Michael Coupling: Engineering Discrete Oligomers by an Iterative Growth Strategy.

Science.gov (United States)

Huang, Zhihao; Zhao, Junfei; Wang, Zimu; Meng, Fanying; Ding, Kunshan; Pan, Xiangqiang; Zhou, Nianchen; Li, Xiaopeng; Zhang, Zhengbiao; Zhu, Xiulin

2017-10-23

Orthogonal maleimide and thiol deprotections were combined with thiol-maleimide coupling to synthesize discrete oligomers/macromolecules on a gram scale with molecular weights up to 27.4 kDa (128mer, 7.9 g) using an iterative exponential growth strategy with a degree of polymerization (DP) of 2 n -1. Using the same chemistry, a "readable" sequence-defined oligomer and a discrete cyclic topology were also created. Furthermore, uniform dendrons were fabricated using sequential growth (DP=2 n -1) or double exponential dendrimer growth approaches (DP=22n -1) with significantly accelerated growth rates. A versatile, efficient, and metal-free method for construction of discrete oligomers with tailored structures and a high growth rate would greatly facilitate research into the structure-property relationships of sophisticated polymeric materials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular Dynamics Simulations of Silica Nanoparticles Grafted with Poly(ethylene oxide) Oligomer Chains

KAUST Repository

Hong, Bingbing; Panagiotopoulos, Athanassios Z.

2012-01-01

A molecular model of silica nanoparticles grafted with poly(ethylene oxide) oligomers has been developed for predicting the transport properties of nanoparticle organic-hybrid materials (NOHMs). Ungrafted silica nanoparticles in a medium of poly(ethylene

Degludec insulin: A novel basal insulin

OpenAIRE

Kalra, Sanjay; Unnikrishnan, Ambika Gopalakrishnan; Baruah, Manash; Kalra, Bharti

2011-01-01

This paper reviews a novel insulin analogue, degludec, which has the potential to emerge as an ideal basal insulin. It reviews the limitations of existing basal insulin and analogues, and highlights the need for a newer molecule. The paper discusses the potential advantages of degludec, while reviewing its pharmacologic and clinical studies done so far. The paper assesses the potential role of insulin degludec and degludec plus in clinical diabetes practice.

The Effect of H2SO4 Concentration on the Ionic Conductivity of Liquid PMMA Oligomer

International Nuclear Information System (INIS)

Norashima Kamaluddin; Famiza Abdul Latif; Han, C.C.; Ruhani Ibrahim; Sharil Fadli Mohamad Zamri; Norashima Kamaluddin; Famiza Abdul Latif; Han, C.C.; Ruhani Ibrahim; Sharil Fadli Mohamad Zamri

2015-01-01

To date gel and film type polymer electrolytes have been widely synthesized due to their wide range of electrical properties. However these types of polymer electrolytes exhibit poor mechanical stability and poor electrode-electrolyte contact hence deprive the overall performance of a battery system. Therefore, in order to indulge the advantages of polymer as electrolyte, a new class of polymer electrolyte was synthesized and investigated. In this study, liquid poly(methyl methacrylate) (PMMA) electrolyte was synthesized using the simplest free radical polymerization technique using benzoyl peroxide as the initiator. At this stage, it was found that this liquid PMMA oligomer (MW=3000 g/ mole) has a potential as electrolyte in electrochemical devices. It was found that an ionic conductivity of ∼10 -7 S/ cm at room temperature can be achieved when only small volume of high molarity of sulfuric acid (H 2 SO 4 ) was doped in the liquid PMMA oligomer. The properties of this liquid PMMA oligomer were further investigated using Fourier Transform Infrared Spectroscopy (FTIR). (author)

Hydrogen bonding as the origin of the switching behavior in dithiolated phenylene-vinylene oligomers

KAUST Repository

Obodo, Tobechukwu Joshua; Gkionis, Konstantinos; Rungger, Ivan; Sanvito, Stefano; Schwingenschlö gl, Udo

2013-01-01

We investigate theoretically the switching behavior of a dithiolated phenylene-vinylene oligomer sandwiched between Au(111) electrodes using self-interaction corrected density-functional theory combined with the nonequilibrium Green

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

Science.gov (United States)

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Atomistic simulation of CO 2 solubility in poly(ethylene oxide) oligomers

KAUST Repository

Hong, Bingbing

2013-10-02

We have performed atomistic molecular dynamics simulations coupled with thermodynamic integration to obtain the excess chemical potential and pressure-composition phase diagrams for CO2 in poly(ethylene oxide) oligomers. Poly(ethylene oxide) dimethyl ether, CH3O(CH 2CH2O)nCH3 (PEO for short) is a widely applied physical solvent that forms the major organic constituent of a class of novel nanoparticle-based absorbents. Good predictions were obtained for pressure-composition-density relations for CO2 + PEO oligomers (2 ≤ n ≤ 12), using the Potoff force field for PEO [J. Chem. Phys. 136, 044514 (2012)] together with the TraPPE model for CO2 [AIChE J. 47, 1676 (2001)]. Water effects on Henrys constant of CO2 in PEO have also been investigated. Addition of modest amounts of water in PEO produces a relatively small increase in Henrys constant. Dependence of the calculated Henrys constant on the weight percentage of water falls on a temperature-dependent master curve, irrespective of PEO chain length. © 2013 Taylor & Francis.

Enhanced Solubilization of Fluoranthene by Hydroxypropyl β-Cyclodextrin Oligomer for Bioremediation

Directory of Open Access Journals (Sweden)

Kyeong Hui Park

2018-01-01

Full Text Available Fluoranthene (FT is a polycyclic aromatic hydrocarbon (PAH, consisting of naphthalene and benzene rings connected by a five-member ring. It is widespread in the environment. The hydrophobicity of FT limits its availability for biological uptake and degradation. In this study, hydroxypropyl β-cyclodextrin oligomers (HP-β-CD-ol were synthesized with epichlorohydrin (EP, while the solubility enhancement of FT by HP-β-CD-ol was investigated in water. The synthesized HP-β-CD-ol was characterized by MALDI-TOF mass spectrometry (MS, 1H NMR, and 13C NMR spectroscopy. The solubility of FT increased 178-fold due to the complex formation with HP-β-CD oligomers. The inclusion complexes of FT/HP-β-CD-ol were analyzed using Fourier-Transform Infrared (FT-IR, Differential Scanning Calorimetry (DSC, Scanning Electron Microscope (SEM, and Nuclear Overhauser Effect Spectroscopy Nuclear magnetic resonance (NOESY NMR spectroscopy. On the basis of these results, HP-β-CD-ol is recommended as a potential solubilizer for the development of PAH removal systems.

QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers

Science.gov (United States)

Brener, Oleksandr; Dunkelmann, Tina; Gremer, Lothar; van Groen, Thomas; Mirecka, Ewa A.; Kadish, Inga; Willuweit, Antje; Kutzsche, Janine; Jürgens, Dagmar; Rudolph, Stephan; Tusche, Markus; Bongen, Patrick; Pietruszka, Jörg; Oesterhelt, Filipp; Langen, Karl-Josef; Demuth, Hans-Ulrich; Janssen, Arnold; Hoyer, Wolfgang; Funke, Susanne A.; Nagel-Steger, Luitgard; Willbold, Dieter

2015-01-01

Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease. PMID:26394756

Association between haptoglobin gene and insulin resistance in Arab-Americans.

Science.gov (United States)

Burghardt, Kyle J; Masri, Dana El; Dass, Sabrina E; Shikwana, Sara S; Jaber, Linda A

2017-11-01

To analyze associations between variation in the HP gene and lipid and glucose-related measures in Arab-Americans. Secondary analyses were performed based on sex. Genomic DNA was extracted from samples obtained from a previous epidemiological study of diabetes in Arab-Americans. The HP 1 and 2 alleles were analyzed by polymerase chain reaction and gel electrophoresis. Associations were analyzed by linear regression. Associations were identified between the heterozygous haptoglobin 2-1 genotype and insulin resistance, fasting insulin and fasting c-peptide. The effect of sex did not remain significant after adjustment for relevant variables. HP genetic variation may have utility as a biomarker of insulin resistance and diabetes risk in Arab-Americans, however, future prospective studies are needed.

Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes

DEFF Research Database (Denmark)

Zinman, Bernard; Philis-Tsimikas, Athena; Cariou, Bertrand

2012-01-01

To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).......To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs)....

Steady State and Time-Resolved Fluorescence Dynamics of Triphenylamine Based Oligomers with Phenylene/Thiophene/Furan in Solvents

International Nuclear Information System (INIS)

Qi, Zeng; Ying-Liang, Liu; Kang, Meng; Xiang-Jie, Zhao; Shu-Feng, Wang; Qi-Huang, Gong

2009-01-01

We investigate the photo-physical properties of a series of triphenylamine-based oligomers by steady-state and picosecond transient fluorescence measurements in solvents. The oligomers are composed alternatively with triphenylamine and phenylene/thiophene/furan group, bridged by vinyl group (PNB/PNT/PNF). Their fluorescence spectra show bathochromic phenomenon with solvent polarity and viscosity increasing. The fluorescence decays are bi-exponential for PNB and PNT, and tri-exponential for PNF in THF and aniline. The strong viscosity dependence suggests conformational relaxation along the PNF chain after photo excitation. (condensed matter: electronicstructure, electrical, magnetic, and opticalproperties)

Rationally designed turn promoting mutation in the amyloid-β peptide sequence stabilizes oligomers in solution.

Directory of Open Access Journals (Sweden)

Jayakumar Rajadas

Full Text Available Enhanced production of a 42-residue beta amyloid peptide (Aβ(42 in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD. The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs in the brain of AD patients. Despite being significant to the understanding of AD mechanism, no atomic-resolution structures are available for these species due to the evanescent nature of ADDLs that hinders most structural biophysical investigations. Based on our molecular modeling and computational studies, we have designed Met35Nle and G37p mutations in the Aβ(42 peptide (Aβ(42Nle35p37 that appear to organize Aβ(42 into stable oligomers. 2D NMR on the Aβ(42Nle35p37 peptide revealed the occurrence of two β-turns in the V24-N27 and V36-V39 stretches that could be the possible cause for the oligomer stability. We did not observe corresponding NOEs for the V24-N27 turn in the Aβ(21-43Nle35p37 fragment suggesting the need for the longer length amyloid peptide to form the stable oligomer promoting conformation. Because of the presence of two turns in the mutant peptide which were absent in solid state NMR structures for the fibrils, we propose, fibril formation might be hindered. The biophysical information obtained in this work could aid in the development of structural models for toxic oligomer formation that could facilitate the development of therapeutic approaches to AD.

Development and in vivo evaluation of an oral insulin-PEG delivery system.

Science.gov (United States)

Calceti, P; Salmaso, S; Walker, G; Bernkop-Schnürch, A

2004-07-01

Insulin-monomethoxypoly(ethylene glycol) derivatives were obtained by preparation of mono- and di-terbutyl carbonate insulin derivatives, reaction of available protein amino groups with activated 750 Da PEG and, finally, amino group de-protection. This procedure allowed for obtaining high yield of insulin-1PEG and insulin-2PEG. In vivo studies carried out by subcutaneous injection into diabetic mice demonstrated that the two bioconjugates maintained the native biological activity. In vitro, PEGylation was found to enhance the hormone stability towards proteases. After 1 h incubation with elastase, native insulin, insulin-1PEG and insulin-2PEG undergo about 70, 30 and 10% degradation, respectively, while in the presence of pepsin protein degradation was 100, 70 and 50%, respectively. The attachment of low molecular weight PEG did not significantly (P >0.05) alter insulin permeation behavior across the intestinal mucosa. Insulin-1PEG was formulated into mucoadhesive tablets constituted by the thiolated polymer poly(acrylic acid)-cysteine. The therapeutic agent was sustained released from these tablets within 5 h. In vivo, by oral administration to diabetic mice, the glucose levels were found to decrease of about 40% since the third hour from administration and the biological activity was maintained up to 30 h. According to these results, the combination of PEGylated insulin with a thiolated polymer used as drug carrier matrix might be a promising strategy for oral insulin administration.

The Role of Insulin, Insulin Growth Factor, and Insulin-Degrading Enzyme in Brain Aging and Alzheimer's Disease

OpenAIRE

Messier, Claude; Teutenberg, Kevin

2005-01-01

Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor-based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity-related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in a...

Reactions of stabilized Criegee Intermediates

Science.gov (United States)

Vereecken, Luc; Harder, Hartwig; Novelli, Anna

2014-05-01

Carbonyl oxides (Criegee intermediates) were proposed as key intermediates in the gas phase ozonolysis of alkenes in 1975 by Rudolf Criegee. Despite the importance of ozonolysis in atmospheric chemistry, direct observation of these intermediates remained elusive, with only indirect experimental evidence for their role in the oxidation of hydrocarbons, e.g. through scavenging experiments. Direct experimental observation of stabilized CI has only been achieved since 2008. Since then, a concerted effort using experimental and theoretical means is in motion to characterize the chemistry and kinetics of these reactive intermediates. We present the results of theoretical investigations of the chemistry of Criegee intermediates with a series of coreactants which may be of importance in the atmosphere, in experimental setups, or both. This includes the CI+CI cross-reaction, which proceeds with a rate coefficient near the collision limit and can be important in experimental conditions. The CI + alkene reactions show strong dependence of the rate coefficient depending on the coreactants, but is generally found to be rather slow. The CI + ozone reaction is sufficiently fast to occur both in experiment and the free troposphere, and acts as a sink for CI. The reaction of CI with hydroperoxides, ROOH, is complex, and leads both to the formation of oligomers, as to the formation of reactive etheroxides, with a moderately fast rate coefficient. The importance of these reactions is placed in the context of the reaction conditions in different atmospheric environments ranging from unpolluted to highly polluted.

Detection of aniline oligomers on polyaniline-gold interface using resonance Raman scattering

Czech Academy of Sciences Publication Activity Database

Trchová, Miroslava; Morávková, Zuzana; Dybal, Jiří; Stejskal, Jaroslav

2014-01-01

Roč. 6, č. 2 (2014), s. 942-950 ISSN 1944-8244 R&D Projects: GA ČR GAP205/12/0911; GA ČR(CZ) GA13-00270S Institutional support: RVO:61389013 Keywords : polyaniline * aniline oligomers * Raman spectroscopy Subject RIV: CD - Macromolecular Chemistry Impact factor: 6.723, year: 2014

Radiation-chemical hardening of phenol-formaldehyde oligomers

International Nuclear Information System (INIS)

Shlapatskaya, V.V.; Omel'chenko, S.I.

1978-01-01

Radiation-chemical hardening of phenol formaldehyde oligomers of the resol type has been studied in the presence of furfural and diallylphthalate diluents. The samples have been hardened on an electron accelerator at an electron energy of 1.0-1.1 MeV and a dose rate of 2-3 Mrad/s. The kinetics of hardening has been studied on the yield of gel fraction within the range of absorbed doses from 7 to 400 Mrad. Radiation-chemical hardening of the studied compositions is activated with sensitizers, namely, amines, metal chlorides, and heterocyclic derivatives of metals. Furfural and diallylphthalate compositions are suitable for forming glass-fibre plastic items by the wet method and coatings under the action of ionizing radiations

Structural Transitions of Solvent-Free Oligomer-Grafted Nanoparticles

KAUST Repository

Chremos, Alexandros

2011-09-01

Novel structural transitions of solvent-free oligomer-grafted nanoparticles are investigated by using molecular dynamics simulations of a coarse-grained bead-spring model. Variations in core size and grafting density lead to self-assembly of the nanoparticles into a variety of distinct structures. At the boundaries between different structures, the nanoparticle systems undergo thermoreversible transitions. This structural behavior, which has not been previously reported, deviates significantly from that of simple liquids. The reversible nature of these transitions in solvent-free conditions offers new ways to control self-assembly of nanoparticles at experimentally accessible conditions. © 2011 American Physical Society.

Insulin receptors

International Nuclear Information System (INIS)

Kahn, C.R.; Harrison, L.C.

1988-01-01

This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

PT-symmetry management in oligomer systems

International Nuclear Information System (INIS)

Horne, R L; Cuevas, J; Kevrekidis, P G; Whitaker, N; Abdullaev, F Kh; Frantzeskakis, D J

2013-01-01

We study the effects of management of the PT-symmetric part of the potential within the setting of Schrödinger dimer and trimer oligomer systems. This is done by rapidly modulating in time the gain/loss profile. This gives rise to a number of interesting properties of the system, which are explored at the level of an averaged equation approach. Remarkably, this rapid modulation provides for a controllable expansion of the region of exact PT-symmetry, depending on the strength and frequency of the imposed modulation. The resulting averaged models are analysed theoretically and their exact stationary solutions are translated into time-periodic solutions through the averaging reduction. These are, in turn, compared with the exact periodic solutions of the full non-autonomous PT-symmetry managed problem and very good agreement is found between the two. (paper)

Improved insulin sensitivity after exercise: focus on insulin signaling

DEFF Research Database (Denmark)

Frøsig, Christian; Richter, Erik

2009-01-01

After a single bout of exercise, the ability of insulin to stimulate glucose uptake is markedly improved locally in the previously active muscles. This makes exercise a potent stimulus counteracting insulin resistance characterizing type 2 diabetes (T2D). It is believed that at least part...... of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4...... translocation allowing for a more potent insulin response. Parallel to unraveling of the insulin signaling cascade, this has been investigated within the past 25 years. Reviewing existing studies clearly indicates that improved insulin action can occur independent of interactions with proximal insulin signaling...

A sensitive and selective electrochemical biosensor for the determination of beta-amyloid oligomer by inhibiting the peptide-triggered in situ assembly of silver nanoparticles

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Xing Y

2017-04-01

Full Text Available Yun Xing,1,2 Xiao-Zhen Feng,2 Lipeng Zhang,1 Jiating Hou,2 Guo-Cheng Han,2 Zhencheng Chen2 1Henan Province of Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 2School of Life and Environmental Sciences, Guilin University of Electronic Technology, Guilin, Guangxi, People’s Republic of China Abstract: Soluble beta-amyloid (Aβ oligomer is believed to be the most important toxic species in the brain of Alzheimer’s disease (AD patients. Thus, it is critical to develop a simple method for the selective detection of Aβ oligomer with low cost and high sensitivity. In this paper, we report an electrochemical method for the detection of Aβ oligomer with a peptide as the bioreceptor and silver nanoparticle (AgNP aggregates as the redox reporters. This strategy is based on the conversion of AgNP-based colorimetric assay into electrochemical analysis. Specifically, the peptide immobilized on the electrode surface and presented in solution triggered together the in situ formation of AgNP aggregates, which produced a well-defined electrochemical signal. However, the specific binding of Aβ oligomer to the immobilized peptide prevented the in situ assembly of AgNPs. As a result, a poor electrochemical signal was observed. The detection limit of the method was found to be 6 pM. Furthermore, the amenability of this method for the analysis of Aβ oligomer in serum and artificial cerebrospinal fluid (aCSF samples was demonstrated. Keywords: electrochemical biosensors, Alzheimer’s disease, beta-amyloid oligomer, peptide, silver nanoparticles

Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition.

Science.gov (United States)

Yang, Chao-Qiang; Xu, Jing-Hua; Yan, Dan-Dan; Liu, Bao-Lin; Liu, Kang; Huang, Fang

2017-09-01

Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Structure of human insulin monomer in water/acetonitrile solution

Energy Technology Data Exchange (ETDEWEB)

Bocian, Wojciech; Sitkowski, Jerzy; Bednarek, Elzbieta [National Medicines Institute (Poland); Tarnowska, Anna; Kawecki, Robert [Institute of Organic Chemistry Polish Academy of Sciences (Poland); Kozerski, Lech [National Medicines Institute (Poland)], E-mail: lkoz@icho.edu.pl

2008-01-15

Here we present evidence that in water/acetonitrile solvent detailed structural and dynamic information can be obtained for important proteins that are naturally present as oligomers under native conditions. An NMR-derived human insulin monomer structure in H{sub 2}O/CD{sub 3}CN, 65/35 vol%, pH 3.6 is presented and compared with the available X-ray structure of a monomer that forms part of a hexamer (Acta Crystallogr. 2003 Sec. D59, 474) and with NMR structures in water and organic cosolvent. Detailed analysis using PFGSE NMR, temperature-dependent NMR, dilution experiments and CSI proves that the structure is monomeric in the concentration and temperature ranges 0.1-3 mM and 10-30 deg. C, respectively. The presence of long-range interstrand NOEs, as found in the crystal structure of the monomer, provides the evidence for conservation of the tertiary structure. Starting from structures calculated by the program CYANA, two different molecular dynamics simulated annealing refinement protocols were applied, either using the program AMBER in vacuum (AMBER{sub V}C), or including a generalized Born solvent model (AMBER{sub G}B)

KARAKTERISASI ENZIM KITOSANASE DAR] ISOLAT BAKTERI KPU 2123 DAN APLIKASINYA UNTUK PRODUKS1 OLIGOMER KITOSAN

Directory of Open Access Journals (Sweden)

Yusro Nuri Fawzya

2009-06-01

Full Text Available Penelitian ini merupakan sebagian dari rangkaian penelitian mengenai eksplorasi enzim kitinolitik dari mikroba lingkungan laut, khususnya dari limbah udang. Tujuan penelitian ini adalah untuk mengidentifikasi isolat bakteri KPU 2123 dari limbah udang, mengkarakterisasi dan mengaplikasikan enzim kitosanase yang dihasilkan oleh bakteri tersebut untuk produksi oligomer kitosan dan menguji bioaktivitas oligomer kitosan tersebut sebagai antitumor dan antibakteri. Karakterisasi enzim dilakukan dengan menguji aktivitas enzim pada berbagai suhu dan pH. Selain itu juga ditentukan besarnya aktivitas yang tersisa setelah enzim diinkubasi pada suhu dan lama waktu tertentu. Pengaruh ion logam terhadap aktivitas enzim juga dilihat dengan mereaksikan enzim dengan 1 mM ion logam dalam bentuk larutan khlorida. Hasil penelitian menunjukkan bahwa berdasarkan analisis gen 16S-rRNA, isolat bakteri KPU 2123 memiliki kemiripan 95% dengan Stanotrophomonas maltophilia. Enzim kitosanase dari isolat ini bekerja optimal pada suhu 50 ºC dan pH 6. Enzim ini cukup stabil pada suhu 37 ºC selama 120 menit. Penambahan ion logam berpengaruh terhadap aktivitas enzim. Ion logam Zn²+ (sebagai garam klorida 1 mM menghambat 100% aktivitas enzim tersebut. Penggunaan enzim kitosanase dalam menghidrolisis substrat kitosan, menghasilkan oligomer kitosan yang mengandung tetramer, pentamer dan heksamer Oligor kitosan tersebut mampu menghambat pertumbuhan bakteri Staphylococcus aureus sebesar 10,06% dan dapat menyebabkan kematian sel HeLa dengan LC50 pada dosis 120 ppm.

Immunocytochemical localization and immunochemical characterization of an insulin-related peptide in the pancreas of the urodele amphibian, Ambystoma mexicanum

DEFF Research Database (Denmark)

Hansen, G N; Hansen, B L; Jørgensen, P N

1989-01-01

The pancreas of the axolotl, Ambystoma mexicanum, was investigated by immunocytochemical methods for the presence of immunoreactivity to a number of antisera raised against mammalian insulins. All anti-insulin antisera tested revealed substantial amounts of reaction products confined solely...

Simulations of absorption spectra of conjugated oligomers: role of planar conformation and aggregation in condensed phase

Science.gov (United States)

Yuan, Xiang-Ai; Wen, Jin; Zheng, Dong; Ma, Jing

2018-04-01

This Review highlights the structure/property relationship underlying the morphology modulation through various factors towards the exploration of light-absorbing materials for efficient utilisation of solar power. Theoretical study using a combination of molecular dynamics imulations and the time-dependent density functional theory demonstrated that the planarity plays an important role in tuning spectral properties of oligomer aggregates. The aggregation-induced blue-shift in absorption spectra of oligothiophenes and the red-shift for oligofluorenols were rationalised in a unified way from the reduced (and increased) content of planar conformations in molecular aggregates. The planarity versus non-planarity of oligomers can be modulated by introduction of alkyl side chain or steric bulky substituents. The substitution with various groups in the ortho-position of azobenzene leads to the distorted backbone, breaking symmetry, and hence the red-shift in spectra, expanding the application in biological systems with visible light absorption. The donor-acceptor substituent groups in conjugated oligomers can increase the degree of planarity, electron delocalisation and polarisation, and charge separation, giving rise to the red-shift in spectra and enhancement in polarisability and charge mobility for device applications. The solvent dependent and pH-sensitive properties and intramolecular hydrogen bonds also caused the shift of absorption spectra with the appearance of planar conformers.

Synthetic oligomer analysis using atmospheric pressure photoionization mass spectrometry at different photon energies

International Nuclear Information System (INIS)

Desmazières, Bernard; Legros, Véronique; Giuliani, Alexandre; Buchmann, William

2014-01-01

Graphical abstract: Atmospheric pressure photoIonization mass spectra of synthetic oligomers were recorded in the negative mode by varying the photon energy using synchrotron radiation. Photon energy required for an efficient ionization of the polymer was correlated to ionization potential of the solvent (for example 9.4 eV for tetrahydrofuran). -- Highlights: •Atmospheric pressure photoionization was performed using synchrotron radiation. •Photoionization of oligomers in THF with 10% CH 2 Cl 2 produces intact [M + Cl] − ions. •The photon energy required corresponds to ionization potential of the solvent. •Polymer distributions depend on source parameters such T °C and applied voltages. •Liquid chromatography was coupled to MS using an APPI interface for polymer analysis. -- Abstract: Atmospheric pressure photoionization (APPI) followed by mass spectrometric detection was used to ionize a variety of polymers: polyethylene glycol, polymethyl methacrylate, polystyrene, and polysiloxane. In most cases, whatever the polymer or the solvent used (dichloromethane, tetrahydrofuran, hexane, acetone or toluene), only negative ion mode produced intact ions such as chlorinated adducts, with no or few fragmentations, in contrast to the positive ion mode that frequently led to important in-source fragmentations. In addition, it was shown that optimal detection of polymer distributions require a fine tuning of other source parameters such as temperature and ion transfer voltage. Series of mass spectra were recorded in the negative mode, in various solvents (dichloromethane, tetrahydrofuran, hexane, toluene, and acetone), by varying the photon energy from 8 eV up to 10.6 eV using synchrotron radiation. To these solvents, addition of a classical APPI dopant (toluene or acetone) was not necessary. Courtesy of the synchrotron radiation, it was demonstrated that the photon energy required for an efficient ionization of the polymer was correlated to the ionization energy

Synthetic oligomer analysis using atmospheric pressure photoionization mass spectrometry at different photon energies

Energy Technology Data Exchange (ETDEWEB)

Desmazières, Bernard [Global Bioenergies, 5 rue Henri Desbruyeres, 91030 Evry (France); Legros, Véronique [CNRS, UMR8587, Université d’Evry-Val-d’Essonne, Laboratoire Analyse et Modélisation pour la Biologie et l’Environnement, F-91025 Evry (France); Giuliani, Alexandre [Synchrotron SOLEIL, L’Orme des Merisiers, Saint-Aubin, 91192 Gif-sur-Yvette (France); UAR1008, CEPIA, INRA, Rue de la Geraudiere, F-44316 Nantes (France); Buchmann, William, E-mail: william.buchmann@univ-evry.fr [CNRS, UMR8587, Université d’Evry-Val-d’Essonne, Laboratoire Analyse et Modélisation pour la Biologie et l’Environnement, F-91025 Evry (France)

2014-01-15

Graphical abstract: Atmospheric pressure photoIonization mass spectra of synthetic oligomers were recorded in the negative mode by varying the photon energy using synchrotron radiation. Photon energy required for an efficient ionization of the polymer was correlated to ionization potential of the solvent (for example 9.4 eV for tetrahydrofuran). -- Highlights: •Atmospheric pressure photoionization was performed using synchrotron radiation. •Photoionization of oligomers in THF with 10% CH{sub 2}Cl{sub 2} produces intact [M + Cl]{sup −} ions. •The photon energy required corresponds to ionization potential of the solvent. •Polymer distributions depend on source parameters such T °C and applied voltages. •Liquid chromatography was coupled to MS using an APPI interface for polymer analysis. -- Abstract: Atmospheric pressure photoionization (APPI) followed by mass spectrometric detection was used to ionize a variety of polymers: polyethylene glycol, polymethyl methacrylate, polystyrene, and polysiloxane. In most cases, whatever the polymer or the solvent used (dichloromethane, tetrahydrofuran, hexane, acetone or toluene), only negative ion mode produced intact ions such as chlorinated adducts, with no or few fragmentations, in contrast to the positive ion mode that frequently led to important in-source fragmentations. In addition, it was shown that optimal detection of polymer distributions require a fine tuning of other source parameters such as temperature and ion transfer voltage. Series of mass spectra were recorded in the negative mode, in various solvents (dichloromethane, tetrahydrofuran, hexane, toluene, and acetone), by varying the photon energy from 8 eV up to 10.6 eV using synchrotron radiation. To these solvents, addition of a classical APPI dopant (toluene or acetone) was not necessary. Courtesy of the synchrotron radiation, it was demonstrated that the photon energy required for an efficient ionization of the polymer was correlated to the

[Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy].

Science.gov (United States)

Pesić, Milica; Zivić, Sasa; Radenković, Sasa; Velojić, Milena; Dimić, Dragan; Antić, Slobodan

2007-04-01

Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

Carbonization of aniline oligomers to electrically polarizable particles and their use in electrorheology

Czech Academy of Sciences Publication Activity Database

Plachý, T.; Sedlačík, M.; Pavlínek, V.; Trchová, Miroslava; Morávková, Zuzana; Stejskal, Jaroslav

2014-01-01

Roč. 256, 15 November (2014), s. 398-406 ISSN 1385-8947 R&D Projects: GA ČR GAP205/12/0911; GA ČR(CZ) GA13-08944S Institutional support: RVO:61389013 Keywords : aniline * aniline oligomers * carbonization Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.321, year: 2014

Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders

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A. Janus

2016-01-01

Full Text Available Insulin resistance and other risk factors for atherosclerosis, such as hypertension and hypercholesterolemia, promote endothelial dysfunction and lead to development of metabolic syndrome which constitutes an introduction to cardiovascular disease. The insulin resistance and endothelial dysfunction cross talk between each other by numerous metabolic pathways. Hence, targeting one of these pathologies with pleiotropic treatment exerts beneficial effect on another one. Combined and expletive treatment of hypertension, lipid disorders, and insulin resistance with nonpharmacological interventions and conventional pharmacotherapy may inhibit the transformation of metabolic disturbances to fully developed cardiovascular disease. This paper summarises the common therapeutic targets for insulin resistance, endothelial dysfunction, and vascular inflammatory reaction at molecular level and analyses the potential pleiotropic effects of drugs used currently in management of cardiovascular disease, metabolic syndrome, and diabetes.

Oligomers, organosulfates, and nitrooxy organosulfates in rainwater identified by ultra-high resolution electrospray ionization FT-ICR mass spectrometry

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K. E. Altieri

2009-04-01

Full Text Available Wet deposition is an important removal mechanism for atmospheric organic matter, and a potentially important input for receiving ecosystems, yet less than 50% of rainwater organic matter is considered chemically characterized. Precipitation samples collected in New Jersey, USA, were analyzed by negative ion ultra-high resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS. Elemental compositions of 552 unique molecular species were determined in the mass range 50–500 Da in the rainwater. Four main groups of organic compounds were identified: compounds containing carbon, hydrogen, and oxygen (CHO only, sulfur (S containing CHOS compounds, nitrogen (N containing CHON compounds, and S- and N- containing CHONS compounds. Organic acids commonly identified in precipitation were detected in the rainwater. Within the four main groups of compounds detected in the rainwater, oligomers, organosulfates, and nitrooxy-organosulfates were assigned based on elemental formula comparisons. The majority of the compounds identified are products of atmospheric reactions and are known contributors to secondary organic aerosol (SOA formed from gas phase, aerosol phase, and in-cloud reactions in the atmosphere. It is suggested that the large uncharacterized component of SOA is the main contributor to the large uncharacterized component of rainwater organic matter.

Intracerebroventricular Administration of Amyloid β-protein Oligomers Selectively Increases Dorsal Hippocampal Dialysate Glutamate Levels in the Awake Rat

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Sean D. O’Shea

2008-11-01

Full Text Available Extensive evidence supports an important role for soluble oligomers of the amyloid β-protein (Aβ in Alzheimer’s Disease pathogenesis. In the present study we combined intracerebroventricular (icv injections with brain microdialysis technology in the fully conscious rat to assess the effects of icv administered SDS-stable low-n Aβ oligomers (principally dimers and trimers on excitatory and inhibitory amino acid transmission in the ipsilateral dorsal hippocampus. Microdialysis was employed to assess the effect of icv administration of Aβ monomers and Aβ oligomers on dialysate glutamate, aspartate and GABA levels in the dorsal hippocampus. Administration of Aβ oligomers was associated with a +183% increase (p<0.0001 vs. Aβ monomer-injected control in dorsal hippocampal glutamate levels which was still increasing at the end of the experiment (260 min, whereas aspartate and GABA levels were unaffected throughout. These findings demonstrate that icv administration and microdialysis technology can be successfully combined in the awake rat and suggests that altered dorsal hippocampal glutamate transmission may be a useful target for pharmacological intervention in Alzheimer’s Disease.

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

Science.gov (United States)

Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

International Nuclear Information System (INIS)

Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

1989-01-01

Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

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Nicole M. Templeman

2017-07-01

Full Text Available The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1 signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan.

Science.gov (United States)

Templeman, Nicole M; Flibotte, Stephane; Chik, Jenny H L; Sinha, Sunita; Lim, Gareth E; Foster, Leonard J; Nislow, Corey; Johnson, James D

2017-07-11

The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 +/- mice to Ins2 +/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 +/- mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

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Chih-Ting Su

2016-11-01

Full Text Available Insulin antibodies (IA associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA found in insulin autoimmune syndrome (IAS, which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%, high insulin concentration (111.9 IU/mL and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly.

Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy

Directory of Open Access Journals (Sweden)

Pešić Milica

2007-01-01

Full Text Available Background/Aim. Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin for basal insulin supply in patients with type 1 diabetes. Methods. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IIT were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15; 2. NPH insulin twice daily (n = 15; 3. insulin glargine once daily (n = 18. Meal time insulin aspart was continued in all groups. Results. Fasting blood glucose (FBG was lower in the glargine group (7.30±0.98 mmol/l than in the twice daily NPH group (7.47±1.06 mmol/l, but without significant difference. FBG was significantly higher in the once daily NPH group (8.44±0.85 mmol/l; p < 0.05. HbA1c after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72±0.86% to 6.87±0.50%, as well as in the twice daily NPH group (from 7.80±0.83% to 7.01±0.63%. Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56±2.09 than in both NPH groups (9.0±1.65 in twice daily NPH group and 8.13±1.30 in other NPH group (episodes/patients-month, p < 0.05. Conclusion. Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbA1c and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

Science.gov (United States)

Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

1997-04-01

The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

Design, synthesis, and characterization of biomimetic oligomers

DEFF Research Database (Denmark)

Laursen, Jonas Striegler

a helical arrangement found by DFT calculations. The designed oligomer indeed proved the existence of a ß-peptoid helical conformation by X-ray. Further studies of these compounds indicated a structured display in solution. These helices thus definitively show that the ß-peptoids should be considered......Peptides and proteins made from the 20 canonical amino acids are responsible for many processes necessary for organisms to function. Beside their composition, proteins obtain their activity and unique selectivity through an ability to display functionalities accurately in the three......, for their ability to mimic the structural elements seen in proteins. Two prominent peptidomimetics are ß-peptides and a-peptoids (N-alkylglycines), which have been shown to fold into helical and sheet-like arrangements. To expand the chemical space available for mimicking protein structure their features have been...

Shaking alone induces de novo conversion of recombinant prion proteins to β-sheet rich oligomers and fibrils.

Directory of Open Access Journals (Sweden)

Carol L Ladner-Keay

Full Text Available The formation of β-sheet rich prion oligomers and fibrils from native prion protein (PrP is thought to be a key step in the development of prion diseases. Many methods are available to convert recombinant prion protein into β-sheet rich fibrils using various chemical denaturants (urea, SDS, GdnHCl, high temperature, phospholipids, or mildly acidic conditions (pH 4. Many of these methods also require shaking or another form of agitation to complete the conversion process. We have identified that shaking alone causes the conversion of recombinant PrP to β-sheet rich oligomers and fibrils at near physiological pH (pH 5.5 to pH 6.2 and temperature. This conversion does not require any denaturant, detergent, or any other chemical cofactor. Interestingly, this conversion does not occur when the water-air interface is eliminated in the shaken sample. We have analyzed shaking-induced conversion using circular dichroism, resolution enhanced native acidic gel electrophoresis (RENAGE, electron microscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence and proteinase K resistance. Our results show that shaking causes the formation of β-sheet rich oligomers with a population distribution ranging from octamers to dodecamers and that further shaking causes a transition to β-sheet fibrils. In addition, we show that shaking-induced conversion occurs for a wide range of full-length and truncated constructs of mouse, hamster and cervid prion proteins. We propose that this method of conversion provides a robust, reproducible and easily accessible model for scrapie-like amyloid formation, allowing the generation of milligram quantities of physiologically stable β-sheet rich oligomers and fibrils. These results may also have interesting implications regarding our understanding of prion conversion and propagation both within the brain and via techniques such as protein misfolding cyclic amplification (PMCA and quaking induced conversion (QuIC.

Inhibition of Heme Peroxidase During Phenol Derivatives Oxidation. Possible Molecular Cloaking of the Active Center

Directory of Open Access Journals (Sweden)

Juozas Kulys

2005-10-01

Full Text Available Abstract: Ab initio quantum chemical calculations have been applied to the study of the molecular structure of phenol derivatives and oligomers produced during peroxidasecatalyzed oxidation. The interaction of substrates and oligomers with Arthromyces ramosus peroxidase was analyzed by docking methods. The most possible interaction site of oligomers is an active center of the peroxidase. The complexation energy increases with increasing oligomer length. However, the complexed oligomers do not form a precise (for the reaction hydrogen bonding network in the active center of the enzyme. It seems likely that strong but non productive docking of the oligomers determines peroxidase inhibition during the reaction.

An Open-Circuit Voltage and Power Conversion Efficiency Study of Fullerene Ternary Organic Solar Cells Based on Oligomer/Oligomer and Oligomer/Polymer.

Science.gov (United States)

Zhang, Guichuan; Zhou, Cheng; Sun, Chen; Jia, Xiaoe; Xu, Baomin; Ying, Lei; Huang, Fei; Cao, Yong

2017-07-01

Variations in the open-circuit voltage (V oc ) of ternary organic solar cells are systematically investigated. The initial study of these devices consists of two electron-donating oligomers, S2 (two units) and S7 (seven units), and the electron-accepting [6,6]-phenyl C71 butyric acid methyl ester (PC 71 BM) and reveals that the V oc is continuously tunable due to the changing energy of the charge transfer state (E ct ) of the active layers. Further investigation suggests that V oc is also continuously tunable upon change in E ct in a ternary blend system that consists of S2 and its corresponding polymer (P11):PC 71 BM. It is interesting to note that higher power conversion efficiencies can be obtained for both S2:S7:PC 71 BM and S2:P11:PC 71 BM ternary systems compared with their binary systems, which can be ascribed to an improved V oc due to the higher E ct and an improved fill factor due to the improved film morphology upon the incorporation of S2. These findings provide a new guideline for the future design of conjugated polymers for achieving higher performance of ternary organic solar cells. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Prospective observational study of insulin detemir in patients with poorly controlled type 2 diabetes mellitus initiating insulin therapy for the first time (SOLVE Study)].

Science.gov (United States)

Orozco-Beltrán, Domingo; Artola-Menéndez, Sara

2016-02-01

Describe the experience in the primary care setting with insulin detemir in patients with poorly controlled type2 diabetes mellitus that need to add-on insulin to their oral antidiabetic drug therapy. Prospective observational study of 6 months of follow up, performed in 10 countries. In Spain, participating sites were only from the primary care setting. Eligible patients were those with poorly controlled type2 diabetes mellitus adding-on once-daily insulin detemir to their existing oral antidiabetic therapy in the month prior to their enrollment. The change of Hb1Ac and of weight at the end of the study and the incidence of hypoglycemia and adverse reactions, were analyzed. We report the results obtained in the Spanish cohort. Overall 17,374 patients were included, 973 in Spain [mean age 64.8 years (SE 12); duration of diabetes 9.4 years (SE 6.2); Hb1Ac 8.9% (DE 1.4)]. In the sample analyzed for efficacy (n=474) the mean change of Hb1Ac was -1.6% (95%CI: -1.75 to -1.42; P<.001), mean change of weight was -2.9 kg (95%CI: -3.72 to -2.08; P<.001). Only one episode of severe hypoglycemia was reported, which was also the only serious adverse reaction reported in the study. The incidence rate of non-severe hypoglycemia was 2.44 events/patient-year. In this cohort of patients with type 2 diabetes mellitus receiving newly initiated insulin therapy, once-daily detemir improved the glycemic control, with low incidence of hypoglycemia and a significant reduction of the weight. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

ENVIRONMENTAL ENRICHMENT STRENGTHENS CORTICOCORTICAL INTERACTIONS AND REDUCES AMYLOID-β OLIGOMERS IN AGED MICE

Directory of Open Access Journals (Sweden)

Marco eMainardi

2014-01-01

Full Text Available Brain aging is characterized by global changes which are thought to underlie age-related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-β (Aβ oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE, a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Aβ oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Aβ oligomers and increased synthesis of the Aβ-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes.

Anti-insulin antibody test

Science.gov (United States)

Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... Normally, there are no antibodies against insulin in your blood. ... different laboratories. Some labs use different measurements or ...

Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

Science.gov (United States)

Zeng, Yi; Zhang, Le; Hu, Zhiping

2016-01-01

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

Science.gov (United States)

ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

2015-12-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), Pobese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

Absence of down-regulation of the insulin receptor by insulin. A possible mechanism of insulin resistance in the rat.

OpenAIRE

Walker, A P; Flint, D J

1983-01-01

Insulin resistance occurs in rat adipocytes during pregnancy and lactation despite increased or normal insulin binding respectively; this suggests that a post-receptor defect exists. The possibility has been examined that, although insulin binding occurs normally, internalization of insulin or its receptor may be impaired in these states. Insulin produced a dose-dependent reduction in the number of insulin receptors on adipocytes from virgin rats maintained in culture medium, probably due to ...

Clinical use of the co-formulation of insulin degludec and insulin aspart

DEFF Research Database (Denmark)

Kumar, A; Awata, T; Bain, S C

2016-01-01

(HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice...... a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins....

Inactivation of lipoprotein lipase occurs on the surface of THP-1 macrophages where oligomers of angiopoietin-like protein 4 are formed

International Nuclear Information System (INIS)

Makoveichuk, Elena; Sukonina, Valentina; Kroupa, Olessia; Thulin, Petra; Ehrenborg, Ewa; Olivecrona, Thomas; Olivecrona, Gunilla

2012-01-01

Highlights: ► Lipoprotein lipase (LPL) activity is controlled by ANGPTL4 in THP-1 macrophages. ► Both LPL and ANGPTL4 bind to THP-1 macrophages in a heparin-releasable fashion. ► Only monomers of ANGPTL4 are present within THP-1 macrophages. ► Covalent oligomers of ANGPTL4 appear on cell surface and in medium. ► Inactivation of LPL coincide with ANGPTL4 oligomer formation on cell surfaces. -- Abstract: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like protein (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPARδ agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL. Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed.

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

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Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

2018-03-14

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance

DEFF Research Database (Denmark)

Højlund, Kurt

2014-01-01

. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes...... described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance....... Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin...

A nontoxic polypeptide oligomer with a fungicide potency under agricultural conditions which is equal or greater than that of their chemical counterparts.

Directory of Open Access Journals (Sweden)

Sara Monteiro

Full Text Available There are literally hundreds of polypeptides described in the literature which exhibit fungicide activity. Tens of them have had attempted protection by patent applications but none, as far as we are aware, have found application under real agricultural conditions. The reasons behind may be multiple where the sensitivity to the Sun UV radiation can come in first place. Here we describe a multifunctional glyco-oligomer with 210 kDa which is mainly composed by a 20 kDa polypeptide termed Blad that has been previously shown to be a stable intermediary product of β-conglutin catabolism. This oligomer accumulates exclusively in the cotyledons of Lupinus species, between days 4 and 12 after the onset of germination. Blad-oligomer reveals a plethora of biochemical properties, like lectin and catalytic activities, which are not unusual per si, but are remarkable when found to coexist in the same protein molecule. With this vast range of chemical characteristics, antifungal activity arises almost as a natural consequence. The biological significance and potential technological applications of Blad-oligomer as a plant fungicide to agriculture, its uniqueness stems from being of polypeptidic in nature, and with efficacies which are either equal or greater than the top fungicides currently in the market are addressed.

Modulation of hematopoietic progenitor cell fate in vitro by varying collagen oligomer matrix stiffness in the presence or absence of osteoblasts.

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Chitteti, Brahmananda Reddy; Kacena, Melissa A; Voytik-Harbin, Sherry L; Srour, Edward F

2015-10-01

To recreate the in vivo hematopoietic cell microenvironment or niche and to study the impact of extracellular matrix (ECM) biophysical properties on hematopoietic progenitor cell (HPC) proliferation and function, mouse bone-marrow derived HPC (Lin-Sca1+cKit+/(LSK) were cultured within three-dimensional (3D) type I collagen oligomer matrices. To generate a more physiologic milieu, 3D cultures were established in both the presence and absence of calvariae-derived osteoblasts (OB). Collagen oligomers were polymerized at varying concentration to give rise to matrices of different fibril densities and therefore matrix stiffness (shear storage modulus, 50-800 Pa). Decreased proliferation and increased clonogenicity of LSK cells was associated with increase of matrix stiffness regardless of whether OB were present or absent from the 3D culture system. Also, regardless of whether OB were or were not added to the 3D co-culture system, LSK within 800 Pa collagen oligomer matrices maintained the highest percentage of Lin-Sca1+ cells as well as higher percentage of cells in quiescent state (G0/G1) compared to 50 Pa or 200Pa matrices. Collectively, these data illustrate that biophysical features of collagen oligomer matrices, specifically fibril density-induced modulation of matrix stiffness, provide important guidance cues in terms of LSK expansion and differentiation and therefore maintenance of progenitor cell function. Copyright © 2015. Published by Elsevier B.V.

Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

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Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

2013-08-01

"Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

Expression of enzymes in yeast for lignocellulose derived oligomer CBP

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McBride, John E.; Wiswall, Erin; Shikhare, Indraneel; Xu, Haowen; Thorngren, Naomi; Hau, Heidi H.; Stonehouse, Emily

2017-08-29

The present invention provides a multi-component enzyme system that hydrolyzes hemicellulose oligomers from hardwood which can be expressed, for example, in yeast such as Saccharomyces cerevisiae. In some embodiments, this invention provides for the engineering of a series of biocatalysts combining the expression and secretion of components of this enzymatic system with robust, rapid xylose utilization, and ethanol fermentation under industrially relevant process conditions for consolidated bioprocessing. In some embodiments, the invention utilizes co-cultures of strains that can achieve significantly improved performance due to the incorporation of additional enzymes in the fermentation system.

Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

International Nuclear Information System (INIS)

Bolinder, J.; Ostman, J.; Arner, P.

1982-01-01

The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono- 125 I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

Science.gov (United States)

Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Functional characterization of autophosphorylation sites of the activated insulin receptor-tyrosine kinase

International Nuclear Information System (INIS)

Flores-Riveros, J.R.; Lane, M.D.

1987-01-01

Insulin receptor, solubilized from 3T3-L1 cellular membranes and then purified, was autophosphorylated with [γ- 32 P]ATP in the absence or presence of insulin. Specific phosphopeptides generated by trypsin digestion of the 32 P-labeled β-subunit were identified and separated by reverse phase HPLC. In the absence of insulin, radioactivity of the phosphopeptides is evenly distributed among four major peaks designated as sites I, II, III and IV, according to their order of elution. This pattern is maintained for at least the first 30 min of autophosphorylation. When the reaction is carried out in the presence of insulin, > 50% of the total 32 P radioactivity is found in site I and the rate of 32 P incorporation into this site is markedly higher than into sites II, III and IV. Maximal activation of tyrosine kinase activity, as estimated by substrate phosphorylation, is coincident with the nearly complete phosphorylation of site I. Delayed activation of previously autophosphorylated receptor by insulin, but not by EGF or IGF-I, produced a similar pattern where phosphorylated site I predominates. These observations indicate that one major insulin-regulated autophosphorylation site in the β-subunit is responsible for activation of the insulin receptor tyrosine kinase. The isolation of this phosphopeptide on a preparative scale and its characterization are now in progress

Differential effects of insulin injections and insulin infusions on levels ...

African Journals Online (AJOL)

Studies have shown that while injections of insulin cause an increase in fat mass, infusions of insulin increase fat mass. The aim of this paper was to test the hypothesis that if an increase in glycogen is an indicator of an impending increase in adipose mass, then insulin infusions should not increase glycogen, while insulin ...

Economic benefits of improved insulin stability in insulin pumps.

Science.gov (United States)

Weiss, Richard C; van Amerongen, Derek; Bazalo, Gary; Aagren, Mark; Bouchard, Jonathan R

2011-05-01

Insulin pump users discard unused medication and infusion sets according to labeling and manufacturer's instructions. The stability labeling for insulin aspart (rDNA origin] (Novolog) was increased from two days to six. The associated savings was modeled from the perspective of a hypothetical one-million member health plan and the total United States population. The discarded insulin volume and the number of infusion sets used under a two-day stability scenario versus six were modeled. A mix of insulin pumps of various reservoir capacities with a range of daily insulin dosages was used. Average daily insulin dose was 65 units ranging from 10 to 150 units. Costs of discarded insulin aspart [rDNA origin] were calculated using WAC (Average Wholesale Price minus 16.67%). The cost of pump supplies was computed for the two-day scenario assuming a complete infusion set change, including reservoirs, every two days. Under the six-day scenario complete infusion sets were discarded every six days while cannulas at the insertion site were changed midway between complete changes. AWP of least expensive supplies was used to compute their costs. For the hypothetical health plan (1,182 pump users) the annual reduction in discarded insulin volume between scenarios was 19.8 million units. The corresponding cost reduction for the plan due to drug and supply savings was $3.4 million. From the U.S. population perspective, savings of over $1 billion were estimated. Using insulin that is stable for six days in pump reservoirs can yield substantial savings to health plans and other payers, including patients.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

Science.gov (United States)

Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

Pregestational diabetes with extreme insulin resistance: use of U-500 insulin in pregnancy.

Science.gov (United States)

Zuckerwise, Lisa C; Werner, Erika F; Pettker, Christian M; McMahon-Brown, Erin K; Thung, Stephen F; Han, Christina S

2012-08-01

Increased insulin requirements in pregnancy can hinder attainment of glycemic control in diabetic patients. U-500 insulin is a concentrated form of regular insulin that can be a valuable tool in the treatment of patients with severe insulin resistance. A 24-year-old woman with pregestational diabetes mellitus experienced increasing insulin requirements during pregnancy, peaking at 650 units daily. The frequent, large-volume injections of standard-concentration insulin were poorly tolerated by the patient and resulted in nonadherence. She subsequently achieved glycemic control on thrice-daily U-500 insulin. Pregnancy exacerbates insulin resistance in diabetic patients, and these patients may require high doses of insulin. U-500 insulin is an effective alternative for patients with severe insulin resistance and should be considered for pregnant women with difficulty achieving glycemic control.

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

Science.gov (United States)

Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

2015-01-01

Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance.

Science.gov (United States)

Kwon, Hayeong; Jang, Donghwan; Choi, Moonjeong; Lee, Jaewoong; Jeong, Kyuho; Pak, Yunbae

2018-06-01

Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2β isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2β-PTP1B-directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2β is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. Copyright © 2018 Elsevier B.V. All rights reserved.

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

Science.gov (United States)

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Nanoparticle for delivery of antisense γPNA oligomers targeting CCR5

OpenAIRE

Bahal, Raman; McNeer, Nicole Ali; Ly, Danith H.; Saltzman, W. Mark; Glazer, Peter M.

2013-01-01

The development of a new class of peptide nucleic acids (PNAs), i.e., gamma PNAs (γPNAs), creates the need for a general and effective method for its delivery into cells for regulating gene expression in mammalian cells. Here we report the antisense activity of a recently developed hydrophilic and biocompatible diethylene glycol (miniPEG)-based gamma peptide nucleic acid called MPγPNAs via its delivery by poly(lactide-co-glycolide) (PLGA)-based nanoparticle system. We show that MPγPNA oligome...

Detergent-Resistant Membrane Microdomains Facilitate Ib Oligomer Formation and Biological Activity of Clostridium perfringens Iota-Toxin

National Research Council Canada - National Science Library

Hale, Martha

2004-01-01

...) were extracted with cold Triton X-100. Western blotting revealed that Ib oligomers localized in DRMs extracted from Vero, but not MRC-5, cells while monomeric Ib was detected in the detergent-soluble fractions of both cell types...

Disrupting self-assembly and toxicity of amyloidogenic protein oligomers by "molecular tweezers" - from the test tube to animal models.

Science.gov (United States)

Attar, Aida; Bitan, Gal

2014-01-01

Despite decades of research, therapy for diseases caused by abnormal protein folding and aggregation (amyloidoses) is limited to treatment of symptoms and provides only temporary and moderate relief to sufferers. The failure in developing successful disease-modifying drugs for amyloidoses stems from the nature of the targets for such drugs - primarily oligomers of amyloidogenic proteins, which are distinct from traditional targets, such as enzymes or receptors. The oligomers are metastable, do not have well-defined structures, and exist in dynamically changing mixtures. Therefore, inhibiting the formation and toxicity of these oligomers likely will require out-of-the-box thinking and novel strategies. We review here the development of a strategy based on targeting the combination of hydrophobic and electrostatic interactions that are key to the assembly and toxicity of amyloidogenic proteins using lysine (K)-specific "molecular tweezers" (MTs). Our discussion includes a survey of the literature demonstrating the important role of K residues in the assembly and toxicity of amyloidogenic proteins and the development of a lead MT derivative called CLR01, from an inhibitor of protein aggregation in vitro to a drug candidate showing effective amelioration of disease symptoms in animal models of Alzheimer's and Parkinson's diseases.

The Investigation of ADAMTS16 in Insulin-Induced Human Chondrosarcoma Cells.

Science.gov (United States)

Cakmak, Ozlem; Comertoglu, Ismail; Firat, Ridvan; Erdemli, Haci Kemal; Kursunlu, S Fatih; Akyol, Sumeyya; Ugurcu, Veli; Altuntas, Aynur; Adam, Bahattin; Demircan, Kadir

2015-08-01

A disintegrin-like metalloproteinase with thrombospondin motifs (ADAMTS) is a group of proteins that have enzymatic activity secreted by cells to the outside extracellular matrix. Insulin induces proteoglycan biosynthesis in chondrosarcoma chondrocytes. The purpose of the present in vitro study is to assess the time course effects of insulin on ADAMTS16 expression in OUMS-27 (human chondrosarcoma) cell line to examine whether insulin regulates ADAMTS16 expression as well as proteoglycan biosynthesis with multifaceted properties or not. Chondrosarcoma cells were cultured in Dulbecco's modified Eagle's medium having either 10 μg/mL insulin or not. While the experiment was going on, the medium containing insulin had been changed every other day. Cells were harvested at 1st, 3rd, 7th, and 11th days; subsequently, RNA and proteins were isolated in every experimental group according to their time interval. RNA expression of ADAMTS was estimated by quantitative real-time polymerase chain reaction (qRT-PCR) by using primers. Immunoreactive protein levels were encountered by the western blot protein detection technique by using proper anti-ADAMTS16 antibodies. ADAMTS16 mRNA expression level of chondrosarcoma cells was found to be insignificantly decreased in chondrosarcoma cells induced by insulin detected by the qRT-PCR instrument. On the other hand, there was a gradual decrease in immune-reactant ADAMTS16 protein amount by the time course in insulin-treated cell groups when compared with control cells. It has been suggested that insulin might possibly regulate ADAMTS16 levels/activities in OUMS-27 chondrosarcoma cells taking a role in extracellular matrix turnover.

Parkinson's disease in the spotlight: unraveling nanoscale α-Synuclein oligomers using ultrasensitive single-molecule spectroscopy

NARCIS (Netherlands)

Zijlstra, Niels

2014-01-01

During the last 15 years, we have witnessed a major shift in the research focus to understand the cause of amyloid diseases. The attention has shifted from the fully matured amyloid fibrils to the nanometer sized aggregation intermediates called oligomers as the potentially cytotoxic species that

Update on insulin treatment for dogs and cats: insulin dosing pens and more

Directory of Open Access Journals (Sweden)

Thompson A

2015-04-01

Full Text Available Ann Thompson,1 Patty Lathan,2 Linda Fleeman3 1School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia; 2College of Veterinary Medicine Mississippi State University, Starkville, MS, USA; 3Animal Diabetes Australia, Melbourne, VIC, Australia Abstract: Insulin therapy is still the primary therapy for all diabetic dogs and cats. Several insulin options are available for each species, including veterinary registered products and human insulin preparations. The insulin chosen depends on the individual patient's requirements. Intermediate-acting insulin is usually the first choice for dogs, and longer-acting insulin is the first choice for cats. Once the insulin type is chosen, the best method of insulin administration should be considered. Traditionally, insulin vials and syringes have been used, but insulin pen devices have recently entered the veterinary market. Pens have different handling requirements when compared with standard insulin vials including: storage out of the refrigerator for some insulin preparations once pen cartridges are in use; priming of the pen to ensure a full dose of insulin is administered; and holding the pen device in place for several seconds during the injection. Many different types of pen devices are available, with features such as half-unit dosing, large dials for visually impaired people, and memory that can display the last time and dose of insulin administered. Insulin pens come in both reusable and disposable options. Pens have several benefits over syringes, including improved dose accuracy, especially for low insulin doses. Keywords: diabetes, mellitus, canine, feline, NPH, glargine, porcine lente

Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization

DEFF Research Database (Denmark)

Vinther, Tine N.; Norrman, Mathias; Strauss, Holger M.

2012-01-01

An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers...... in the circulation, and it is stabilized by hexamer formation in the presence of zinc ions during storage in the pancreatic ß-cell. Due to the transient nature of insulin dimer, direct investigation of this important form is inherently difficult. To address the relationship between insulin oligomerization...... and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further oligomerization...

Insulin analogues: have they changed insulin treatment and improved glycaemic control?

DEFF Research Database (Denmark)

Madsbad, Sten

2002-01-01

To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studies....... This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin...... administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting...

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

Science.gov (United States)

Farb, Melissa G; Karki, Shakun; Park, Song-Young; Saggese, Samantha M; Carmine, Brian; Hess, Donald T; Apovian, Caroline; Fetterman, Jessica L; Bretón-Romero, Rosa; Hamburg, Naomi M; Fuster, José J; Zuriaga, María A; Walsh, Kenneth; Gokce, Noyan

2016-12-01

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m 2 ) and five metabolically normal non-obese (BMI 26±2 kg/m 2 ) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease. © The Author(s) 2016.

Chemical evolution. XXI - The amino acids released on hydrolysis of HCN oligomers

Science.gov (United States)

Ferris, J. P.; Wos, J. D.; Nooner, D. W.; Oro, J.

1974-01-01

Major amino acids released by hydrolysis of acidic and basic HCN oligomers are identified by chromatography as Gly, Asp, and diaminosuccinic acid. Smaller amounts of Ala, Ile and alpha-aminoisobutyric acid are also detected. The amino acids released did not change appreciably when the hydrolysis medium was changed from neutral to acidic or basic. The presence of both meso and d, l-diaminosuccinic acids was established by paper chromatography and on an amino acid analyzer.

Alteration in insulin action

DEFF Research Database (Denmark)

Tanti, J F; Gual, P; Grémeaux, T

2004-01-01

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

Self-Healable and Reprocessable Polysulfide Sealants Prepared from Liquid Polysulfide Oligomer and Epoxy Resin.

Science.gov (United States)

Gao, Wentong; Bie, Mengyao; Liu, Fu; Chang, Pengshan; Quan, Yiwu

2017-05-10

Polysulfide sealants have been commercially applied in many industrial fields. In this article, we study the self-healing property of the epoxy resin-cured polysulfide sealants for the first time. The obtained sealants showed a flexible range of ultimate elongation of 157-478% and a tensile strength of 1.02-0.75 MPa corresponding to different polysulfide oligomers. By taking advantage of the dynamic reversible exchange of disulfide bonds, polysulfide sealants exhibited good self-healing ability under a moderate thermal stimulus. A higher molecular weight and a lower degree of cross-linking of polysulfide oligomer were helpful in improving the ultimate elongation and healing efficiency of the polysulfide sealants. After subjecting to a temperature of 75 °C for 60 min, both the tensile strength and ultimate elongation of a fully cut sample, LP55-F, were restored to 91% of the original values, without affecting the sealing property. Furthermore, the sample exhibited excellent reshaping and reprocessing abilities. These outcomes offer a paradigm toward sustainable industrial applications of the polysulfide-based sealants.

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

DEFF Research Database (Denmark)

Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

2005-01-01

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting...... insulin (130%, P Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P

Aging Enables Ca2+ Overload and Apoptosis Induced by Amyloid-β Oligomers in Rat Hippocampal Neurons: Neuroprotection by Non-Steroidal Anti-Inflammatory Drugs and R-Flurbiprofen in Aging Neurons.

Science.gov (United States)

Calvo-Rodríguez, María; García-Durillo, Mónica; Villalobos, Carlos; Núñez, Lucía

2016-07-22

The most important risk factor for Alzheimer's disease (AD) is aging. Neurotoxicity in AD has been linked to dyshomeostasis of intracellular Ca2+ induced by small aggregates of the amyloid-β peptide 1-42 (Aβ42 oligomers). However, how aging influences susceptibility to neurotoxicity induced by Aβ42 oligomers is unknown. In this study, we used long-term cultures of rat hippocampal neurons, a model of neuronal in vitro aging, to investigate the contribution of aging to Ca2+ dishomeostasis and neuron cell death induced by Aβ42 oligomers. In addition, we tested whether non-steroidal anti-inflammatory drugs (NSAIDs) and R-flurbiprofen prevent apoptosis acting on subcellular Ca2+ in aged neurons. We found that Aβ42 oligomers have no effect on young hippocampal neurons cultured for 2 days in vitro (2 DIV). However, they promoted apoptosis modestly in mature neurons (8 DIV) and these effects increased dramatically after 13 DIV, when neurons display many hallmarks of in vivo aging. Consistently, cytosolic and mitochondrial Ca2+ responses induced by Aβ42 oligomers increased dramatically with culture age. At low concentrations, NSAIDs and the enantiomer R-flurbiprofen lacking anti-inflammatory activity prevent Ca2+ overload and neuron cell death induced by Aβ42 oligomers in aged neurons. However, at high concentrations R-flurbiprofen induces apoptosis. Thus, Aβ42 oligomers promote Ca2+ overload and neuron cell death only in aged rat hippocampal neurons. These effects are prevented by low concentrations of NSAIDs and R-flurbiprofen acting on mitochondrial Ca2+ overload.

Simple Protein Modification Using Zwitterionic Polymer to Mitigate the Bioactivity Loss of Conjugated Insulin.

Science.gov (United States)

Xie, Jinbing; Lu, Yang; Wang, Wei; Zhu, Hui; Wang, Zhigang; Cao, Zhiqiang

2017-06-01

Polymer-protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer-protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non-site specific way, or a more complex site-specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB-insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB-insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB-insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB-insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one-step coupling reaction without complex site-specific linkage technique. The synthesized PCB-insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization.

Directory of Open Access Journals (Sweden)

Tine N Vinther

Full Text Available An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers in the circulation, and it is stabilized by hexamer formation in the presence of zinc ions during storage in the pancreatic β-cell. Due to the transient nature of insulin dimer, direct investigation of this important form is inherently difficult. To address the relationship between insulin oligomerization and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further oligomerization to form the structural equivalent of the classical hexamer. The covalently linked dimer neither bound to the insulin receptor, nor induced a metabolic response in vitro. However, it was extremely thermodynamically stable and did not form amyloid fibrils when subjected to mechanical stress, underlining the importance of oligomerization for insulin stability.

The Nernst equation applied to oxidation-reduction reactions in myoglobin and hemoglobin. Evaluation of the parameters.

Science.gov (United States)

Saroff, Harry A

Analyses of the binding of oxygen to monomers such as myoglobin employ the Mass Action equation. The Mass Action equation, as such, is not directly applicable for the analysis of the binding of oxygen to oligomers such as hemoglobin. When the binding of oxygen to hemoglobin is analyzed, models incorporating extensions of mass action are employed. Oxidation-reduction reactions of the heme group in myoglobin and hemoglobin involve the binding and dissociation of electrons. This reaction is described with the Nernst equation. The Nernst equation is applicable only to a monomeric species even if the number of electrons involved is greater than unity. To analyze the oxidation-reduction reaction in a molecule such as hemoglobin a model is required which incorporates extensions of the Nernst equation. This communication develops models employing the Nernst equation for oxidation-reduction reactions analogous to those employed for hemoglobin in the analysis of the oxygenation (binding of oxygen) reaction.

Inactivation of lipoprotein lipase occurs on the surface of THP-1 macrophages where oligomers of angiopoietin-like protein 4 are formed

Energy Technology Data Exchange (ETDEWEB)

Makoveichuk, Elena; Sukonina, Valentina; Kroupa, Olessia [Department of Medical Biosciences, Physiological Chemistry Umea University, SE-901 87 Umea (Sweden); Thulin, Petra; Ehrenborg, Ewa [Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm (Sweden); Olivecrona, Thomas [Department of Medical Biosciences, Physiological Chemistry Umea University, SE-901 87 Umea (Sweden); Olivecrona, Gunilla, E-mail: Gunilla.Olivecrona@medbio.umu.se [Department of Medical Biosciences, Physiological Chemistry Umea University, SE-901 87 Umea (Sweden)

2012-08-24

Highlights: Black-Right-Pointing-Pointer Lipoprotein lipase (LPL) activity is controlled by ANGPTL4 in THP-1 macrophages. Black-Right-Pointing-Pointer Both LPL and ANGPTL4 bind to THP-1 macrophages in a heparin-releasable fashion. Black-Right-Pointing-Pointer Only monomers of ANGPTL4 are present within THP-1 macrophages. Black-Right-Pointing-Pointer Covalent oligomers of ANGPTL4 appear on cell surface and in medium. Black-Right-Pointing-Pointer Inactivation of LPL coincide with ANGPTL4 oligomer formation on cell surfaces. -- Abstract: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like protein (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPAR{delta} agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL. Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin

NARCIS (Netherlands)

ter Horst, K. W.; Gilijamse, P. W.; Koopman, K. E.; de Weijer, B. A.; Brands, M.; Kootte, R. S.; Romijn, J. A.; Ackermans, M. T.; Nieuwdorp, M.; Soeters, M. R.; Serlie, M. J.

2015-01-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely

Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

Science.gov (United States)

Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

2014-08-01

Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes

DEFF Research Database (Denmark)

Niskanen, Leo; Leiter, Lawrence A; Franek, Edward

2012-01-01

Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30)....

Molecular Mechanisms of Insulin Secretion and Insulin Action.

Science.gov (United States)

Flatt, Peter R.; Bailey, Clifford J.

1991-01-01

Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

Type 1 Ig-E mediated allergy to human insulin, insulin analogues and beta-lactam antibiotics Hipersensibilidade imediata a insulina humana, análogos de insulina e a antibióticos beta-lactâmicos

Directory of Open Access Journals (Sweden)

Pedro Andrade

2012-12-01

Full Text Available Insulin, a crucial therapeutic agent for diabetes mellitus, has been rarely associated with hypersensitivity events. We present a 69-year-old type-2 diabetic patient with urticariform lesions on the sites of subcutaneous injection of insulin. The patient denied any known allergies, except for an unspecific cutaneous reaction after intramuscular penicillin administration in childhood. Prick tests revealed positive reactions to all tested human insulins and insulin analogues. Serum IgE levels were above normal range and RAST tests were positive for human, bovine and porcine insulins, as well as beta-lactams. Type 1 IgEmediated allergy to insulin analogues demands a prompt diagnosis and represents a significant therapeutic challenge in diabetic patients.A insulina é um agente indispensável para o controlo da diabetes mellitus. Os efeitos adversos da sua administração, em particular fenómenos de hipersensibilidade, são raros. Apresentamos um doente de 69 anos, diabético do tipo 2, com episódios recorrentes de lesões urticariformes nos locais de administração subcutânea de insulina. Negava alergias medicamentosas, à excepção de reacção não especificada na infância após penicilina intramuscular. Foram realizados testes cutâneos por puntura (prick tests com diversos tipos de insulina humana e análogos, todos com reacções positivas, associando elevação dos níveis de IgE sérica e provas RAST positivas para as insulinas humana, bovina e porcina e para os antibióticos beta-lactâmicos. A alergia a análogos de insulina exige um diagnóstico precoce, originando um desafio terapêutico importante no doente diabético.

Insulin Biosynthetic Interaction Network Component, TMEM24, Facilitates Insulin Reserve Pool Release

Directory of Open Access Journals (Sweden)

Anita Pottekat

2013-09-01

Full Text Available Insulin homeostasis in pancreatic β cells is now recognized as a critical element in the progression of obesity and type II diabetes (T2D. Proteins that interact with insulin to direct its sequential synthesis, folding, trafficking, and packaging into reserve granules in order to manage release in response to elevated glucose remain largely unknown. Using a conformation-based approach combined with mass spectrometry, we have generated the insulin biosynthetic interaction network (insulin BIN, a proteomic roadmap in the β cell that describes the sequential interacting partners of insulin along the secretory axis. The insulin BIN revealed an abundant C2 domain-containing transmembrane protein 24 (TMEM24 that manages glucose-stimulated insulin secretion from a reserve pool of granules, a critical event impaired in patients with T2D. The identification of TMEM24 in the context of a comprehensive set of sequential insulin-binding partners provides a molecular description of the insulin secretory pathway in β cells.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

Energy Technology Data Exchange (ETDEWEB)

Affholter, J.A.; Roth, R.A. (Stanford Univ. School of Medicine, CA (USA)); Cascieri, M.A.; Bayne, M.L. (Merck Sharp and Dohme Research Labs., Rahway, NJ (USA)); Brange, J. (Novo Research Institute, Bagsvaerd (Denmark)); Casaretto, M. (Deutsches Wollforschungsinstitut an der Technischen, Aachen (West Germany))

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants (B25-Asp)insulin and (B25-His)insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants (B1-24-His{sup 25}-NH{sub 2})insulin and (B1-24-Leu{sup 25}-NH{sub 2})insulin, but not (B1-24-Trp{sup 25}-NH{sub 2})insulin and (B1-24-Tyr{sup 25}-NH{sub 2})insulin. The truncated analogue with the lowest affinity for IDE ((B1-24-His{sup 25}-NH{sub 2})insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

International Nuclear Information System (INIS)

Affholter, J.A.; Roth, R.A.; Cascieri, M.A.; Bayne, M.L.; Brange, J.; Casaretto, M.

1990-01-01

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants [B1-24-His 25 -NH 2 ]insulin and [B1-24-Leu 25 -NH 2 ]insulin, but not [B1-24-Trp 25 -NH 2 ]insulin and [B1-24-Tyr 25 -NH 2 ]insulin. The truncated analogue with the lowest affinity for IDE ([B1-24-His 25 -NH 2 ]insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

NARCIS (Netherlands)

Swinnen, S. G.; Dain, M.-P.; Mauricio, D.; DeVries, J. H.; Hoekstra, J. B.; Holleman, F.

2010-01-01

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

Science.gov (United States)

Hu, Xiaolei; Chen, Fengling

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

The effect of tubing dwell time on insulin adsorption during intravenous insulin infusions.

Science.gov (United States)

Thompson, Cecilia D; Vital-Carona, Jessica; Faustino, E Vincent S

2012-10-01

Insulin adsorbs to plastic tubing, which decreases the concentration of an insulin solution delivered from an intravenous infusion set. Dwelling insulin within tubing before starting the infusion decreases adsorption but delays treatment initiation and wastes time in infusion preparation. The lack of data on dwell time effects results in wide variability in practice. We aim to determine the effect of dwell time on insulin concentration from intravenous infusion tubing. In this in vitro study, we used insulin solutions with concentrations of 0.1 unit/mL, 1 unit/mL, and 10 units/mL. Each solution dwelled in intravenous infusion sets for 0, 15, 30, or 60 min. After the dwell, we measured insulin concentrations from the solution bags and tubing. We repeated each insulin concentration-dwell time combination five times. Comparisons were performed using analyses of variance. For each of the three insulin concentrations, the mean insulin concentrations from the tubing were not significantly different between dwell times. Duration of dwell time did not affect insulin adsorption in polypropylene intravenous infusion sets. We recommend that following a 20-mL flush, insulin infusions can be started without any dwell time. Removal of dwell times may improve clinical practice by minimizing preparation time and will allow faster initiation of insulin infusion therapy.

Characterization of radiation modified κ-carrageenan oligomers for bio-based materials development

International Nuclear Information System (INIS)

Abad, Lucille V.; Relleve, Lorna S.; Aranilla, Charito T.; Racadio, Darwin T.; Dela Rosa, Alumanda M.

2011-01-01

κ-carrageenan oligomers are known to have several biological activities such as anti-HIV, anti-herpes, antitumor and antioxidant properties. Recent progress in the development of radiation modified κ-carrageenan has resulted in new applications such as plant growth promoter, radiation dose indicator and hydrogels for wound dressing. This presentation would touch on the changes in chemical structure, gelation and conformational transition behavior and molecular size of κ-carrageenan at doses from 0 to 200 kGy and would be correlated to these functions for the development of bio-based materials. Chemical and spectral analyses were carried out using UV-Vis spectroscopy, FT-IR spectroscopy, NMR spectroscopy, reducing sugar analysis, free sulfate and carboxylic acid analysis. The chemical and spectral analyses of the radiolytic products indicated increasing reducing sugars, carbonyl, carboxylic acids, and sulfates with increasing doses which reached a maximum level at a certain dose depending on the irradiation condition. Values were very much lower in solid irradiation (in vacuum and in air) as compared to aqueous irradiation. NMR data also revealed an intact structure of the oligomer irradiated at 100 kGy in the specific fraction that contains an Mw = (3-10) kDa. κ-carrageenan oligomers exhibited antioxidant properties as determined by hydroxyl radical scavenging activity, reducing power and DPPH radical scavenging capacity assay. The degree of oxidative inhibition increased with increasing dose which can be attributed to higher reducing sugar. Dynamic light scattering (DLS) experiments showed that a dose of up to 50 kGy, sol-gelation transition was still observed. Beyond 50 kGy, no gelation took place, instead appearance of fast relax-carrageenan mode in characteristic decay time function was observed at doses of (75-150) kGy. Optimum peak intensity was found at 100 kGy (mol wt. 5-10 kDa) which coincides with the optimum plant growth promoter effect in κ

Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children.

Science.gov (United States)

Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R; Mlcak, Ronald P; Qian, Ting; Chinkes, David L; Herndon, David N

2010-06-01

To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. Prospective, randomized study. An acute pediatric burn unit in a tertiary teaching hospital. Children, 4-18 yrs old, with total body surface area burned > or =40% and who arrived within 1 wk after injury were enrolled in the study. Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 +/- 124 to 1925 +/- 291 kcal/m(2) x day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 +/- 0.8 conventional insulin therapy vs. 6.8 +/- 0.9 mg/kg x min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 +/- 1.3 intensive insulin therapy versus 4.8 +/- 0.6 mg/kg x min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 +/- 0.9 vs. 2.5 +/- 0.6 mg/kg x min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 +/- 0.1 to 1.7 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .004; and 0.7 +/- 0.1 to 1.3 +/- 0.1 microm O(2)/CS/mg protein/min for state 4, p protocol improves insulin sensitivity and mitochondrial

Insulin-loaded poly(epsilon-caprolactone) nanoparticles: efficient, sustained and safe insulin delivery system.

Science.gov (United States)

de Araújo, Thiago M; Teixeira, Zaine; Barbosa-Sampaio, Helena C; Rezende, Luiz F; Boschero, Antonio C; Durán, Nelson; Höehr, Nelci F

2013-06-01

The aim of this work was to develop an efficient, biodegradable, biocompatible and safe controlled release system using insulin-loaded poly(epsilon-caprolactone) (PCL) nanoparticles. The insulin-loaded PCL nanoparticles were prepared by double emulsion method (water-in-oil-in-water) using Pluronic F68 as emulsifier. Using the double emulsion method a high insulin encapsulation efficiency (90.6 +/-1.6%) with a zeta potential of -29 +/-2.7 mV and average particle size of 796 +/-10.5 nm was obtained. Insulin-loaded PCL nanoparticles showed no toxicity to MIN6 cells. Insulin nanoparticles administered subcutaneously and intraperitoneally in rats reduced glycaemia of basal levels after 15 minutes, and presented a sustainable hypoglycemic effect on insulin-dependent type 1 diabetic rats, showing to be more efficient than unencapsulated insulin. Furthermore, these nanoparticles were not hepatotoxic, as evaluated by the effect over liver cell-death and oxidative stress scavenger system in rats. These results suggest that insulin-loaded PCL nanoparticles prepared by water-in-oil-in-water emulsion method are biocompatible, efficient and safe insulin-delivering system with controlled insulin release, which indicates that it may be a powerful tool for insulin-dependent patients care.

Insulin pumps and insulin quality--requirements and problems.

Science.gov (United States)

Brange, J; Havelund, S

1983-01-01

In developing insulin solution suitable for delivery devices the chemical and biological stability, as well as the physical stability, must be taken into consideration. Addition of certain mono- and disaccharides increases the physical stability of neutral insulin solutions, but concurrently the chemical and biological stability decrease to an unacceptable degree. Addition of Ca-ions in low concentrations offers a physiologically acceptable method for stabilizing neutral insulin solutions against heat precipitation without affecting the quality, including the chemical and biological stability.

Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

DEFF Research Database (Denmark)

Deshmukh, Atul S

2016-01-01

transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....

Dynamic conformations of nucleophosmin (NPM1 at a key monomer-monomer interface affect oligomer stability and interactions with granzyme B.

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Wei D Duan-Porter

Full Text Available Nucleophosmin (NPM1 is an abundant, nucleolar tumor antigen with important roles in cell proliferation and putative contributions to oncogenesis. Wild-type NPM1 forms pentameric oligomers through interactions at the amino-terminal core domain. A truncated form of NPM1 found in some hepatocellular carcinoma tissue formed an unusually stable oligomer and showed increased susceptibility to cleavage by granzyme B. Initiation of translation at the seventh methionine generated a protein (M7-NPM that shared all these properties. We used deuterium exchange mass spectrometry (DXMS to perform a detailed structural analysis of wild-type NPM1 and M7-NPM, and found dynamic conformational shifts or local "unfolding" at a specific monomer-monomer interface which included the β-hairpin "latch." We tested the importance of interactions at the β-hairpin "latch" by replacing a conserved tyrosine in the middle of the β-hairpin loop with glutamic acid, generating Y67E-NPM. Y67E-NPM did not form stable oligomers and further, prevented wild-type NPM1 oligomerization in a dominant-negative fashion, supporting the critical role of the β-hairpin "latch" in monomer-monomer interactions. Also, we show preferential cleavage by granzyme B at one of two available aspartates (either D161 or D122 in M7-NPM and Y67E-NPM, whereas wild-type NPM1 was cleaved at both sites. Thus, we observed a correlation between the propensity to form oligomers and granzyme B cleavage site selection in nucleophosmin proteins, suggesting that a small change at an important monomer-monomer interface can affect conformational shifts and impact protein-protein interactions.

Toward understanding insulin fibrillation.

Science.gov (United States)

Brange, J; Andersen, L; Laursen, E D; Meyn, G; Rasmussen, E

1997-05-01

Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear aggregates. Shielding of hydrophobic domains is the main driving force for this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues, including A2, A3, B11, and B15, plays a crucial role in the fibrillation process. Recent crystal analyses and molecular modeling studies have suggested that when insulin fibrillates this exposed domain interacts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils did not elicit an increased immune response with respect to formation of IgG insulin antibodies when compared with native insulin. In contrast, the IgE response increased with increasing content of insulin in fibrillar form. Strategies and practical approaches to prevent insulin from forming fibrils are reviewed. Stabilization of the insulin hexameric structure and blockage of hydrophobic interfaces by addition of surfactants are the most effective means of counteracting insulin fibrillation.

Reductive methylation of insulin. Production of a biologically active tritiated insulin

Energy Technology Data Exchange (ETDEWEB)

Marsh, J W; Nahum, A; Steiner, D F [Department of Biochemistry, University of Chicago, Illinois, USA

1983-01-01

Reductive methylation of the three amino groups of porcine insulin was accomplished by incubation with formaldehyde and sodium cyanoborohydride. The two amino termini and the epsilon amino group of B29 lysine were each dimethylated within 1 h of incubation. The fully methylated insulin bound more tightly to a reverse phase column than did native insulin, had a slightly more acid isoelectric point, and maintained approximately 50% biological activity when examined with an insulin sensitive cultured cell line. Reductive methylation with sodium cyanoboro (/sup 3/H) hydride resulted in a (/sup 3/H) methylated insulin with a specific activity of 6 Ci/mmol.

Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

DEFF Research Database (Denmark)

Bot, M; Pouwer, F; De Jonge, P

2013-01-01

Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin......AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin...... sensitivity (OGIS) index. Insulin secretion was estimated using three model-based parameters of insulin secretion (beta-cell glucose sensitivity, the potentiation factor ratio, and beta-cell rate sensitivity). RESULTS: A total of 162 out of 1027 participants (16%) had significant depressive symptoms. Having...

Insulin aspart in diabetic pregnancy

DEFF Research Database (Denmark)

Mathiesen, Elisabeth R

2008-01-01

in insulin requirements during pregnancy necessitate short-acting insulins for postprandial control of hyperglycemia. The fast-acting insulin analogue insulin aspart has been tested in a large, randomized trial of pregnant women with Type 1 diabetes and offers benefits in control of postprandial...... hyperglycemia with a tendency towards fewer episodes of severe hypoglycemia compared with human insulin. Treatment with insulin aspart was associated with a tendency toward fewer fetal losses and preterm deliveries than treatment with human insulin. Insulin aspart could not be detected in the fetal circulation...... and no increase in insulin antibodies was found. Thus, the use of insulin aspart in pregnancy is regarded safe....

Comparison of metformin and insulin versus insulin alone for type 2 diabetes

DEFF Research Database (Denmark)

Hemmingsen, Bianca; Christensen, Louise Lundby; Wetterslev, Jørn

2012-01-01

To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.......To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes....

Pancreas transplantation for treatment of generalized allergy to human insulin in type 1 diabetes.

Science.gov (United States)

Malaise, J; Leonet, J; Goffin, E; Lefebvre, C; Tennstedt, D; Vandeleene, B; Buysschaert, M; Squifflet, J P

2005-01-01

We report the case of a 29-year-old man with a 14-year history of type 1 diabetes, normal renal function, and mild diabetic retinopathy. The patient progressively developed a generalized allergic reaction to two insulin excipients--protamine and metacresol--with systemic manifestations of tremor, tachycardia, vertigo, shortness of breath, and short episodes of unconsciousness causing him to be out of work. In June 2003, he received a vascularized cadaveric pancreas transplant using induction with polyclonal antibodies along with tacrolimus and sirolimus but without steroids. A hyperglycemic episode following corticosteroid therapy for rejection treatment required reintroduction of insulin therapy with prompt reappearance of allergic manifestations. Now, the patient is euglycemic without insulin or allergic manifestations and a glycated hemoglobin of 6.4%.

Peptide nucleic acid (PNA) cell penetrating peptide (CPP) conjugates as carriers for cellular delivery of antisense oligomers

DEFF Research Database (Denmark)

Shiraishi, Takehiko; Nielsen, Peter E

2012-01-01

We have explored the merits of a novel delivery strategy for the antisense oligomers based on cell penetrating peptide (CPP) conjugated to a carrier PNA with sequence complementary to part of the antisense oligomer. The effect of these carrier CPP-PNAs was evaluated by using antisense PNA targeting......-PNA (cPNA1(7)-(D-Arg)8) and hexamer carrier decanoyl-CPP-PNA (Deca-cPNA1(6)-(D-Arg)8), respectively, without showing significant additional cellular toxicity. Most interestingly, the activity reached the same level obtained by enhancement with endosomolytic chloroquine (CQ) treatment, suggesting...... that the carrier might facilitate endosomal escape. Furthermore, 50% downregulation of luciferase expression at 60 nM siRNA was obtained using this carrier CPP-PNA delivery strategy (with CQ co-treatment) for a single stranded antisense RNA targeting normal luciferase mRNA. These results indicated that CPP...

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

DEFF Research Database (Denmark)

Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

2005-01-01

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy....... insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant...

Insulin glulisine compared to insulin aspart and to insulin lispro administered by continuous subcutaneous insulin infusion in patients with type 1 diabetes: a randomized controlled trial

NARCIS (Netherlands)

van Bon, Arianne C.; Bode, Bruce W.; Sert-Langeron, Caroline; DeVries, J. Hans; Charpentier, Guillaume

2011-01-01

In a previous pilot study comparing insulin glulisine (GLU) with insulin aspart (ASP) administered by continuous subcutaneous insulin infusion (CSII), GLU-treated patients did show a trend toward fewer catheter occlusions compared with ASP-treated patients. Here we performed a randomized open-label,

Comparison of insulin analogue B9AspB27Glu and soluble human insulin in insulin-treated diabetes.

Science.gov (United States)

Kang, S; Owens, D R; Vora, J P; Brange, J

1990-02-10

Postprandial plasma glucose excursions and plasma levels of free insulin after subcutaneous bolus injection of a rapidly absorbed monomeric insulin analogue (B9AspB27Glu) or soluble human insulin ('Actrapid HM' U100) were studied in six insulin-treated diabetic subjects. 10 U actrapid or an equimolar amount of the analogue were injected, in random order with an interval of 1 week, immediately before a 500 kcal test meal. Basal insulin levels were similar on the 2 study days (mean 74.1 [SE 5.1] pmol/l, actrapid; 79.7 [13.0] pmol/l, analogue). After injection of actrapid plasma free insulin levels rose slowly, reaching a plateau by 105 min at 222 (19) pmol/l. Injection of the analogue resulted in a rapid early peak at 30 min (798 [112] pmol/l), and levels were significantly higher than those after actrapid between 15 and 210 min. The more physiological plasma insulin levels achieved with the analogue were accompanied by a substantial reduction in postprandial plasma glucose excursions; the integrated area under the incremental plasma glucose curve was 45% lower after the analogue than after actrapid.

Mechanical stress regulates insulin sensitivity through integrin-dependent control of insulin receptor localization.

Science.gov (United States)

Kim, Jung; Bilder, David; Neufeld, Thomas P

2018-01-15

Insulin resistance, the failure to activate insulin signaling in the presence of ligand, leads to metabolic diseases, including type 2 diabetes. Physical activity and mechanical stress have been shown to protect against insulin resistance, but the molecular mechanisms remain unclear. Here, we address this relationship in the Drosophila larval fat body, an insulin-sensitive organ analogous to vertebrate adipose tissue and livers. We found that insulin signaling in Drosophila fat body cells is abolished in the absence of physical activity and mechanical stress even when excess insulin is present. Physical movement is required for insulin sensitivity in both intact larvae and fat bodies cultured ex vivo. Interestingly, the insulin receptor and other downstream components are recruited to the plasma membrane in response to mechanical stress, and this membrane localization is rapidly lost upon disruption of larval or tissue movement. Sensing of mechanical stimuli is mediated in part by integrins, whose activation is necessary and sufficient for mechanical stress-dependent insulin signaling. Insulin resistance develops naturally during the transition from the active larval stage to the immotile pupal stage, suggesting that regulation of insulin sensitivity by mechanical stress may help coordinate developmental programming with metabolism. © 2018 Kim et al.; Published by Cold Spring Harbor Laboratory Press.

Stereocomplexation, Thermal and Mechanical Properties of Conetworks Composed of Star-Shaped l-Lactide, d-Lactide and ε-Caprolactone Oligomers Utilizing Sugar Alcohols as Core Molecules

Directory of Open Access Journals (Sweden)

Kaito Sugane

2017-11-01

Full Text Available It is important to develop tailor-made biodegradable/biocompatible polymer networks usable for biomaterials whose thermal and mechanical properties are easily controlled by changing the composition. We synthesized sugar-alcohol-based polymer networks (SPN-mscLAO/3CLO, m = 4, 5 or 6 by the crosslinking reactions of erythritol, xylitol or sorbitol-based m-armed star-shaped l-lactide and d-lactide oligomers (HmSLLAO and HmSDLAO, a glycerol-based 3-armed star-shaped ε-caprolactone oligomer (H3SCLO and hexamethylene diisocyanate (HDI at the weight ratios of HmSLLAO/HmSDLAO = 1/1 and (HmSLLAO + HmSDLAO/H3CLO = 100/0, 75/25, 50/50, 25/75 or 0/100. The influence of the arm number on the crystallization behavior, thermal and mechanical properties of SPN-mscLAO/3CLOs were systematically investigated by comparing with those of sugar-alcohol-based homochiral polymer network (SPN-mLLAO, m = 4, 5 or 6 prepared by the reaction of HmSLLAO and HDI. Stereocomplex (sc crystallites are dominantly formed for SPN-mscLAO/3CLOs 100/0–25/75, whereas SPN-mLLAOs were amorphous. The higher order of melting temperature of sc-crystals for SPN-mscLAO/3CLOs 100/0–25/75 was m = 5 > m = 6 > m = 4. The sc-crystallinities of SPN-4scLAO/3CLOs 100/0–50/50 were significantly lower than those of SPN-mscLAO/3CLOs 100/0–50/50 (m = 5 and 6. The larger order of the sc-spherulite size at crystallization temperature of 110 °C was m = 5 > m = 6 > m = 4 for SPN-mscLAO/3CLO 100/0. The size and number of sc-spherulites decreased with increasing crystallization temperature over the range of 110–140 °C and with increasing CLO fraction. Among all the networks, SPN-5scLAO/3CLOs 75/25 and 50/50 exhibited the highest and second highest tensile toughnesses (21.4 and 20.3 MJ·m−3, respectively.

Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

Directory of Open Access Journals (Sweden)

Paula I. Moreira

2009-12-01

Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release

Directory of Open Access Journals (Sweden)

Claudia Weber

2015-01-01

Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.

Synthesis and optoelectronic properties of a monodispersed macrocycle oligomer consisting of three triarylamine units

Energy Technology Data Exchange (ETDEWEB)

Kong, Qinggang, E-mail: gangq0172@163.com [Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, College of Environmental Science and Engineering, Nanjing University of Information Science and Technology, 219 Ningliu Road, Pukou District, Nanjing 210044 (China); Qian, Haiyan, E-mail: qianhaiy@163.com [College of Material Science and Technology, Nanjing University of Technology, 5 Xinmofan Road, Nanjing 210009 (China); Zhou, Yonghui; Li, Jun; Xiao, Huining [Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, College of Environmental Science and Engineering, Nanjing University of Information Science and Technology, 219 Ningliu Road, Pukou District, Nanjing 210044 (China)

2012-08-15

A monodispersed macrocyclic oligomer constructed by three triarylmine units ((TPAT){sub 3}) was designed and readily synthesized from the monomer of 3-(4 Prime -(phenyl(4 Double-Prime -methylphenyl)amino)-phenyl)pentan-3-ol (TPAT) by means of a simple Friedel-Crafts alkylation reaction. The structure of the resultant macrocycle was examined using FT-IR, NMR and MALDI-TOF mass spectroscopy. Compared with 1,10-bis(di-4-tolylaminophenyl) cyclohexane (TAPC) and tri-p-tolylamine (TTA), (TPAT){sub 3} possesses the three-dimensional chair conformation and the higher T{sub g}. In the photoluminescence (PL) spectrum of (TPAT){sub 3} film, there are no excimer emission peaks in the range of 400-550 nm region as those of TAPC and TTA. Besides an EL peak at 386 nm, the single-layer device occured only the 438 nm excimer emission peak, whose intensity increased with the excitation voltage increase. Using 1,3,5-Tris(N-phenylbenzimidazol-2-yl)-benzene (TPBI) as the electron-transporting layer, the resulting double-layer device ITO/(TPAT){sub 3} (40 nm)/TPBI (40 nm)/Mg:Ag (10:1; 50 nm)/Ag (100 nm) only exhibited a 438 nm maximum symmetrical emission peak under an excitation voltage of 14 V. However, as the applied voltage was increased from 14 V to 19 V, the intensity of the symmetrical curve with a 468 nm peak from exciplex emission gets stronger and stronger. In fact, the resultant emission curve was asymmetrical, due to the overlap of two symmetrical curves with 438 nm and 468 nm peaks, respectively. The maximum luminance and luminous efficiency are 2240 cd m{sup -2} at 18.8 V and 1.73 cd A{sup -1} at 1878 cd m{sup -2} (13.9 V). Highlights: Black-Right-Pointing-Pointer The monodispersed macrocyclic oligomer constructed by three triarylamine units was synthesized and characterized. Black-Right-Pointing-Pointer The PL of (TPAT){sub 3} film does not emerge TAPC and TTA's emission peaks of over 400 nm region. Black-Right-Pointing-Pointer The 438 nm emission peak was found from

Classifying insulin regimens

DEFF Research Database (Denmark)

Neu, A; Lange, K; Barrett, T

2015-01-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...

Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

Science.gov (United States)

Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

2015-01-01

Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

Insulin aspart pharmacokinetics

DEFF Research Database (Denmark)

Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

2014-01-01

Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

Simple introduction of anion trapping site to polymer electrolytes through dehydrocoupling or hydroboration reaction using 9-borabicyclo[3.3.1]nonane

International Nuclear Information System (INIS)

Mizumo, Tomonobu; Sakamoto, Kenji; Matsumi, Noriyoshi; Ohno, Hiroyuki

2005-01-01

Organoboron-based anion trapping polymer electrolytes were synthesized through hydroboration or dehydrocoupling reaction between poly(propylene oxide) (PPO) oligomer (M n =400, 1200, 2000 and 4000) and 9-borabicyclo[3.3.1]nonane (9-BBN). Obtained oligomers were added various lithium salts (LiN(CF 3 SO 2 ) 2 , LiSO 3 CF 3 , LiCO 2 CF 3 or LiBr) to analyze the ionic conductivity and lithium ion transference number (t Li + ). The ionic conductivity of the oligomer in the presence of LiN(CF 3 SO 2 ) 2 showed higher ionic conductivity than other systems, however, the t Li + was less than 0.3. When LiSO 3 CF 3 or LiCO 2 CF 3 , was added high t Li + over 0.6 was obtained. Such difference in t Li + can be explained by HSAB principle. Since boron is a hard acid, soft (CF 3 SO 2 ) 2 N - anion can not be trapped effectively. High ionic conductivity of 1.3x10 -6 Scm -1 and high t Li + of 0.73 was obtained when PPO chain length was 2000. These values of facilely prepared polymer electrolytes are comparable to those of the PPOs having covalently bonded salt moieties on the chain ends

Exogenous insulin antibody syndrome (EIAS: a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients

Directory of Open Access Journals (Sweden)

Xiaolei Hu

2018-01-01

Full Text Available Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs. IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS. The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS.

Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome.

Science.gov (United States)

Derkach, K V; Ivantsov, A O; Chistyakova, O V; Sukhov, I B; Buzanakov, D M; Kulikova, A A; Shpakov, A O

2017-06-01

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

Insulin production rate in normal man as an estimate for calibration of continuous intravenous insulin infusion in insulin-dependent diabetic patients.

Science.gov (United States)

Waldhäusl, W K; Bratusch-Marrain, P R; Francesconi, M; Nowotny, P; Kiss, A

1982-01-01

This study examines the feasibility of deriving the 24-h insulin requirement of insulin-dependent diabetic patients who were devoid of any endogenous insulin release (IDD) from the insulin-production rate (IPR) of healthy man (basal, 17 mU/min; stimulated 1.35 U/12.5 g glucose). To this end, continuous intravenous insulin infusion (CIVII) was initiated at a precalculated rate of 41.2 +/- 4.6 (SD) U/24 h in IDD (N - 12). Blood glucose profiles were compared with those obtained during intermittent subcutaneous (s.c.) insulin therapy (IIT) and those of healthy controls (N = 7). Regular insulin (Hoechst CS) was infused with an adapted Mill Hill Infuser at a basal infusion rate of 1.6 U/h (6:00 a.m. to 8:00 p.m.), and of 0.8 U/h from 8:00 p.m. to 6:00 a.m. Preprandial insulin (3.2-6.4 U) was added for breakfast, lunch, and dinner. Daily individual food intake totaled 7688 +/- 784 kJ (1836 +/- 187 kcal)/24 h including 184 +/- 37 g of glucose. Proper control of blood glucose (BG) (mean BG 105 +/- 10 mg/dl; mean amplitude of glycemic excursions 54 +/- 18 mg/dl; and 1 h postprandial BG levels not exceeding 160 mg/dl) and of plasma concentrations of beta-hydroxybutyrate and lactate was maintained by 41.4 +/- 4.4 U insulin/24 h. Although BG values only approximated the upper normal range as seen in healthy controls, they were well within the range reported by others during CIVII. Therefore, we conclude that in adult IDD completely devoid of endogenous insulin (1) the IPR of normal man can be used during CIVII as an estimate for the patient's minimal insulin requirement per 24 h, and (2) this approach allows for a blood glucose profile close to the upper range of a normal control group. Thus, deriving a patient's daily insulin dose from the insulin production rate of healthy man may add an additional experimental protocol which aids in making general calculations of a necessary insulin dose instead of using trial and error or a closed-loop insulin infusion system.

Combined HILIC-ELSD/ESI-MSn enables the separation, identification and quantification of sugar beet pectin derived oligomers

NARCIS (Netherlands)

Remoroza, C.A.; Cord-Landwehr, S.; Leijdekkers, A.G.M.; Moerschbacher, B.M.; Schols, H.A.; Gruppen, H.

2012-01-01

The combined action of endo-polygalacturonase (endo-PGII), pectin lyase (PL), pectin methyl esterase (fungal PME) and RG-I degrading enzymes enabled the extended degradation of methylesterified and acetylated sugar beet pectins (SBPs). The released oligomers were separated, identified and quantified

Insulin resistance in dairy cows.

Science.gov (United States)

De Koster, Jenne D; Opsomer, Geert

2013-07-01

Glucose is the molecule that drives milk production, and insulin plays a pivotal role in the glucose metabolism of dairy cows. The effect of insulin on the glucose metabolism is regulated by the secretion of insulin by the pancreas and the insulin sensitivity of the skeletal muscles, the adipose tissue, and the liver. Insulin resistance may develop as part of physiologic (pregnancy and lactation) and pathologic processes, which may manifest as decreased insulin sensitivity or decreased insulin responsiveness. A good knowledge of the normal physiology of insulin is needed to measure the in vivo insulin resistance of dairy cows. Copyright © 2013 Elsevier Inc. All rights reserved.

Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

Science.gov (United States)

Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

2016-03-01

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important

Imaging of beta-Cell Mass and Insulitis in Insulin-Dependent (Type 1) Diabetes Mellitus

NARCIS (Netherlands)

Di Gialleonardo, Valentina; de Vries, Erik F. J.; Di Girolamo, Marco; Quintero, Ana M.; Dierckx, Rudi A. J. O.; Signore, Alberto

2012-01-01

Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic beta-cells, called insulitis, confirmed in pancreatic samples obtained at

Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Almind, K; Bjørbaek, C; Vestergaard, H

1993-01-01

Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate...

Metformin and insulin receptors

International Nuclear Information System (INIS)

Vigneri, R.; Gullo, D.; Pezzino, V.

1984-01-01

The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

Science.gov (United States)

Vora, J P; Owens, D R; Dolben, J; Atiea, J A; Dean, J D; Kang, S; Burch, A; Brange, J

1988-11-12

To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. Study in normal people at a diabetes research unit and a university department of medical physics. Seven healthy male volunteers aged 20-39 not receiving any other drugs. After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and

Reaction of Acetylenedicarboxylic Acid Made Easy: High-Pressure Route for Polymerization

DEFF Research Database (Denmark)

Delori, Amit; Hutchison, Ian B.; Bull, Craig L.

2018-01-01

A breakthrough has been achieved in improving the efficiency of solid-state polymerization of acetylenedicarboxylic acid (ADCA). Traditional solid-state polymerization of ADCA is marked by long exposure times of γ-radiation (>10 days) and very low yields (around 5.5%). We have been able to perform...... a reaction to an n = 8 oligomer, as confirmed by matrix-assisted laser desorption/ionization-time of flight, in less than 2 min by employing ∼6 GPa of pressure. We have determined the crystal structure of ADCA on increasing pressure to (5.2 GPa) to provide insight into the process of polymerization...... with Pixel calculations supporting our evaluation of the polymerization process....

Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin.

Science.gov (United States)

Morçöl, T; Nagappan, P; Nerenbaum, L; Mitchell, A; Bell, S J D

2004-06-11

An oral delivery system for insulin was developed and functional activity was tested in a non-obese diabetic (NOD) mice model. Calcium phosphate particles containing insulin was synthesized in the presence of PEG-3350 and modified by aggregating the particles with caseins to obtain the calcium phosphate-PEG-insulin-casein (CAPIC) oral insulin delivery system. Single doses of CAPIC formulation were tested in NOD mice under fasting or fed conditions to evaluate the glycemic activity. The blood glucose levels were monitored every 1-2h for 12h following the treatments using an ACCU CHECK blood glucose monitoring system. Orally administered and subcutaneously injected free insulin solution served as controls in the study. Based on the results obtained we propose that: (1). the biological activity of insulin is preserved in CAPIC formulation; (2). insulin in CAPIC formulations, but not the free insulin, displays a prolonged hypoglycemic effect after oral administration to diabetic mice; (3). CAPIC formulation protects insulin from degradation while passing through the acidic environment of the GI track until it is released in the less acidic environment of the intestines where it can be absorbed in its biologically active form; (4). CAPIC formulation represents a new and unique oral delivery system for insulin and other macromolecules.

Insulin and the Brain

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Grosu Cristina

2017-12-01

Full Text Available The brain represents an important site for the action of insulin. Besides the traditionally known importance in glucoregulation, insulin has significant neurotrophic properties and influences the brain activity: insulin influences eating behavior, regulates the storage of energy and several aspects concerning memory and knowledge. Insulin resistance and hyperinsulinism could be associated with brain aging, vascular and metabolic pathologies. Elucidating the pathways and metabolism of brain insulin could have a major impact on future targeted therapies.

Insulin Secretagogues

Science.gov (United States)

... than sulfonylureas. What are the side effects and disadvantages of insulin secretagogues? Both types of insulin-releasing ... help find the cause. Questions to ask your doctor What else can I do to keep my ...

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme.

Science.gov (United States)

Affholter, J A; Cascieri, M A; Bayne, M L; Brange, J; Casaretto, M; Roth, R A

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, we have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor I (25 nM and approximately 16,000 nM, respectively), the first set of analogues studied were hybrid molecules of insulin and IGF I. IGF I mutants [insB1-17,17-70]IGF I, [Tyr55,Gln56]IGF I, and [Phe23,Phe24,Tyr25]IGF I have been synthesized and share the property of having insulin-like amino acids at positions corresponding to primary sites of cleavage of insulin by IDE. Whereas the first two exhibit affinities for IDE similar to that of wild type IGF I, the [Phe23,Phe24,Tyr25]IGF I analogue has a 32-fold greater affinity for the immobilized enzyme. Replacement of Phe-23 by Ser eliminates this increase. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered insulin distribution and metabolism in type I diabetics assessed by [123I]insulin scanning

International Nuclear Information System (INIS)

Hachiya, H.L.; Treves, S.T.; Kahn, C.R.; Sodoyez, J.C.; Sodoyez-Goffaux, F.

1987-01-01

Scintigraphic scanning with [ 123 I]insulin provides a direct and quantitative assessment of insulin uptake and disappearance at specific organ sites. Using this technique, the biodistribution and metabolism of insulin were studied in type 1 diabetic patients and normal subjects. The major organ of [ 123 I]insulin uptake in both diabetic and normal subjects was the liver. After iv injection in normal subjects, the uptake of [ 123 I]insulin by the liver was rapid, with peak activity at 7 min. Activity declined rapidly thereafter, consistent with rapid insulin degradation and clearance. Rapid uptake of [ 123 I]insulin also occurred in the kidneys, although the uptake of insulin by the kidneys was about 80% of that by liver. In type 1 diabetic patients, uptake of [ 123 I]insulin in these organ sites was lower than that in normal subjects; peak insulin uptakes in liver and kidneys were 21% and 40% lower than those in normal subjects, respectively. The kinetics of insulin clearance from the liver was comparable in diabetic and normal subjects, whereas clearance from the kidneys was decreased in diabetics. The plasma clearance of [ 123 I]insulin was decreased in diabetic patients, as was insulin degradation, assessed by trichloroacetic acid precipitability. Thirty minutes after injection, 70.9 +/- 3.8% (+/- SEM) of [ 123 I]insulin in the plasma of diabetics was trichloroacetic acid precipitable vs. only 53.9 +/- 4.0% in normal subjects. A positive correlation was present between the organ uptake of [123I]insulin in the liver or kidneys and insulin degradation (r = 0.74; P less than 0.001)

Treatment of severe insulin resistance in pregnancy with 500 units per milliliter of concentrated insulin.

Science.gov (United States)

Mendez-Figueroa, Hector; Maggio, Lindsay; Dahlke, Joshua D; Daley, Julie; Lopes, Vrishali V; Coustan, Donald R; Rouse, Dwight J

2013-07-01

To evaluate glycemic control and pregnancy outcomes among pregnant women with severe insulin resistance treated with 500 units/mL concentrated insulin. Retrospective analysis of gravid women with severe insulin resistance (need for greater than 100 units of insulin per injection or greater than 200 units/d) treated with either 500 units/mL concentrated insulin or conventional insulin therapy. We performed a two-part analysis: 1) between gravid women treated with and without 500 units/mL concentrated insulin; and 2) among gravid women treated with 500 units/mL concentrated insulin, comparing glycemic control before and after its initiation. Seventy-three pregnant women with severe insulin resistance were treated with 500 units/mL concentrated insulin and 78 with conventional insulin regimens. Patients treated with 500 units/mL concentrated insulin were older and more likely to have type 2 diabetes mellitus. Average body mass index was comparable between both groups (38.6 compared with 40.4, P=.11) as were obstetric and perinatal outcomes and glycemic control during the last week of gestation. Within the 500 units/mL concentrated insulin cohort, after initiation of this medication, fasting and postprandial blood glucose concentrations improved. However, the rates of blood glucose values less than 60 mg/dL and less than 50 mg/dL were higher in the 500 units/mL concentrated insulin group after initiation than before, 4.8% compared with 2.0% (Pinsulin in severely obese insulin-resistant pregnant women confers similar glycemic control compared with traditional insulin regimens but may increase the risk of hypoglycemia. II.

Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

International Nuclear Information System (INIS)

Salhanick, A.I.; Amatruda, J.M.

1988-01-01

Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5'-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable [ 14 C]sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus

Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

Directory of Open Access Journals (Sweden)

Dhindsa G

2004-04-01

Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity.

Directory of Open Access Journals (Sweden)

Pernilla Lång

2008-03-01

Full Text Available Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer.Using mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity.Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

The Na(+) cycle in Acetobacterium woodii: identification and characterization of a Na(+) translocating F(1)F(0)-ATPase with a mixed oligomer of 8 and 16 kDa proteolipids.

Science.gov (United States)

Müller, V; Aufurth, S; Rahlfs, S

2001-05-01

The homoacetogenic bacterium Acetobacterium woodii relies on a sodium ion current across its cytoplasmic membrane for energy-dependent reactions. The sodium ion potential is established by a yet to be identified primary, electrogenic pump connected to the Wood-Ljungdahl pathway. Reactions possibly involved in Na(+) export are discussed. The electrochemical sodium ion potential generated is used to drive endergonic reactions such as flagellar rotation and ATP synthesis. Biochemical and molecular data identified the Na(+)-ATPase of A. woodii as a typical member of the F(1)F(0) class of ATPases. Its catalytic properties and the hypothetical sodium ion binding site in subunit c are discussed. The encoding genes were cloned and, surprisingly, the atp operon was shown to contain multiple copies of genes encoding subunit c. Two copies encode identical 8 kDa proteolipids, and a third copy arose by duplication and subsequent fusion of two genes. Furthermore, the duplicated subunit c does not contain the ion binding site in hair pin two. Biochemical and molecular data revealed that all three copies of subunit c constitute a mixed oligomer. The evolution of the structure and function of subunit c in ATPases from eucarya, bacteria, and archaea is discussed.

Insulin promotes diacylglycerol kinase activation by different mechanisms in rat cerebral cortex synaptosomes.

Science.gov (United States)

Zulian, Sandra E; Ilincheta de Boschero, Mónica G; Giusto, Norma M

2006-10-01

The mechanism by which insulin increases diacylglycerol kinase (DAGK) activity has been studied in cerebral cortex (CC) synaptosomes from adult (3-4 months of age) rats. The purpose of this study was to identify the role of phospholipases C and D (PLC and PLD) in DAGK activation by insulin. Neomycin, an inhibitor of PLC phosphatidylinositol-bisphosphate (PIP2) specific; ethanol, an inhibitor of phosphatidic acid (PA) formation by the promotion of a transphosphatidyl reaction of phosphatidylcholine phospholipase D (PC-PLD); and DL propranolol, an inhibitor of phosphatidate phosphohydrolase (PAP), were used in this study. Insulin (0.1 microM) shielded an increase in PA synthesis by [32P] incorporation using [gamma-32P]ATP as substrate and endogenous diacylglycerol (DAG) as co-substrate. This activated synthesis was strongly inhibited either by ethanol or DL propranolol. Pulse chase experiments also showed a PIP2-PLC activation within 1 min exposure to insulin. When exogenous unsaturated 18:0-20:4 DAG was present, insulin increased PA synthesis significantly. However, this stimulatory effect was not observed in the presence of exogenous saturated (di-16:0). In the presence of R59022, a selective DAGK inhibitor, insulin exerted no stimulatory effect on [32P]PA formation, suggesting a strong relationship between increased PA formation by insulin and DAGK activity. These data indicate that the increased synthesis of PA by insulin could be mediated by the activation of both a PC-PLD pathway to provide DAG and a direct DAGK activation that is associated to the use of 18:0-20:4 DAG species. PIP2-PLC activation may contribute at least partly to the insulin effect on DAGK activity. Copyright 2006 Wiley-Liss, Inc.

Treatment of Type 1 and Type 2 Diabetes Mellitus with Insulin Detemir, a Long-Acting Insulin Analog

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Jason R. Young

2010-01-01

Full Text Available Insulin detemir is a long-acting basal insulin approved for use in patients with type 1 (T1DM or type 2 diabetes (T2DM. Insulin detemir has demonstrated equivalent glycemic control and hypoglycemic risk when compared to insulin glargine, and insulin detemir has generally but not consistently demonstrated less weight gain than insulin glargine in T2DM. The benefits of basal insulin analogs relative to NPH insulin are well recognized, including less FBG variability, lower risk of hypoglycemia, and less weight gain specifically with insulin detemir. However, NPH insulin continues to be widely prescribed, which may be due in part to economic considerations. While NPH insulin generally costs less per prescription, insulin detemir has been shown to be cost effective compared to NPH insulin as well as insulin glargine. Therefore, insulin detemir is an effective option from both clinical and economic perspectives for patients with T1DM or T2DM who require basal insulin to achieve glycemic control.

Immunohistochemical expression of insulin, glucagon, and somatostatin in pancreatic islets of horses with and without insulin resistance.

Science.gov (United States)

Newkirk, Kim M; Ehrensing, Gordon; Odoi, Agricola; Boston, Raymond C; Frank, Nicholas

2018-02-01

OBJECTIVE To assess insulin, glucagon, and somatostatin expression within pancreatic islets of horses with and without insulin resistance. ANIMALS 10 insulin-resistant horses and 13 insulin-sensitive horses. PROCEDURES For each horse, food was withheld for at least 10 hours before a blood sample was collected for determination of serum insulin concentration. Horses with a serum insulin concentration horses with a serum insulin concentration > 20 μU/mL underwent a frequently sampled IV glucose tolerance test to determine sensitivity to insulin by minimal model analysis. Horses with a sensitivity to insulin horses were euthanized with a barbiturate overdose, and pancreatic specimens were harvested and immunohistochemically stained for determination of insulin, glucagon, and somatostatin expression in pancreatic islets. Islet hormone expression was compared between insulin-resistant and insulin-sensitive horses. RESULTS Cells expressing insulin, glucagon, and somatostatin made up approximately 62%, 12%, and 7%, respectively, of pancreatic islet cells in insulin-resistant horses and 64%, 18%, and 9%, respectively, of pancreatic islet cells in insulin-sensitive horses. Expression of insulin and somatostatin did not differ between insulin-resistant and insulin-sensitive horses, but the median percentage of glucagon-expressing cells in the islets of insulin-resistant horses was significantly less than that in insulin-sensitive horses. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, in insulin-resistant horses, insulin secretion was not increased but glucagon production might be downregulated as a compensatory response to hyperinsulinemia.

Chemical stability of insulin. 2. Formation of higher molecular weight transformation products during storage of pharmaceutical preparations.

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Brange, J; Havelund, S; Hougaard, P

1992-06-01

Formation of covalent, higher molecular weight transformation (HMWT) products during storage of insulin preparations at 4-45 degrees C was studied by size exclusion chromatography. The main products are covalent insulin dimers (CID), but in protamine-containing preparations the concurrent formation of covalent insulin-protamine (CIP) products takes place. At temperatures greater than or equal to 25 degrees C parallel or consecutive formation of covalent oligo- and polymers can also be observed. Rate of HMWT is only slightly influenced by species of insulin but varies with composition and formulation, and for isophane (NPH) preparations, also with the strength of preparation. Temperature has a pronounced effect on CID, CIP, and, especially, covalent oligo- and polymer formation. The CIDs are apparently formed between molecules within the hexameric unit common for all types of preparations and rate of formation is generally faster in glycerol-containing preparations. Compared with insulin hydrolysis reactions (see the preceding paper), HMWT is one order of magnitude slower, except for NPH preparations.

Changing the insulin receptor to possess insulin-like growth factor I ligand specificity

International Nuclear Information System (INIS)

Andersen, A.S.; Kjeldsen, T.; Wiberg, F.C.; Christensen, P.M.; Rasmussen, J.S.; Norris, K.; Moeller, K.B.; Moeller, N.P.H.

1990-01-01

To examine the role of the N-terminal part of the insulin-like growth factor I (IGF-I) receptor and insulin receptor in determining ligand specificity, the authors prepared an expression vector encoding a hybrid receptor where exon 1 (encoding the signal peptide and seven amino acids of the α-subunit), exon 2, and exon 3 of the insulin receptor were replaced with the corresponding IGF-I receptor cDNA (938 nucleotides). To allow direct quantitative comparison of the binding capabilities of this hybrid receptor with those of the human IGF-I receptor and the insulin receptor, all three receptors were expressed in baby hamster kidney (BHK) cells as soluble molecules and partially purified before characterization. The hybrid IGF-I/insulin receptor bound IGF-I with an affinity comparable to that of the wild-type IGF-I receptor. In contrast, the hybrid receptor no longer displayed high-affinity binding of insulin. These results directly demonstrate that it is possible to change the specificity of the insulin receptor to that of the IGF-I receptor and, furthermore, that the binding specificity for IGF-I is encoded within the nucleotide sequence from 135 to 938 of the IGF-I receptor cDNA. Since the hybrid receptor only bound insulin with low affinity, the insulin binding region is likely to be located within exons 2 and 3 of the insulin receptor

Insulin and the Lung

DEFF Research Database (Denmark)

Singh, Suchita; Prakash, Y S; Linneberg, Allan

2013-01-01

, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

Comparison of Subcutaneous Regular Insulin and Lispro Insulin in Diabetics Receiving Continuous Nutrition

Science.gov (United States)

Stull, Mamie C.; Strilka, Richard J.; Clemens, Michael S.; Armen, Scott B.

2015-01-01

Background: Optimal management of non–critically ill patients with diabetes maintained on continuous enteral feeding (CEN) is poorly defined. Subcutaneous (SQ) lispro and SQ regular insulin were compared in a simulated type 1 and type 2 diabetic patient receiving CEN. Method: A glucose-insulin feedback mathematical model was employed to simulate type 1 and type 2 diabetic patients on CEN. Each patient received 25 SQ injections of regular insulin or insulin lispro, ranging from 0-6 U. Primary endpoints were the change in mean glucose concentration (MGC) and change in glucose variability (GV); hypoglycemic episodes were also reported. The model was first validated against patient data. Results: Both SQ insulin preparations linearly decreased MGC, however, SQ regular insulin decreased GV whereas SQ lispro tended to increase GV. Hourly glucose concentration measurements were needed to capture the increase in GV. In the type 2 diabetic patient, “rebound hyperglycemia” occurred after SQ lispro was rapidly metabolized. Although neither SQ insulin preparation caused hypoglycemia, SQ lispro significantly lowered MGC compared to SQ regular insulin. Thus, it may be more likely to cause hypoglycemia. Analyses of the detailed glucose concentration versus time data suggest that the inferior performance of lispro resulted from its shorter duration of action. Finally, the effects of both insulin preparations persisted beyond their duration of actions in the type 2 diabetic patient. Conclusions: Subcutaneous regular insulin may be the short-acting insulin preparation of choice for this subset of diabetic patients. Clinical trial is required before a definitive recommendation can be made. PMID:26134836

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

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Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

2017-07-01

Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity.

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Takayama, S; White, M F; Kahn, C R

1988-03-05

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the function of the insulin receptor was examined in intact hepatoma cells (Fao) and in solubilized extracts purified by wheat germ agglutinin chromatography. Incubation of ortho[32P]phosphate-labeled Fao cells with TPA increased the phosphorylation of the insulin receptor 2-fold after 30 min. Analysis of tryptic phosphopeptides from the beta-subunit of the receptor by reverse-phase high performance liquid chromatography and determination of their phosphoamino acid composition suggested that TPA predominantly stimulated phosphorylation of serine residues in a single tryptic peptide. Incubation of the Fao cells with insulin (100 nM) for 1 min stimulated 4-fold the phosphorylation of the beta-subunit of the insulin receptor. Prior treatment of the cells with TPA inhibited the insulin-stimulated tyrosine phosphorylation by 50%. The receptors extracted with Triton X-100 from TPA-treated Fao cells and purified on immobilized wheat germ agglutinin retained the alteration in kinase activity and exhibited a 50% decrease in insulin-stimulated tyrosine autophosphorylation and phosphotransferase activity toward exogenous substrates. This was due primarily to a decrease in the Vmax for these reactions. TPA treatment also decreased the Km of the insulin receptor for ATP. Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. These data suggest that protein kinase C may regulate the function

Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary absorption of encapsulated insulin compared with co-administered insulin.

Science.gov (United States)

Chono, Sumio; Togami, Kohei; Itagaki, Shirou

2017-11-01

We have previously shown that aerosolized liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhance the pulmonary absorption of encapsulated insulin. In this study, we aimed to compare insulin encapsulated into the liposomes versus co-administration of empty liposomes and unencapsulated free insulin, where the DPCC liposomes would serve as absorption enhancer. The present study provides the useful information for development of noninvasive treatment of diabetes. Co-administration of empty DPPC liposomes and unencapsulated free insulin was investigated in vivo to assess the potential enhancement in protein pulmonary absorption. Co-administration was compared to DPPC liposomes encapsulating insulin, and free insulin. DPPC liposomes enhanced the pulmonary absorption of unencapsulated free insulin; however, the enhancing effect was lower than that of the DPPC liposomes encapsulating insulin. The mechanism of the pulmonary absorption of unencapsulated free insulin by DPPC liposomes involved the opening of epithelial cell space in alveolar mucosa, and not mucosal cell damage, similar to that of the DPPC liposomes encapsulating insulin. In an in vitro stability test, insulin in the alveolar mucus layer that covers epithelial cells was stable. These findings suggest that, although unencapsulated free insulin spreads throughout the alveolar mucus layer, the concentration of insulin released near the absorption surface is increased by the encapsulation of insulin into DPPC liposomes and the absorption efficiency is also increased. We revealed that the encapsulation of insulin into DPPC liposomes is more effective for pulmonary insulin absorption than co-administration of DPPC liposomes and unencapsulated free insulin.

Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes.

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Derosa, G; Franzetti, I; Querci, F; Romano, D; D'Angelo, A; Maffioli, P

2015-06-01

To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic

Flexibility in insulin prescription

Directory of Open Access Journals (Sweden)

Sanjay Kalra

2016-01-01

Full Text Available This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage.

Glucose tolerance, insulin release, and insulin binding to monocytes in kidney transplant recipients

International Nuclear Information System (INIS)

Briggs, W.A.; Wielechowski, K.S.; Mahajan, S.K.; Migdal, S.D.; McDonald, F.D.

1982-01-01

In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific 125 I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulin release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific 125 I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity

Generation of insulin-producing human mesenchymal stem cells using recombinant adeno-associated virus.

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Kim, Jeong Hwan; Park, Si-Nae; Suh, Hwal

2007-02-28

The purpose of current experiment is the generation of insulin-producing human mesenchymal stem cells as therapeutic source for the cure of type 1 diabetes. Type 1 diabetes is generally caused by insulin deficiency accompanied by the destruction of islet beta-cells. In various trials for the treatment of type 1 diabetes, cell-based gene therapy using stem cells is considered as one of the most useful candidate for the treatment. In this experiment, human mesenchymal stem cells were transduced with AAV which is containing furin-cleavable human preproinsulin gene to generate insulin-producing cells as surrogate beta-cells for the type 1 diabetes therapy. In the rAAV production procedure, rAAV was generated by transfection of AD293 cells. Human mesenchymal stems cells were transduced using rAAV with a various multiplicity of infection. Transduction of recombinant AAV was also tested using beta-galactosidse expression. Cell viability was determined by using MTT assay to evaluate the toxicity of the transduction procedure. Expression and production of Insulin were tested using reverse transcriptase-polymerase chain reaction and immunocytochemistry. Secretion of human insulin and C-peptide from the cells was assayed using enzyme-linked immunosorbent assay. Production of insulin and C-peptide from the test group represented a higher increase compared to the control group. In this study, we examined generation of insulin-producing cells from mesenchymal stem cells by genetic engineering for diabetes therapy. This work might be valuable to the field of tissue engineering for diabetes treatment.

Kinetic properties of two Rhizopus exo-polygalacturonase enzymes hydrolyzing galacturonic acid oligomers using isothermal titration calorimetry

Science.gov (United States)

The kinetic characteristics of two Rhizopus oryzae exo-polygalacturonases acting on galacturonic acid oligomers (GalpA) were determined using isothermal titration calorimetry (ITC). RPG15 hydrolyzing (GalpA)2 demonstrated a Km of 55 uM and kcat of 10.3 s^-1^ while RPG16 was shown to have greater af...

Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

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Catalano, Karyn J.; Maddux, Betty A.; Szary, Jaroslaw; Youngren, Jack F.; Goldfine, Ira D.; Schaufele, Fred

2014-01-01

Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered ‘insulin refractory’ IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based ‘memory’ of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states. PMID:25259572

Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain.

Directory of Open Access Journals (Sweden)

Karyn J Catalano

Full Text Available Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered 'insulin refractory' IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based 'memory' of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

Science.gov (United States)

Aye, Myint M; Atkin, Stephen L

2014-01-01

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long

Insulin, cognition, and dementia

Science.gov (United States)

Cholerton, Brenna; Baker, Laura D.; Craft, Suzanne

2015-01-01

Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer’s disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer’s disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer’s disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain’s insulin sensitivity. PMID:24070815

Insulin and the brain.

Science.gov (United States)

Derakhshan, Fatemeh; Toth, Cory

2013-03-01

Mainly known for its role in peripheral glucose homeostasis, insulin has also significant impact within the brain, functioning as a key neuromodulator in behavioral, cellular, biochemical and molecular studies. The brain is now regarded as an insulin-sensitive organ with widespread, yet selective, expression of the insulin receptor in the olfactory bulb, hypothalamus, hippocampus, cerebellum, amygdala and cerebral cortex. Insulin receptor signaling in the brain is important for neuronal development, glucoregulation, feeding behavior, body weight, and cognitive processes such as with attention, executive functioning, learning and memory. Emerging evidence has demonstrated insulin receptor signaling to be impaired in several neurological disorders. Moreover, insulin receptor signaling is recognized as important for dendritic outgrowth, neuronal survival, circuit development, synaptic plasticity and postsynaptic neurotransmitter receptor trafficking. We review the multiple roles of insulin in the brain, as well as its endogenous trafficking to the brain or its exogenous intervention. Although insulin can be directly targeted to the brain via intracerebroventricular (ICV) or intraparenchymal delivery, these invasive techniques are with significant risk, necessitating repeated surgical intervention and providing potential for systemic hypoglycemia. Another method, intranasal delivery, is a non-invasive, safe, and alternative approach which rapidly targets delivery of molecules to the brain while minimizing systemic exposure. Over the last decades, the delivery of intranasal insulin in animal models and human patients has evolved and expanded, permitting new hope for associated neurodegenerative and neurovascular disorders.

The increase of plasma galectin-9 in a patient with insulin allergy: a case report

Directory of Open Access Journals (Sweden)

Chagan-Yasutan Haorile

2010-08-01

Full Text Available Abstract Allergic reaction to insulin is known to be associated with eosinophilia and hyper IgE. Recent report showed that eosinophilia is related with the increased synthesis of galectin-9 (GAL-9 and osteopontin (OPN. Here, we examined plasma levels of GAL-9 and OPN first time in a case of 65-year old patient with insulin allergy. Insulin aspart & insulin aspart 30 mix were given to the patient and an elevation of the eosinophil count (8440/μl, 17.6 fold and a moderate increase of IgE (501 U/ml, reference range: 10-350 U/ml, eotaxin-3 (168 pg/ml, 2 fold, histamine (0.95 ng/ml, 5.3 fold were found 33 days later. The plasma levels of GAL-9 and OPN were 22.5 and 1.7 fold higher than the cut-off point, respectively. After one month cessation of insulin therapy, elevations of the eosinophil count (3,480/μl; 7.3 fold, and OPN (1.4 fold still occurred but the GAL-9 levels became normal. Therefore, we noted the increases of GAL-9 and OPN in plasma for the first time in a patient with insulin allergy and propose that GAL-9 reflects the conditions of allergy more accurately.

Insulin sensitivity and insulin secretion at birth in intrauterine growth retarded infants.

Science.gov (United States)

Setia, Sajita; Sridhar, M G; Bhat, Vishnu; Chaturvedula, Lata; Vinayagamoorti, R; John, Mathew

2006-06-01

To study insulin sensitivity, secretion and relation of insulin levels with birth weight and ponderal index in intrauterine growth retarded (IUGR) infants at birth. We studied 30 IUGR and 30 healthy newborns born at term by vaginal delivery in Jipmer, Pondicherry, India. Cord blood was collected at the time of delivery for measurement of plasma glucose and insulin. When compared with healthy newborns, IUGR newborns had lower plasma glucose levels (mean 2.3+/-0.98 versus 4.1+/-0.51 mmol/L, p<0.001); lower plasma insulin levels (mean 4.5+/-2.64 versus 11.03+/-1.68 microU/L, p<0.001); higher insulin sensitivity calculated using G/I ratio (mean 11.6+/-5.1 versus 6.7+/-0.31, p<0.001), HOMA IS (mean 5.5+/-6.0 versus 0.53+/-0.15, p<0.001), and QUICKI (mean 0.47+/-0.12 versus 0.34+/-0.02, p<0.001); and decreased pancreatic beta-cell function test measured as I/G (mean 0.10+/-0.037 versus 0.15+/-0.006, p<0.001). A positive correlation was identified between insulin levels and birth weight in both the healthy control group (r2 = 0.17, p = 0.024) and IUGR group (r2 = 0.13, p = 0.048). However correlation of insulin levels with ponderal index was much more confident in both healthy control (r2 = 0.90, p<0.001) and IUGR groups (r2 = 0.28, p = 0.003). Insulin status correlated both with birth weight and ponderal index more confidently in control group than in IUGR group. At birth, IUGR infants are hypoglycaemic, hypoinsulinaemic and display increased insulin sensitivity and decreased pancreatic beta-cell function. Insulin levels correlate with ponderal index much more confidently than with birth weight.

Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion.

Science.gov (United States)

Hung, C T; Beyer, J; Schulz, G

1986-07-01

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.

Insulin sensitivity and albuminuria

DEFF Research Database (Denmark)

Pilz, Stefan; Rutters, Femke; Nijpels, Giel

2014-01-01

OBJECTIVE: Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases. We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN...... AND METHODS: We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 ± 8.3 years; 54.3% women) from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity...... was assessed by hyperinsulinemic-euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS...

Effect of side chain length and degree of polymerization on the decomposition and crystallization behaviour of chlorinated poly(vinyl ester) oligomers

International Nuclear Information System (INIS)

Heinze, D.; Mang, Th.; Popescu, C.; Weichold, O.

2016-01-01

Highlights: • Thermal behaviour of telomerized polyvinyl esters is investigated. • Thermal stability relies mainly on the contribution of side chains. • At equal molecular weights thermal stability is dictated by length of side chain. • Increasing the length of side chains improves also the packing degree of polymer. - Abstract: Four members of a homologous series of chlorinated poly(vinyl ester) oligomers CCl_3–(CH_2CH (OCO(CH_2)_mCH_3))_n–Cl with degrees of polymerization of 10 and 20 were prepared by telomerisation using carbon tetrachloride. The number of side chain carbon atoms ranges from 2 (poly(vinyl acetate) to 18 (poly(vinyl stearate)). The effect of the n-alkyl side chain length and of the degree of polymerization on the thermal stability and crystallization behaviour of the synthesized compounds was investigated. All oligomers degrade in two major steps by first losing HCl and side chains with subsequent breakdown of the backbone. The members with short side chains, up to poly(vinyl octanoate), are amorphous and show internal plasticization, whereas those with high number of side chain carbon atoms are semi-crystalline due to side-chain crystallization. A better packing for poly(vinyl stearate) is also noticeable. The glass transition and melting temperatures as well as the onset temperature of decomposition are influenced to a larger extent by the side chain length than by the degree of polymerization. Thermal stability is improved if both the size and number of side chains increase, but only a long side chain causes a significant increase of the resistance to degradation. This results in a stabilization of PVAc so that oligomers from poly(vinyl octanoate) on are stable under atmospheric conditions. Thus, the way to design stable, chlorinated PVEs oligomers is to use a long n-alkyl side chain.

Effect of side chain length and degree of polymerization on the decomposition and crystallization behaviour of chlorinated poly(vinyl ester) oligomers

Energy Technology Data Exchange (ETDEWEB)

Heinze, D.; Mang, Th. [Aachen University of Applied Sciences, Heinrich-Mussmann-Str. 1, 52428 Jülich (Germany); Popescu, C., E-mail: crisan.popescu@kao.com [KAO Germany GmbH, Pfungstädterstr. 98-100, 64297 Darmstadt (Germany); Weichold, O., E-mail: weichold@ibac.rwth-aachen.de [Institute of Building Materials Research, Schinkelstr. 3, 52062 Aachen (Germany)

2016-08-10

Highlights: • Thermal behaviour of telomerized polyvinyl esters is investigated. • Thermal stability relies mainly on the contribution of side chains. • At equal molecular weights thermal stability is dictated by length of side chain. • Increasing the length of side chains improves also the packing degree of polymer. - Abstract: Four members of a homologous series of chlorinated poly(vinyl ester) oligomers CCl{sub 3}–(CH{sub 2}CH (OCO(CH{sub 2}){sub m}CH{sub 3})){sub n}–Cl with degrees of polymerization of 10 and 20 were prepared by telomerisation using carbon tetrachloride. The number of side chain carbon atoms ranges from 2 (poly(vinyl acetate) to 18 (poly(vinyl stearate)). The effect of the n-alkyl side chain length and of the degree of polymerization on the thermal stability and crystallization behaviour of the synthesized compounds was investigated. All oligomers degrade in two major steps by first losing HCl and side chains with subsequent breakdown of the backbone. The members with short side chains, up to poly(vinyl octanoate), are amorphous and show internal plasticization, whereas those with high number of side chain carbon atoms are semi-crystalline due to side-chain crystallization. A better packing for poly(vinyl stearate) is also noticeable. The glass transition and melting temperatures as well as the onset temperature of decomposition are influenced to a larger extent by the side chain length than by the degree of polymerization. Thermal stability is improved if both the size and number of side chains increase, but only a long side chain causes a significant increase of the resistance to degradation. This results in a stabilization of PVAc so that oligomers from poly(vinyl octanoate) on are stable under atmospheric conditions. Thus, the way to design stable, chlorinated PVEs oligomers is to use a long n-alkyl side chain.

Insulin Resistance and Mitochondrial Dysfunction.

Science.gov (United States)

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Eckmaxol, a Phlorotannin Extracted from Ecklonia maxima, Produces Anti-β-amyloid Oligomer Neuroprotective Effects Possibly via Directly Acting on Glycogen Synthase Kinase 3β.

Science.gov (United States)

Wang, Jialing; Zheng, Jiachen; Huang, Chunhui; Zhao, Jiaying; Lin, Jiajia; Zhou, Xuezhen; Naman, C Benjamin; Wang, Ning; Gerwick, William H; Wang, Qinwen; Yan, Xiaojun; Cui, Wei; He, Shan

2018-04-10

Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble β-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, could produce neuroprotective effects in SH-SY5Y cells. Eckmaxol effectively prevented but did not rescue β-amyloid oligomer-induced neuronal apoptosis and increase of intracellular reactive oxygen species. Eckmaxol also significantly reversed the decreased expression of phospho-Ser9-glycogen synthase kinase 3β and increased expression of phospho-extracellular signal-regulated kinase, which was induced by Aβ oligomer. Moreover, both glycogen synthase kinase 3β and mitogen activated protein kinase inhibitors produced neuroprotective effects in SH-SY5Y cells. Furthermore, eckmaxol showed favorable interaction in the ATP binding site of glycogen synthase kinase 3β and mitogen activated protein kinase. These results suggested that eckmaxol might produce neuroprotective effects via concurrent inhibition of glycogen synthase kinase 3β and extracellular signal-regulated kinase pathways, possibly via directly acting on glycogen synthase kinase 3β and mitogen activated protein kinase. Based on the central role that β-amyloid oligomers play in the pathogenesis of Alzheimer's disease and the high annual production of Ecklonia maxima for alginate and other nutritional ingredients, this report represents a new candidate for the treatment of Alzheimer's disease, and also expands the potential application of Ecklonia maxima and its constituents in the field of pharmacology.

Selective Insulin Resistance in Adipocytes*

Science.gov (United States)

Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

2015-01-01

Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

Insulin resistance: definition and consequences.

Science.gov (United States)

Lebovitz, H E

2001-01-01

Insulin resistance is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin action is the consequence of insulin binding to its plasma membrane receptor and is transmitted through the cell by a series of protein-protein interactions. Two major cascades of protein-protein interactions mediate intracellular insulin action: one pathway is involved in regulating intermediary metabolism and the other plays a role in controlling growth processes and mitoses. The regulation of these two distinct pathways can be dissociated. Indeed, some data suggest that the pathway regulating intermediary metabolism is diminished in type 2 diabetes while that regulating growth processes and mitoses is normal.--Several mechanisms have been proposed as possible causes underlying the development of insulin resistance and the insulin resistance syndrome. These include: (1) genetic abnormalities of one or more proteins of the insulin action cascade (2) fetal malnutrition (3) increases in visceral adiposity. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome". This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance.--In this context, we need to consider whether insulin resistance should be defined as a disease entity which needs to be diagnosed and treated with specific drugs to improve insulin action.

Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients.

Science.gov (United States)

Janukonyté, Jurgita; Parkner, Tina; Bruun, Niels Henrik; Lauritzen, Torsten; Christiansen, Jens Sandahl; Laursen, Torben

2015-05-01

Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s-IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present.

Studies on interaction of insulin and insulin receptor in rat liver cell membranes

Energy Technology Data Exchange (ETDEWEB)

Sakai, Y; Hara, H; Kawate, R; Kawasaki, T [Hiroshima Univ. (Japan). School of Medicine

1975-07-01

Rat liver was homogenized with a Polytron PT 20 ST and fractionated by differential centrifugation. Prepared plasma membranes (100 ..mu..g protein) were incubated with enzymatically iodinated /sup 125/I-insulin (0.3 ng, specific activity 107 ..mu..Ci/..mu..g) in 25 mM Tris-HCl buffer, pH 7.5, containing 0.9% NaCl and 1% bovine serum albumin. The 12,000xg- and 17,000xg-sediments obtained after subfractionation of liver homogenates showed almost equally high specific binding activity with /sup 125/I-insulin and less activity was detected in the 600 g-, 5,000 g- and 40,000 g- sediments and the 40,000 g- supernatant. Specific binding of insulin with the membrane fraction was time-, temperature- and ionic strength-dependent. The highest binding was obtained under conditions in which the membrane fraction was incubated with insulin for 24 hours at 4/sup 0/C in the buffer containing 1 M NaCl. Under these conditions, specific binding of /sup 125/I-insulin was 26.8% of the total radioactivity. The effect of native insulin on the binding of /sup 125/I-insulin with the membrane fraction was studied in the range of 0--6.4 x 10/sup 5/ ..mu..U/ml of unlabeled insulin and a distinct competitive displacement of /sup 125/I-insulin with native insulin was observed between 10 and 10/sup 4/ ..mu..U/ml. Kinetic studies by Scatchard plot analysis of the above results revealed heterogeneity in insulin receptors or receptor sites, one with a high affinity of 10/sup 9/ M/sup -1/ order and the other with a low affinity of 10/sup 8/ M/sup -1/ order. Both affinities were also affected by temperature and ionic strength.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Casablanca cohort of the A 1 chieve study

Directory of Open Access Journals (Sweden)

Ahmed Farouqi

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Casablanca, Morocco. Results: A total of 495 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231, insulin detemir (n = 151, insulin aspart (n = 19, basal insulin plus insulin aspart (n = 53 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.2% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.3%, insulin users: −1.8%. Major hypoglycaemia was observed in the insulin naïve group after 24 weeks. SADRs were reported in 1.2% of insulin naïve and 2.1% of insulin user groups. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Identification of chlorinated oligomers formed during anodic oxidation of phenol in the presence of chloride

International Nuclear Information System (INIS)

Chen, Linxi; Campo, Pablo; Kupferle, Margaret J.

2015-01-01

Graphical abstract: - Highlights: • By-products from anodic oxidation of phenol in the presence of chloride are investigated. • Chlorinated oligomer formation is demonstrated by LC-QTOF-MS. • They have structures similar to triclosan and polychlorinated dibenzo-p-dioxins. - Abstract: Chlorinated oligomer intermediates formed during the anodic electrochemical oxidation of phenol with a boron-doped diamond electrode were studied at two different concentrations of chloride (5 mM and 50 mM). Under the same ionic strength, with sodium sulfate being the make-up ion, a 10-fold increase in Cl − led to removal rates 10.8, 1.5, and 1.4 times higher for phenol, TOC, and COD, respectively. Mono-, di- and trichlorophenols resulting from electrophilic substitution were the identified by-products. Nevertheless, discrepancies between theoretical and measured TOC values along with gaps in the mass balance of chlorine-containing species indicated the formation of unaccounted-for chlorinated by-products. Accurate mass measurements by liquid chromatography quadrupole time-of-flight mass spectrometry and MS-MS fragmentation spectra showed that additional compounds formed were dimers and trimers of phenol with structures similar to triclosan and polychlorinated dibenzo-p-dioxins

Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse.

Science.gov (United States)

Fletcher, Sue; Honeyman, Kaite; Fall, Abbie M; Harding, Penny L; Johnsen, Russell D; Steinhaus, Joshua P; Moulton, Hong M; Iversen, Patrick L; Wilton, Stephen D

2007-09-01

Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterized by an absence of functional protein, whereas Becker muscular dystrophy, commonly caused by in-frame deletions, shows synthesis of partially functional protein. Anti-sense oligonucleotides can induce specific exon removal during processing of the dystrophin primary transcript, while maintaining or restoring the reading frame, and thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation in exon 23 of the dystrophin gene that precludes functional dystrophin production, and this model has been used in the development of treatment strategies for dystrophinopathies. A phosphorodiamidate morpholino oligomer (PMO) has previously been shown to exclude exon 23 from the dystrophin gene transcript and induce dystrophin expression in the mdxmouse, in vivo and in vitro. In this report, a cell-penetrating peptide (CPP)-conjugated oligomer targeted to the mouse dystrophin exon 23 donor splice site was administered to mdxmice by intraperitoneal injection. We demonstrate dystrophin expression and near-normal muscle architecture in all muscles examined, except for cardiac muscle. The CPP greatly enhanced uptake of the PMO, resulting in widespread dystrophin expression.

Identification of chlorinated oligomers formed during anodic oxidation of phenol in the presence of chloride

Energy Technology Data Exchange (ETDEWEB)

Chen, Linxi; Campo, Pablo; Kupferle, Margaret J., E-mail: margaret.kupferle@uc.edu

2015-02-11

Graphical abstract: - Highlights: • By-products from anodic oxidation of phenol in the presence of chloride are investigated. • Chlorinated oligomer formation is demonstrated by LC-QTOF-MS. • They have structures similar to triclosan and polychlorinated dibenzo-p-dioxins. - Abstract: Chlorinated oligomer intermediates formed during the anodic electrochemical oxidation of phenol with a boron-doped diamond electrode were studied at two different concentrations of chloride (5 mM and 50 mM). Under the same ionic strength, with sodium sulfate being the make-up ion, a 10-fold increase in Cl{sup −} led to removal rates 10.8, 1.5, and 1.4 times higher for phenol, TOC, and COD, respectively. Mono-, di- and trichlorophenols resulting from electrophilic substitution were the identified by-products. Nevertheless, discrepancies between theoretical and measured TOC values along with gaps in the mass balance of chlorine-containing species indicated the formation of unaccounted-for chlorinated by-products. Accurate mass measurements by liquid chromatography quadrupole time-of-flight mass spectrometry and MS-MS fragmentation spectra showed that additional compounds formed were dimers and trimers of phenol with structures similar to triclosan and polychlorinated dibenzo-p-dioxins.

Insulin Resistance in Alzheimer's Disease

Science.gov (United States)

Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

2014-01-01

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact

DEFF Research Database (Denmark)

Mulder, Hindrik; Sörhede-Winzell, Maria; Contreras, Juan Antonio

2003-01-01

of increased amounts of insulin. Impaired insulin sensitivity was further indicated by retarded glucose disposal during an insulin tolerance test. A euglycemic hyperinsulinemic clamp revealed that hepatic glucose production was insufficiently blocked by insulin in HSL null mice. In vitro, insulin......-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance....... Insulin secretion in vitro, examined by perifusion of isolated islets, was not impacted by HSL deficiency. Thus, HSL deficiency results in a moderate impairment of insulin sensitivity in multiple target tissues of the hormone but is compensated by hyperinsulinemia....

Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

NARCIS (Netherlands)

Bot, M.; Pouwer, F.; de Jonge, P.; Nolan, J.J.; Mari, A.; Højlund, K.; Golay, A.; Balkau, B.; Dekker, J.M.

2013-01-01

Aim This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. Methods The study population was derived from the 3-year follow-up of the Relationship between Insulin Sensitivity

Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

NARCIS (Netherlands)

Bot, M.; Pouwer, F.; De Jonge, P.; Nolan, J. J.; Mari, A.; Hojlund, K.; Golay, A.; Balkau, B.; Dekker, J. M.

Aim. This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. Methods. The study population was derived from the 3-year follow-up of the Relationship between Insulin Sensitivity

Diabetes, insulin and exercise

DEFF Research Database (Denmark)

Richter, Erik; Galbo, H

1986-01-01

The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained...... by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so......-called counter-regulatory hormones tend to increase plasma glucose by increasing hepatic glucose production and adipose tissue lipolysis. If the pre-exercise plasma insulin level is high, hypoglycaemia may develop during exercise whereas hyperglycaemia and ketosis may develop if pre-exercise plasma insulin...

[News and perspectives in insulin treatment].

Science.gov (United States)

Haluzík, Martin

2014-09-01

Insulin therapy is a therapeutic cornerstone in patients with type 1 diabetes and also in numerous patients with type 2 diabetes especially with longer history of diabetes. The initiation of insulin therapy in type 2 diabetes patients is often delayed which is at least partially due to suboptimal pharmacokinetic characteristics of available insulins. The development of novel insulins with more favorable characteristics than those of current insulins is therefore still ongoing. The aim of this paper is to review current knowledge of novel insulins that have been recently introduced to the market or are getting close to routine clinical use. We will also focus on the perspectives of insulin therapy in the long-term run including the alternative routes of insulin administration beyond its classical subcutaneous injection treatment.Key words: alternative routes of insulin administration - diabetes mellitus - hypoglycemia - insulin - insulin analogues.

[Continuous insulin therapy versus multiple insulin injections in the management of type 1 diabetes: a longitutinal study].

Science.gov (United States)

Ribeiro, Maria Estela Bellini; Del Roio Liberatore Junior, Raphael; Custodio, Rodrigo; Martinelli Junior, Carlos Eduardo

2016-01-01

To compare multiple doses of insulin and continuous insulin infusion therapy as treatment for type 1 diabetes melito. 40 patients with type 1 diabetes melito (21 female) with ages between 10 and 20 years (mean=14.2) and mean duration of diabetes of 7 years used multiple doses of insulin for at least 6 months and after that, continuous insulin infusion therapy for at least 6 months. Each one of the patients has used multiple doses of insulin and continuous insulin infusion therapy. For analysis of HbA1c, mean glycated hemoglobin levels (mHbA1c) were obtained during each treatment period (multiple doses of insulin and continuous insulin infusion therapy period). Although mHbA1c levels were lower during continuous insulin infusion therapy the difference was not statistically significant. During multiple doses of insulin, 14.2% had mHbA1c values below 7.5% vs. 35.71% while on continuous insulin infusion therapy; demonstrating better glycemic control with the use of continuous insulin infusion therapy. During multiple doses of insulin, 15-40 patients have severe hypoglycemic events versus 5-40 continuous insulin infusion therapy. No episodes of ketoacidosis events were recorded. This is the first study with this design comparing multiple doses of insulin and continuous insulin infusion therapy in Brazil showing no significant difference in HbA1c; hypoglycemic events were less frequent during continuous insulin infusion therapy than during multiple doses of insulin and the percentage of patients who achieved a HbA1c less than 7.5% was greater during continuous insulin infusion therapy than multiple doses of insulin therapy. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

Pitfalls of Insulin Pump Clocks

Science.gov (United States)

Reed, Amy J.

2014-01-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

Reaction of Acetaldehyde with Wine Flavonoids in the Presence of Sulfur Dioxide.

Science.gov (United States)

Sheridan, Marlena K; Elias, Ryan J

2016-11-16

Acetaldehyde is responsible for many of the beneficial changes that occur in red wine as a result of oxidation. Ethylidene bridges are formed between flavonoids upon their reaction with acetaldehyde, which can contribute to improvements in color stability and SO 2 -resistant pigments. In the present study, the reactions between acetaldehyde and various flavonoids (catechin, tannins from grape seed extract, and malvidin-3-glucoside) were examined in a model wine system. Lower pH conditions were seen to significantly increase the rate of reaction with acetaldehyde, whereas dissolved oxygen did not affect the rate. In systems containing SO 2 , the rate of reaction of acetaldehyde with catechin was slowed but was not prevented until SO 2 was in great excess. Significant improvements in color stability were also observed after treatment with acetaldehyde, despite the presence of equimolar SO 2 . These results demonstrate that acetaldehyde is reactive in its sulfonate form, which is contrary to widely held assumptions. In addition, the products of the reaction of flavonoids with acetaldehyde were characterized using MALDI-TOF MS in this study. Ethyl-bridged catechin nonamers were observed, as well as anthocyanin and pyranoanthocyanin derivatives of catechin and tannin oligomers. The results of this work illustrate the significance of acetaldehyde reactions in forming stable pigments in wine and the reactivity of acetaldehyde from its sulfonate form.

Cyclodextrin-insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery.

Science.gov (United States)

Sajeesh, S; Sharma, Chandra P

2006-11-15

Present investigation was aimed at developing an oral insulin delivery system based on hydroxypropyl beta cyclodextrin-insulin (HPbetaCD-I) complex encapsulated polymethacrylic acid-chitosan-polyether (polyethylene glycol-polypropylene glycol copolymer) (PMCP) nanoparticles. Nanoparticles were prepared by the free radical polymerization of methacrylic acid in presence of chitosan and polyether in a solvent/surfactant free medium. Dynamic light scattering (DLS) experiment was conducted with particles dispersed in phosphate buffer (pH 7.4) and size distribution curve was observed in the range of 500-800 nm. HPbetaCD was used to prepare non-covalent inclusion complex with insulin and complex was analyzed by Fourier transform infrared (FTIR) and fluorescence spectroscopic studies. HPbetaCD complexed insulin was encapsulated into PMCP nanoparticles by diffusion filling method and their in vitro release profile was evaluated at acidic/alkaline pH. PMCP nanoparticles displayed good insulin encapsulation efficiency and release profile was largely dependent on the pH of the medium. Enzyme linked immunosorbent assay (ELISA) study demonstrated that insulin encapsulated inside the particles was biologically active. Trypsin inhibitory effect of PMCP nanoparticles was evaluated using N-alpha-benzoyl-L-arginine ethyl ester (BAEE) and casein as substrates. Mucoadhesive studies of PMCP nanoparticles were conducted using freshly excised rat intestinal mucosa and the particles were found fairly adhesive. From the preliminary studies, cyclodextrin complexed insulin encapsulated mucoadhesive nanoparticles appear to be a good candidate for oral insulin delivery.

Antisense Phosphorodiamidate Morpholino Oligomers as Novel Antiviral Compounds

Directory of Open Access Journals (Sweden)

Yuchen Nan

2018-04-01

Full Text Available Phosphorodiamidate morpholino oligomers (PMO are short single-stranded DNA analogs that are built upon a backbone of morpholine rings connected by phosphorodiamidate linkages. As uncharged nucleic acid analogs, PMO bind to complementary sequences of target mRNA by Watson–Crick base pairing to block protein translation through steric blockade. PMO interference of viral protein translation operates independently of RNase H. Meanwhile, PMO are resistant to a variety of enzymes present in biologic fluids, a characteristic that makes them highly suitable for in vivo applications. Notably, PMO-based therapy for Duchenne muscular dystrophy (DMD has been approved by the United States Food and Drug Administration which is now a hallmark for PMO-based antisense therapy. In this review, the development history of PMO, delivery methods for improving cellular uptake of neutrally charged PMO molecules, past studies of PMO antagonism against RNA and DNA viruses, PMO target selection, and remaining questions of PMO antiviral strategies are discussed in detail and new insights are provided.

TLR4 and Insulin Resistance

Directory of Open Access Journals (Sweden)

Jane J. Kim

2010-01-01

Full Text Available Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4, involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide and endogenous ligands (e.g., free fatty acids which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Mumbai cohort of the A1chieve study.

Science.gov (United States)

Talwalkar, P G; Gupta, Vishal; Kovil, Rajiv

2013-11-01

The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Mumbai, India. A total of 2112 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1561), insulin detemir (n = 313), insulin aspart (n = 144), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.7%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: -1.4%, insulin users: -1.8%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Sodium retention and insulin treatment in insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Nørgaard, K; Feldt-Rasmussen, B

1994-01-01

subcutaneously, contributes to the increased ENa. Three studies were performed. Study 1 was a cross-sectional study comprising 28 type 1 diabetic men (aged 18-35 years) with short-duration diabetes (diabetic complications, and 22 control subjects. Study 2 was a prospective study of 17...... subcutaneous insulin infusion for improvement of glycaemic control or to remain on conventional insulin treatment. In study 1, ENa was higher in short-duration type 1 diabetic men than in controls (3003 +/- 325 vs 2849 +/- 207 mEq/1.73 m2, P ...The hypothesis that total body exchangeable sodium (ENa) is elevated in type 1 (insulin-dependent) diabetic patients with short-duration diabetes and no signs of microangiopathy was tested. Also tested was whether peripheral hyperinsulinaemia, in terms of the amounts of insulin injected...

The interaction of insulin, glucose, and insulin-glucose mixtures with a phospholipid monolayer.

Science.gov (United States)

Shigenobu, Hayato; McNamee, Cathy E

2012-12-15

We determined how glucose or insulin interacts with a phospholipid monolayer at the air/water interface and explained these mechanisms from a physico-chemical point of view. The 1,2-dipalmitoyl-2-sn-glycero-3-phosphatidylcholine (DPPC) monolayer at an air/water interface acted as a model membrane, which allowed the effect of the molecular packing density in the monolayer on the interactions to be determined. The interaction of glucose, insulin, and a mixture of glucose and insulin to the DPPC monolayer were investigated via surface pressure-area per molecule Langmuir isotherms and fluorescence microscopy. Glucose adsorbed to the underside of the DPPC monolayer, while insulin was able to penetrate through the monolayer when the phospholipid molecules were not densely packed. The presence of a mixture of insulin and glucose affected the molecular packing in the DPPC monolayer differently than the pure insulin or glucose solutions, and the glucose-insulin mixture was seen to be able to penetrate through the monolayer. These results indicated that glucose and insulin interact with one another, giving a material that may then transported through a pore in the monolayer or through the spaces between the molecules of the monolayer. Copyright © 2012 Elsevier Inc. All rights reserved.

Insulin resistance and chronic inflammation

Directory of Open Access Journals (Sweden)

Natalia Matulewicz

2016-12-01

Full Text Available Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFκB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low-grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance.

Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal.

Directory of Open Access Journals (Sweden)

Mimi Z Chen

Full Text Available Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB, and compared this to lean volunteers.The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2 patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2. Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50 and maximal (GDR100 GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001. Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004 but not GDR100 (P=0.3. These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001. Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA, and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA, and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively.Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.

Glycosphingolipids and insulin resistance

NARCIS (Netherlands)

Langeveld, Mirjam; Aerts, Johannes M. F. G.

2009-01-01

Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple

Insulin receptors in the mammary gland

International Nuclear Information System (INIS)

Smith, D.H.

1986-01-01

Insulin binding studies were conducted using mammary membrane preparations to further the authors understanding of insulin's role in regulating mammary metabolism, particularly ruminant mammary metabolism. Specific objectives were to: (1) characterize insulin binding to bovine mammary microsomes and determine if the specificity and kinetics of binding indicate the presence of insulin receptors in bovine mammary gland; (2) examine and compare insulin binding by liver and mammary microsomes of the pig and dairy cow; (3) examine insulin binding to bovine milk fat globule membranes (MFGM) and evaluate this model's usefulness in assessing insulin receptor regulation in the mammary gland of the cow; (4) examine the effect of dietary fat in insulin binding by rat mammary and liver microsomes. The specificity and kinetics of 125 I-insulin binding of bovine mammary microsomes indicated the presence of insulin receptors in bovine mammary gland. Bovine liver and mammary microsomes specifically bound less 125 I-insulin than did the corresponding porcine microsomes, and mammary microsomes, regardless of species, specifically bound less 125 I-insulin than did liver microsomes. These differences in binding suggest differences in insulin responsiveness between pigs and cattle, as well as between the liver and mammary glands

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation

OpenAIRE