bluuebunny/crossref_metadata_2025 huggingface dataset:
Layer Manufacturing for in Vivo Devices
Authors: Savalani M M , Harris R A
Published: June 2006

Traditional in vivo devices fabricated to be used as implantation devices included sutures, plates, pins, screws, and joint replacement implants. Also, akin to developments in regenerative medicine and drug delivery, there has been the pursuit of less conventional in vivo devices that demand complex architecture and composition, such as tissue scaffolds. Commercial means of fabricating traditional devices include machining and moulding processes. Such manufacturing techniques impose considerable lead times and geometrical limitations, and restrict the economic production of customized products. Attempts at the production of non-conventional devices have included particulate leaching, solvent casting, and phase transition. These techniques cannot provide the desired total control over internal architecture and compositional variation, which subsequently restricts the application of these products. Consequently, several parties are investigating the use of freeform layer manufacturing techniques to overcome these difficulties and provide viable in vivo devices of greater functionality. This paper identifies the concepts of rapid manufacturing (RM) and the development of biomanufacturing based on layer manufacturing techniques. Particular emphasis is placed on the development and experimentation of new materials for bio-RM, production techniques based on the layer manufacturing concept, and computer modelling of in vivo devices for RM techniques.
Analysis of Combustion in a Small Homogeneous Charge Compression Assisted Ignition Engine
Authors: Ma H , Kar K , Stone R , Raine R , Thorwarth H
Published: June 2006

Combustion analysis has been conducted on a small two-stroke glow ignition engine, which has similar combustion characteristics to homogeneous charge compression ignition (HCCI) engines. Difficulties such as unknown ignition timing and the polytropic index have been addressed by combining both heat release and mass fraction burn analyses. Results for all operating conditions have shown good correlations between the two methods.

The engine has been fuelled with a mixture of methanol, nitromethane, and lubrication oil. The effect of nitromethane on combustion is difficult to determine, since altering nitromethane content also changes the air-fuel ratio under the current experiment set-up. However, it is still possible to show that nitromethane shortens the combustion periods beyond the uncertainty created by the mixture strength and cycle-by-cycle variations. The results further show that a faster combustion does not necessarily give a higher indicative mean effective pressure (i.m.e.p.) in this engine. This is because the start of combustion can shift away from its optimum value when nitromethane is added. The initial combustion period is found to be between 10 and 30° CA (crank angle); the main combustion period is between 25 and 50° CA. These combustion periods are comparable to a traditional spark ignition engine. In a very rich mixture, the ‘hot’ glow plug has been found to change significantly the combustion characteristics. Further study would be recommended to elucidate the effect of glow plugs. Lastly, in the case of poor combustion, cycle-by-cycle analysis shows that a misfire or partial burn cycles are always followed by high i.m.e.p. and fast burn cycles.
Spray Characteristics of a Multi-hole Injector for Direct-Injection Gasoline Engines
Authors: Mitroglou N , Nouri J M , Gavaises M , Arcoumanis C
Published: June 2006

The sprays from a high-pressure multi-hole nozzle injected into a constant-volume chamber have been visualized and quantified in terms of droplet velocity and diameter with a two-component phase Doppler anemometry (PDA) system at injection pressures up to 200 bar and chamber pressures varying from atmospheric to 12 bar. The flow characteristics within the injection system were quantified by means of a fuel injection equipment (FIE) one-dimensional model, providing the injection rate and the injection velocity in the presence of hole cavitation, by an in-house three-dimensional computational fluid dynamics (CFD) model providing the detailed flow distribution for various combinations of nozzle hole configurations, and by a fuel atomization model giving estimates of the droplet size very near to the nozzle exit. The overall spray angle relative to the axis of the injector was found to be almost independent of injection and chamber pressure, a significant advantage relative to swirl pressure atomizers. Temporal droplet velocities were found to increase sharply at the start of injection and then to remain unchanged during the main part of injection, before decreasing rapidly towards the end of injection. The spatial droplet velocity profiles were jet-like at all axial locations, with the local velocity maximum found at the centre of the jet. Within the measured range, the effect of injection pressure on droplet size was rather small while the increase in chamber pressure from atmospheric to 12 bar resulted in much smaller droplet velocities, by up to four-fold, and larger droplet sizes by up to 40 per cent.
Numerical Simulation of Cavitation Flows Based on Their Hydrodynamic Similarity
Authors: Martynov S B , Mason D J , Heikal M R
Published: June 2006

Hydrodynamic similarity of cavitation flows in nozzles of different scales has been observed experimentally. In this paper a model of cavitation has been developed, taking into account the bubbly nature of cavitation and assuming local homogeneity of the vapour-liquid flow. The model of cavitation is built from correlations for evaporation and condensation, based on bubble dynamics theory, and an equation for the number density of cavitation bubbles, derived by assuming hydrodynamic similarity of cavitation flows. Compared with conventional models of cavitation, which fix the number density of cavitation bubbles, the present model takes into account the effect of liquid tension on the number density of active cavitation nuclei. The model has been implemented within the VECTIS computational fluid dynamics code and applied to the simulation of cavitating flows in nozzles.
Combustion Limits and Efficiency in a Homogeneous Charge Compression Ignition Engine
Authors: Kalghatgi G T , Head R A
Published: June 2006

Combustion phasing is characterized by CA50, the crank angle position where 50 per cent of the total heat release occurs. CA50 = ( a + b) [OI - OI0] where OI is the octane index defining the fuel auto-ignition quality given by OI = (1 - K) RON + K MON = RON - KS and S is the sensitivity of the fuel, (RON - MON). K, ( a + b), and OI0, which is the requirement of the engine, can be estimated from in-cylinder thermodynamic parameters and engine operating conditions. If OI is much smaller or greater than OI0, combustion will reach, respectively, the ‘knock limit’ with unacceptably high rate pressure rise or the ‘instability limit’ with unacceptably high cyclic variation. Nineteen different gasoline-like fuels with RON > 60 have been tested at many different operating conditions in a single-cylinder homogeneous charge compression ignition (HCCI) engine. This generates a data set across which the correlations between CA50 and other operating parameters such as the equivalence ratio and the inlet pressure Pin are broken. Regression analysis shows that the maximum pressure rise rate (MPRR) increases with increasing φ and Pin and decreases with increasing CA50 and S if other parameters are kept constant. X = 1.55CA50 - 52 can be used to discriminate between conditions of high and low cyclic variation. For X < 0, the coefficient of variation (COV) of indicated mean effective pressure (i.m.e.p.) is less than 10 per cent in about 90 per cent of the cases, but if X>0, COV of i.m.e.p. is less than 10 per cent in only about 12 per cent of the cases. The i.m.e.p. increases with fuel energy content per cycle. The indicated fuel conversion efficiency ηi increases with increase in i.m.e.p. With other parameters kept constant, ηi decreases with increasing φ, intake air density, and intake temperature and increases with increasing CA50 and maximum pressure. An HCCI engine can be operated with an acceptable noise level and cyclic variation only within a narrow range of CA50 between about –5 and +10° from top dead centre.
Prototype Support Structure for Seabed Mounted Tidal Current Turbines
Authors: Owen A , Bryden I G
Published: June 2006

This paper introduces the patented concept of the Sea Snail, a pin-jointed tubular steel structure carrying an array of symmetrical section hydrofoils, which is used as a means of fixing a tidal turbine, or other devices, to the seabed. The concept is evaluated as a simple mathematical model, tested as a one-eighth-scale model and subsequently developed into a 21 t model fit for sea trials. Pressure differences created by the flow over the upper and lower surfaces of the hydrofoils generate negative lift, or downforce, which is communicated to the supporting structure. The effects of induced drag on low-aspect-ratio hydrofoils are discussed. This paper gives an overview of the evaluative techniques employed in the Sea Snail's concept and design. The need for the device is outlined and its conceptual basis discussed. In particular, the response of a hydrofoil to increasing angles of attack within a steady flow is examined. Field measurements of the drag and lift forces applied to an NACA0013 section hydrofoil is presented in the context of the Sea Snail. The fundamental design criteria are discussed and the Sea Snail's ability to match these criteria is demonstrated.
The Tishchenko Reaction: A Classic and Practical Tool for Ester Synthesis
Authors: Seki Tsunetake , Nakajo Tetsuo , Onaka Makoto
Published: June 2006

This article reviews the Tishchenko reaction: 2 RCHO → RCOOCH2R (R = hydrogen, alkyl, and aryl), describing the reaction mechanisms, homogeneous and heterogeneous catalysts developed for the reaction, a number of specific examples, and the utility of the reaction in the industrially large-scale production of ethyl acetate from acetaldehyde.
Singlet Oxygen Generation Photocatalyzed by TiO2 Particles and Its Contribution to Biomolecule Damage
Authors: Hirakawa Kazutaka , Hirano Toru
Published: June 2006

The study of near-infrared emission has shown that singlet oxygen (1O2) is generated via superoxide by the photocatalytic reaction of titanium dioxide (TiO2) dispersed in solvents. The 1O2 was deactivated on the TiO2 surface and could not oxidize nicotinamide adenine dinucleotide, which has no affinity to the TiO2 surface. The generation of photocatalytic 1O2 was enhanced in the phospholipid membrane, and a water soluble protein acted as an effective scavenger of the generated 1O2. These findings suggest that 1O2 generated by TiO2 contributes to the phototoxic effect through the oxidation of the membrane protein.
Synthesis of a New Water Soluble 2,2-Bifunctionalized Spin Label and Its Application to Troponin C
Authors: Hirayama Tasuku , Taki Masayasu , Nakamura Motoyoshi , Arata Toshiaki , Yamamoto Yukio
Published: June 2006

A new water soluble 2,2-bifunctionalized spin label (2,2E-BSL) having pyrrolidine nitroxide moiety was synthesized starting from a nitro compound with two hydroxymethyl group converted to the linkers of the 2,2E-BSL, and was applied to label troponin C (TnC). Labeled TnC through two linkages were successfully isolated, and 2,2E-BSL was proved to be immobilized on TnC by EPR measurement.
Selective Hydrosilylation of 1-Alkynes Using Iridium Catalyst with Biphosphinine Ligand
Authors: Miyake Yoshihiro , Isomura Eigo , Iyoda Masahiko
Published: June 2006

The iridium-catalyzed hydrosilylation of alkynes in the presence of 4,4′,5,5′-tetramethylbiphosphinine (tmbp) has been explored. The hydrosilylation of alkynes in the presence of tmbp proceeds effectively to give β-(E)-vinylsilanes highly selectively in moderate to high yields, whereas a similar hydrosilylation in the absence of tmbp produces β-(Z)-vinylsilanes selectively. The stereoselectivity of these reactions suggests the importance of the electron-withdrawing properties of tmbp coordinated to iridium.
Amination of the Ortho C–H Bonds by the Cu(OAc)2-mediated Reaction of 2-Phenylpyridines with Anilines
Authors: Uemura Takeshi , Imoto Shinya , Chatani Naoto
Published: June 2006

The reaction of 2-phenylpyridines with anilines in the presence of Cu(OAc)2 as a promoter results in selective mono-amination of the ortho C–H bonds in 2-phenylpyridines to give amine derivatives in high yields per the conversion. This is the rare example of the functionalization of C–H bonds to C–N bonds.
Lead-free Accumulators for Renewable and Clean Energy Technologies
Authors: Ohzuku Tsutomu , Ariyoshi Kingo
Published: June 2006

Lead-free accumulators consisting of lithium aluminum manganese oxide (LAMO) and lithium titanium oxide (LTO) having spinel-framework structures are examined in 1 M LiBF4 acetonitrile. Results on zero-volt storage for 2 weeks, cycle tests at 1 mA cm−2 in voltages of 0 to 2.9 V for 20 cycles and then at 2 mA cm−2 in voltages of 2.0 to 2.9 V for 100 cycles, and rate-capability tests ranging from 0.3 to 16.7 mA cm−2 are presented and 12 V lead-free accumulators, in which 5 cells are connected in series, are proposed for renewable and clean energy technologies.
Thermolysis of Dialkyl Dithiophosphates in Porous Anodic Alumina Template: A Versatile Route to Produce Semiconductor Metal Sulfide Nanowires
Authors: Lou Wenjing , Chen Miao , Wang Xiaobo , Zhang Yanan , Liu Weimin
Published: June 2006

A facile and versatile method characterized by thermolysis of metal dialkyl dithiophosphates in porous anodic alumina templates was proposed for producing semiconductor metal sulfide nanowires. Highly crystalline nanowires of binary metal sulfide ME (M = Cd, Pb, or Zn) have been prepared and characterized by X-ray diffraction and electron microscopy (SAED, SEM, and TEM).
Tubular Stress Proteins and Nitric Oxide Synthase Expression in Rat Kidney Exposed to Mercuric Chloride and Melatonin
Authors: Stacchiotti Alessandra , Ricci Francesca , Rezzani Rita , Volti Giovanni Li , Borsani Elisa , Lavazza Antonio , Bianchi Rossella , Rodell Luigi Fabrizio
Published: June 2006

Stress proteins such as HSP70 members (HSP72 and GRP75) and metallothionein (MT) protect the kidney against oxidative damage and harmful metals, whereas inducible nitric oxide synthase (iNOS) regulates tubular functions. A single dose of mercuric chloride (HgCl2) can cause acute renal failure in rats, its main target being the proximal tubule. Oxidative damage has been proposed as one of its pathogenic mechanisms. In this study we tested whether melatonin (MEL), a powerful antioxidant compound, is effective against HgCl2nephrotoxicity. Rats were treated with saline, HgCl2(3.5 mg/kg), MEL (5 mg/kg), and MEL + HgCl2and examined after 24 hr for HSP72, GRP75, MT, and iNOS by immunohistochemistry and immunoblotting. Tubular effects of the treatment were then characterized by ultrastructure. In the HgCl2group, all markers were overexpressed in convoluted proximal tubules and sometimes in distal tubules. In the MEL + HgCl2group, GRP75 and iNOS decreased in convoluted and straight proximal tubules, whereas HSP72 and MT persisted more than the saline and MEL-only groups. Tubular damage and mitochondrial morphometry were improved by MEL pretreatment. In conclusion, the beneficial effect of MEL against HgCl2nephrotoxicity was outlined morphologically and by the reduction of the tubular expression of stress proteins and iNOS. These markers could represent sensitive recovery index against mercury damage. (J Histochem Cytochem 54:1149-1157, 2006)
HuD Distribution Changes in Response to Heat Shock but Not Neurotrophic Stimulation
Authors: Burry Richard W. , Smith Catherine L.
Published: June 2006

Cellular stress leads to a change in distribution of RNA-binding proteins. HuR, a member of the ELAV/Hu family of RNA-binding proteins, is nuclear in distribution and following heat shock is found in large cytoplasmic stress granules where translation is inhibited. HuD, another ELAV/Hu RNA-binding protein, stabilizes the GAP-43 mRNA in response to nerve growth factor (NGF) stimulation in PC12 cells. We were interested in determining the nuclear distribution of HuD and if neurotrophic stimulation induced changes in the distribution of HuD. In PC12 cells, we found, as expected, that HuR translocates from the nucleus to the cytoplasm in response to heat shock. In response to heat shock, HuD forms large cytoplasmic stress granules, consistent with a role for HuD in the cessation of translation. In unstimulated cells, HuD is distributed in small granules in the cytoplasm and is consistently present at low levels in the nucleus. Stimulation of PC12 cells with NGF induces neuronal differentiation including outgrowth of neurites and increased levels of GAP-43 protein, whereas HuD remains localized in small cytoplasm granules and is still present in the nucleus. These results suggest that, following neurotrophic stimulation, the lack of changes in HuD distribution are due to continued steady state of HuD nuclear shuttling in PC12 cells, or that HuD is not normally shuttled from the nucleus in response to NGF. (J Histochem Cytochem 54:1129-1138, 2006)
Disposable Colorimetric Carbon Dioxide Detector Use as an Indicator of a Patent Airway During Noninvasive Mask Ventilation
Authors: Leone Tina A. , Lange Allison , Rich Wade , Finer Neil N.
Published: June 2006

Colorimetric carbon dioxide detectors are useful indicators of proper endotracheal tube placement. We have found that they also are helpful during bag and mask ventilation as an indicator of a patent airway. In this report, we describe our experience with these devices for use during preintubation airway stabilization as observed during videotaped performances from a prospective, randomized trial of intubation premedication.
Spontaneous Tracheal Rupture After Severe Coughing in a 7-Year-Old Boy
Authors: Roh Jong-Lyel , Lee Jae-Ho
Published: June 2006

Tracheal lacerations are rare but potentially life-threatening. They are recognized sequelae of cervical or thoracic injuries or complications of endotracheal intubation. Spontaneous tracheal rupture is extremely uncommon and has not been reported in a pediatric patient. This report is the first pediatric case of a spontaneous longitudinal laceration of the posterior membranous cervical trachea, which occurred after violent coughing in a 7-year-old boy with acute tracheobronchitis. The tracheal rupture was detected early with an endoscopic examination and computed tomography. The rupture and emphysema were small, with no major complications, and disappeared with conservative management. This rare case is presented with a review of the possible mechanism, diagnosis, and treatment.
Functional Insights Gained from Structural Analyses of DNA Duplexes that Contain UV‐Damaged Photoproducts†
Authors: Park Chin‐Ju , Lee Joon‐Hwa , Choi Byong‐Seok
Published: June 2006

Ultraviolet photolesions endow DNA with distinct structural and dynamic properties. Biophysical studies of photoproduct‐containing DNA have shown that these lesions affect the mutagenic properties of DNA and damage recognition by DNA repair systems. Recently obtained high‐resolution co‐crystal structures of damaged DNA bound to either DNA polymerase or DNA repair enzymes have enriched our understanding of the mechanisms by which DNA lesions are bypassed or recognized by DNA metabolizing proteins. Here, we summarize the results of these structural studies and discuss their implications for DNA metabolism.
Primary Processes During the Light‐signal Transduction of Phototropin
Authors: Matsuoka Daisuke , Iwata Tatsuya , Zikihara Kazunori , Kandori Hideki , Tokutomi Satoru
Published: June 2006

Phototropin is a blue‐light photoreceptor in plants that mediates phototropism, chloroplast relocation, stomata opening and leaf expansion. Phototropin molecule has two photoreceptive domains named LOV1 (light–oxygen–voltage) and LOV2 in the N‐terminus and a serine/threonine kinase domain in the C‐terminus, and acts as a blue light‐regulated kinase. Each LOV domain binds a flavin mononucleotide as a chromophore and undergoes unique cyclic reactions upon blue‐light absorption that comprises a cysteinyl‐flavin adduct formation through a triplet‐excited state and a successive adduct break to revert to the initial ground state. The molecular reactions underlying the photocycle are reviewed and one of the probable molecular schemes is presented. Adduct formation alters the secondary protein structure of the LOV domains. This structural change could be transferred to the linker between the kinase domain and involved in the photoregulation of the kinase activity. The structural changes as well as the oligomeric structures seem to differ between LOV1 and LOV2, which may explain the proposed roles of each domain in the photoregulation of the kinase activity. The photoregulation mechanism of phototropin kinase is reviewed and discussed in reference to the regulation mechanism of protein kinase A, which it resembles.
Statin‐Associated Pleiotropy: Possible Beneficial Effects Beyond Cholesterol Reduction
Authors: Ito Matthew K. , Talbert Robert L. , Tsimikas Sotirios
Published: June 2006

Because elevated serum cholesterol levels are strongly associated with coronary heart disease, cholesterol reduction by 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (or statins) has been assumed to be the predominant, if not the only, mechanism underlying the beneficial effects of these drugs in cardiovascular diseases. Subgroup analyses of large clinical trials, however, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol‐independent or “pleiotropic” effects of statins may be mediated through improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation.
Research and Practice of Student Retention: What Next?
Authors: Tinto Vincent
Published: June 2006

After reviewing the state of student retention research and practice, past and present, the author looks to the future and identifies three areas of research and practice that call for further exploration. These concern issues of institutional action, program implementation, and the continuing challenge of promoting the success of low-income students.
The Influence of Athletic Participation on the College Adjustment of Freshmen and Sophomore Student Athletes
Authors: Melendez Mickey C.
Published: June 2006

Research exploring the experiences of college student athletes has traditionally revealed low levels of academic achievement and success. This was especially true of minority college athletes, who demonstrated lower graduation rates than their majority counterparts. However, more recent data suggests the reverse of this trend may now be true. The purpose of the current study was to examine the relationship between race/ethnicity, gender, athletic participation, and college adjustment in 207 freshmen and sophomore college student athletes and non-athletes. All participants completed questionnaires assessing background demographics, athletic status, and college adjustment. Findings revealed gender and athletic status were significantly related to college adjustment. In addition, gender and race/ethnicity significantly interacted, and were related to scores on college adjustment. Implications for retention policy and future research are discussed.
Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell–Mediated Regulation and Type 1 Diabetes Development in NOD Mice
Authors: Alard Pascale , Manirarora Jean N. , Parnell Sarah A. , Hudkins Jason L. , Clark Sherry L. , Kosiewicz Michele M.
Published: June 2006

Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type 1 diabetes development in NOD mice. CD4+CD25+ regulatory cells play a crucial role in controlling various autoimmune diseases, and a deficiency in their number or function could be involved in disease development. The current study shows that NOD mice had fewer CD4+CD25+ regulatory cells, which expressed normal levels of glucocorticoid-induced tumor necrosis factor receptor and cytotoxic T-lymphocyte–associated antigen-4. We have also found that NOD CD4+CD25+ cells regulate poorly in vitro after stimulation with anti-CD3 and NOD APCs in comparison with B6 CD4+CD25+ cells stimulated with B6 APCs. Surprisingly, stimulation of NOD CD4+CD25+ cells with B6 APCs restored regulation, whereas with the reciprocal combination, NOD APCs failed to activate B6 CD4+CD25+ cells properly. Interestingly, APCs from disease-free (>30 weeks of age), but not diabetic, NOD mice were able to activate CD4+CD25+ regulatory function in vitro and apparently in vivo because only spleens of disease-free NOD mice contained potent CD4+CD25+ regulatory cells that prevented disease development when transferred into young NOD recipients. These data suggest that the failure of NOD APCs to activate CD4+CD25+ regulatory cells may play an important role in controlling type 1 diabetes development in NOD mice.
Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN
Authors: Mahimainathan Lenin , Das Falguni , Venkatesan Balachandar , Choudhury Goutam Ghosh
Published: June 2006

Diabetic nephropathy is characterized early in its course by glomerular hypertrophy and, importantly, mesangial hypertrophy, which correlate with eventual glomerulosclerosis. The mechanism of hypertrophy, however, is not known. Gene disruption of the tumor suppressor PTEN, a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway, in fruit flies and mice demonstrated its role in size control in a cell-specific manner. Here, we investigated the mechanism of mesangial hypertrophy in response to high extracellular glucose. We link early renal hypertrophy with significant reduction in PTEN expression in the streptozotocin-induced diabetic kidney cortex and glomeruli, concomitant with activation of Akt. Similarly, exposure of mesangial cells to high concentrations of glucose also decreased PTEN expression and its phosphatase activity, resulting in increased Akt activity. Expression of PTEN inhibited high-glucose–induced mesangial cell hypertrophy, and expression of dominant-negative PTEN was sufficient to induce hypertrophy. In diabetic nephropathy, the hypertrophic effect of hyperglycemia is thought to be mediated by transforming growth factor-β (TGF-β). TGF-β significantly reduced PTEN expression in mesangial cells, with a reduction in its phosphatase activity and an increase in Akt activation. PTEN and dominant-negative Akt attenuated TGF-β–induced hypertrophy of mesangial cells. Finally, we show that inhibition of TGF-β signal transduction blocks the effect of high glucose on PTEN downregulation. These data identify a novel mechanism placing PTEN as a key regulator of diabetic mesangial hypertrophy involving TGF-β signaling.
Spontaneous Recovery From Hyperglycemia by Regeneration of Pancreatic β-Cells in Kir6.2G132S Transgenic Mice
Authors: Oyama Kazunobu , Minami Kohtaro , Ishizaki Katsuhiko , Fuse Masanori , Miki Takashi , Seino Susumu
Published: June 2006

The ATP-sensitive K+ channel (KATP channel) in pancreatic β-cells is a critical regulator in insulin secretion. We previously reported that transgenic mice expressing a dominant-negative form (Kir6.2G132S) of Kir6.2, a subunit of the KATP channel, specifically in β-cells develop severe hyperglycemia in adults (8 weeks of age). In this study, we conducted a long-term investigation of the phenotype of these transgenic mice. Surprisingly, hyperglycemia was spontaneously improved with concomitant improvement of pancreatic insulin content in the transgenic mice at >25 weeks of age. Insulin-positive cells and pancreatic duodenal homeobox 1 (PDX1)-positive cells both were clearly increased in the older compared with the younger transgenic mice. Interestingly, cells labeled with the lectin Dolichos biflorus agglutinin (DBA), a potential indicator of uncommitted pancreatic epithelial/ductal cells, were detected in the islets of the transgenic mice but not in those of wild-type mice. In addition, a subset of the DBA-labeled cells was positive for PDX1, insulin, glucagon, somatostatin, or pancreatic polypeptide. Moreover, some of the DBA-labeled cells were also positive for a proliferating cell marker. These results show that the Kir6.2G132S transgenic mouse is a useful model for studying β-cell regeneration and that DBA-labeled cells participate in the process.
Regulation of Metabolic Responses by Adipocyte/ Macrophage Fatty Acid–Binding Proteins in Leptin-Deficient Mice
Authors: Cao Haiming , Maeda Kazuhisa , Gorgun Cem Z. , Kim Hyo-Jeong , Park So-Young , Shulman Gerald I. , Kim Jason K. , Hotamisligil Gökhan S.
Published: June 2006

Fatty acid–binding proteins (FABPs) are cytosolic fatty acid chaperones that play a critical role in systemic regulation of lipid and glucose metabolism. In animals lacking the adipocyte/macrophage FABP isoforms aP2 and mal1, there is strong protection against diet-induced obesity, insulin resistance, type 2 diabetes, fatty liver disease, and hypercholesterolemic atherosclerosis. On high-fat diet, FABP-deficient mice also exhibit enhanced muscle AMP-activated kinase (AMPK) and reduced liver stearoyl-CoA desaturase-1 (SCD-1) activities. Here, we performed a cross between aP2−/−, mal1−/−, and leptin-deficient (ob/ob) mice to elucidate the role of leptin action on the metabolic phenotype of aP2-mal1 deficiency. The extent of obesity in the ob/ob-aP2-mal1−/− mice was comparable with ob/ob mice. However, despite severe obesity, ob/ob-aP2-mal1−/− mice remained euglycemic and demonstrated improved peripheral insulin sensitivity. There was also a striking protection from liver fatty infiltration in the ob/ob-aP2-mal1−/− mice with strong suppression of SCD-1 activity. On the other hand, the enhanced muscle AMPK activity in aP2-mal1−/− mice was lost in the ob/ob background. These results indicated that both decreased body weight and enhanced muscle AMPK activity in aP2-mal1−/− mice are potentially leptin dependent but improved systemic insulin sensitivity and protection from liver fatty infiltration are largely unrelated to leptin action and that insulin-sensitizing effects of FABP deficiency are, at least in part, independent of its effects on total-body adiposity.
Comparison of Serum High–Molecular Weight (HMW) Adiponectin With Total Adiponectin Concentrations in Type 2 Diabetic Patients With Coronary Artery Disease Using a Novel Enzyme-Linked Immunosorbent Assay to Detect HMW Adiponectin
Authors: Aso Yoshimasa , Yamamoto Ruriko , Wakabayashi Sadao , Uchida Toshihiko , Takayanagi Kan , Takebayashi Kohzo , Okuno Takehiko , Inoue Teruo , Node Koichi , Tobe Takashi , Inukai Toshihiko , Nakano Yasuko
Published: June 2006

Adiponectin (Acrp30), an adipocyte-derived protein, exists in serum as a trimer, a hexamer, and a high–molecular weight (HMW) form, including 12–18 subunits. Because HMW adiponectin may be biologically active, we measured it in serum using a novel enzyme-linked immunosorbent assay (ELISA) confirmed by gel filtration chromatography that the ELISA detected mainly adiponectin with 12–18 subunits, and we compared HMW with total adiponectin concentration in patients with type 2 diabetes. We next investigated the relationship between serum HMW and coronary artery disease (CAD) in 280 consecutive type 2 diabetic patients, including 59 patients with angiographically confirmed CAD. Total adiponectin was measured in serum by a commercially available ELISA. Like serum total adiponectin, HMW adiponectin correlated positively with HDL cholesterol and negatively with triglyceride, insulin sensitivity, creatinine clearance, and circulating inflammatory markers. Total and HMW adiponectin were significantly higher in women than in men, as was the HMW-to-total adiponectin ratio. Serum HMW and the HMW-to-total adiponectin ratio were significantly lower in men with than without CAD (P < 0.05, respectively). In women, the ratio, but neither total nor HMW adiponectin, tended to be lower when CAD was present. In conclusion, determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating CAD in type 2 diabetic patients.
Increased Dicarbonyl Metabolism in Endothelial Cells in Hyperglycemia Induces Anoikis and Impairs Angiogenesis by RGD and GFOGER Motif Modification
Authors: Dobler Darin , Ahmed Naila , Song Lijiang , Eboigbodin Kevin E. , Thornalley Paul J.
Published: June 2006

Chronic vascular disease in diabetes is associated with disruption of extracellular matrix (ECM) interactions with adherent endothelial cells, compromising cell survival and impairing vasculature structure. Loss of functional contact with integrins activates anoikis and impairs angiogenesis. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Here, we show that increased modification of vascular basement membrane type IV collagen by methylglyoxal, a dicarbonyl glycating agent with increased formation in hyperglycemia, formed arginine-derived hydroimidazolone residues at hotspot modification sites in RGD and GFOGER integrin-binding sites of collagen, causing endothelial cell detachment, anoikis, and inhibition of angiogenesis. Endothelial cells incubated in model hyperglycemia in vitro and experimental diabetes in vivo produced the same modifications of vascular collagen, inducing similar responses. Pharmacological scavenging of methylglyoxal prevented anoikis and maintained angiogenesis, and inhibition of methylglyoxal metabolism with a cell permeable glyoxalase I inhibitor provoked these responses in normoglycemia. Thus, increased formation of methylglyoxal and ECM glycation in hyperglycemia impairs endothelial cell survival and angiogenesis and likely contributes to similar vascular dysfunction in diabetes.
β-Cell Deficit Due to Increased Apoptosis in the Human Islet Amyloid Polypeptide Transgenic (HIP) Rat Recapitulates the Metabolic Defects Present in Type 2 Diabetes
Authors: Matveyenko Aleksey V. , Butler Peter C.
Published: June 2006

Type 2 diabetes is characterized by defects in insulin secretion and action and is preceded by impaired fasting glucose (IFG). The islet anatomy in IFG and type 2 diabetes reveals an ∼50 and 65% deficit in β-cell mass, with increased β-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Defects in insulin action include both hepatic and extrahepatic insulin resistance. The relationship between changes in β-cell mass, β-cell function, and insulin action leading to type 2 diabetes are unresolved, in part because it is not possible to measure β-cell mass in vivo, and most available animal models do not recapitulate the islet pathology in type 2 diabetes. We evaluated the HIP rat, a human IAPP transgenic rat model that develops islet pathology comparable to humans with type 2 diabetes, at age 2 months (nondiabetic), 5 months (with IFG), and 10 months (with diabetes) to prospectively examine the relationship between changes in islet morphology versus insulin secretion and action. We report that increased β-cell apoptosis and impaired first-phase insulin secretion precede the development of IFG, which coincides with an ∼50% defect in β-cell mass and onset of hepatic insulin resistance. Diabetes was characterized by ∼70% deficit in β-cell mass, progressive hepatic and extrahepatic insulin resistance, and hyperglucagonemia. We conclude that IAPP-induced β-cell apoptosis causes defects in insulin secretion and β-cell mass that lead first to hepatic insulin resistance and IFG and then to extrahepatic insulin resistance, hyperglucagonemia, and diabetes. We conclude that a specific β-cell defect can recapitulate the metabolic phenotype of type 2 diabetes and note that insulin resistance in type 2 diabetes may at least in part be secondary to β-cell failure.
Effects of Age and Sex on Postprandial Glucose Metabolism
Authors: Basu Rita , Dalla Man Chiara , Campioni Marco , Basu Ananda , Klee George , Toffolo Gianna , Cobelli Claudio , Rizza Robert A.
Published: June 2006

To determine the effects of age and sex on the regulation of postprandial glucose metabolism, glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction were concurrently measured in 145 healthy elderly (aged 70 ± 1 years) and in 58 young (aged 28 ± 1 years) men and women before and after ingestion of a mixed meal containing [1-13C]glucose. At the time of meal ingestion, [6-3H]glucose and [6,6-2H2]glucose were infused intravenously to enable concurrent measurement of the rates of postprandial endogenous glucose production (EGP), meal appearance, and glucose disappearance. Fasting and postprandial glucose concentrations were higher (P < 0.001) in both elderly women and elderly men compared with young individuals of the same sex. The higher postprandial glucose concentrations in the elderly than young women were caused by higher rates of meal appearance (P < 0.01) and slightly lower (P < 0.05) rates of glucose disappearance immediately after eating. In contrast, higher glucose concentrations in the elderly than young men were solely due to decreased (P < 0.001) glucose disappearance. Although postprandial glucose concentrations did not differ in elderly women and elderly men, rates of meal appearance and glucose disappearance rates both were higher (P < 0.001) in the women. Fasting EGP was higher (P < 0.05) in elderly than young subjects of both sexes and in women than men regardless of age. On the other hand, postprandial suppression of EGP was rapid all groups. Insulin action and secretion were lower (P < 0.001) in the elderly than young men but did not differ in the elderly and young women. This resulted in lower (P < 0.001) meal disposition indexes in elderly than young men but no difference in elderly and young women. Total meal disposition indexes were lower (P < 0.05) in elderly men than elderly women, indicating impaired insulin secretion, whereas disposition indexes were higher (P < 0.05) in young men than young women. Hepatic insulin clearance was greater (P < 0.001) in the elderly than young subjects of both sexes but did not differ between men and women regardless of age. In contrast, the ability of glucose to facilitate its own uptake (glucose effectiveness) was higher (P < 0.001) in women than men but did not differ in elderly and young subjects. Thus, age and sex impact on insulin secretion, insulin action, hepatic insulin extraction, and glucose effectiveness, resulting in substantial differences in the regulation of postprandial glucose metabolism in men and women and in elderly and young subjects.
Transgenic Insulin (B:9-23) T-Cell Receptor Mice Develop Autoimmune Diabetes Dependent Upon RAG Genotype, H-2g7 Homozygosity, and Insulin 2 Gene Knockout
Authors: Jasinski Jean M. , Yu Liping , Nakayama Maki , Li Marcella M. , Lipes Myra A. , Eisenbarth George S. , Liu Edwin
Published: June 2006

A series of recent studies in humans and the NOD mouse model have highlighted the central role that autoimmunity directed against insulin, in particular the insulin B chain 9-23 peptide, may play in the pathogenesis of type 1 diabetes. Both pathogenic and protective T-cell clones recognizing the B:9-23 peptide have been produced. This report describes the successful creation of BDC12-4.1 T-cell receptor (TCR) transgenic mice with spontaneous insulitis in F1 mice (FVB × NOD) and spontaneous diabetes in NOD.RAG−/− (backcross 1 generation). Disease progression is heterogeneous and is modified by a series of genetic factors including heterozygosity (H-2g7/H-2q) versus homozygosity for H-2g7, the presence of additional T-/B-cell receptor–rearranged genes (RAG+ versus RAG−/−), and the insulin 2 gene knockout (the insulin gene expressed in the NOD thymus). Despite lymphopenia, 40% of H-2g7/g7 BDC12-4.1 TCR+ RAG−/− Ins2−/− mice are diabetic by 10 weeks of age. As few as 13,500 transgenic T-cells from a diabetic TCR+ RAG−/− mouse can transfer diabetes to an NOD.scid mouse. The current study demonstrates that the BDC12-4.1 TCR is sufficient to cause diabetes at NOD backcross 1, bypassing polygenic inhibition of insulitis and diabetogenesis.
Mechanisms of Recovery From Type 2 Diabetes After Malabsorptive Bariatric Surgery
Authors: Guidone Caterina , Manco Melania , Valera-Mora Elena , Iaconelli Amerigo , Gniuli Donatella , Mari Andrea , Nanni Giuseppe , Castagneto Marco , Calvani Menotti , Mingrone Geltrude
Published: June 2006

Currently, there are no data in the literature regarding the pathophysiological mechanisms involved in the rapid resolution of type 2 diabetes after bariatric surgery, which was reported as an additional benefit of the surgical treatment for morbid obesity. With this question in mind, insulin sensitivity, using euglycemic-hyperinsulinemic clamp, and insulin secretion, by the C-peptide deconvolution method after an oral glucose load, together with the circulating levels of intestinal incretins and adipocytokines, have been studied in 10 diabetic morbidly obese subjects before and shortly after biliopancreatic diversion (BPD) to avoid the weight loss interference. Diabetes disappeared 1 week after BPD, while insulin sensitivity (32.96 ± 4.3 to 65.73 ± 3.22 μmol · kg fat-free mass−1 · min−1 at 1 week and to 64.73 ± 3.42 μmol · kg fat-free mass−1 · min−1 at 4 weeks; P < 0.0001) was fully normalized. Fasting insulin secretion rate (148.16 ± 20.07 to 70.0.2 ± 8.14 and 83.24 ± 8.28 pmol/min per m2; P < 0.01) and total insulin output (43.76 ± 4.07 to 25.48 ± 1.69 and 30.50 ± 4.71 nmol/m2; P < 0.05) dramatically decreased, while a significant improvement in β-cell glucose sensitivity was observed. Both fasting and glucose-stimulated gastrointestinal polypeptide (13.40 ± 1.99 to 6.58 ± 1.72 pmol/l at 1 week and 5.83 ± 0.80 pmol/l at 4 weeks) significantly (P < 0.001) decreased, while glucagon-like peptide 1 significantly increased (1.75 ± 0.16 to 3.42 ± 0.41 pmol/l at 1 week and 3.62 ± 0.21 pmol/l at 4 weeks; P < 0.001). BPD determines a prompt reversibility of type 2 diabetes by normalizing peripheral insulin sensitivity and enhancing β-cell sensitivity to glucose, these changes occurring very early after the operation. This operation may affect the enteroinsular axis function by diverting nutrients away from the proximal gastrointestinal tract and by delivering incompletely digested nutrients to the ileum.
AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits
Authors: Treebak Jonas T. , Glund Stephan , Deshmukh Atul , Klein Ditte K. , Long Yun Chau , Jensen Thomas E. , Jørgensen Sebastian B. , Viollet Benoit , Andersson Leif , Neumann Dietbert , Wallimann Theo , Richter Erik A. , Chibalin Alexander V. , Zierath Juleen R. , Wojtaszewski Jørgen F.P.
Published: June 2006

AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 β-d-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (α1β1γ1 and α2β2γ1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (α2 AMPK knockout [KO], α2 AMPK kinase dead [KD], and γ3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing α2 and γ3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in α2 AMPK KO and KD but not γ3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.
Deletion of Nicotinamide Nucleotide Transhydrogenase
Authors: Freeman Helen C. , Hugill Alison , Dear Neil T. , Ashcroft Frances M. , Cox Roger D.
Published: June 2006

The C57BL/6J mouse displays glucose intolerance and reduced insulin secretion. The genetic locus underlying this phenotype was mapped to nicotinamide nucleotide transhydrogenase (Nnt) on mouse chromosome 13, a nuclear-encoded mitochondrial protein involved in β-cell mitochondrial metabolism. C57BL/6J mice have a naturally occurring in-frame five-exon deletion in Nnt that removes exons 7–11. This results in a complete absence of Nnt protein in these mice. We show that transgenic expression of the entire Nnt gene in C57BL/6J mice rescues their impaired insulin secretion and glucose-intolerant phenotype. This study provides direct evidence that Nnt deficiency results in defective insulin secretion and inappropriate glucose homeostasis in male C57BL/6J mice.
Copper (II) complexes of sterically hindered o-diphenol derivatives: synthesis, characterization and microbiological studies
Authors: Loginova Natalia , Koval’chuk Tat’yana , Zheldakova Rimma , Chernyavskaya Anna , Osipovich Nikolai , Glushonok Gennady , Polozov Henry , Sorokin Victor , Shadyro Oleg
Published: June 2006

Cu (II) complexes with the sterically hindered diphenol derivatives 3,5-di(tert-butyl)-1,2-benzenediol (I), 4,6-di(tert-butyl)-1,2,3-benzenetriol (II) and the sulfur-containing 4,6-di(tert-butyl)-3-(2-hydroxyethylsulfanyl)-1,2-benzenediol (III) and 2-[4,6-di(tert-butyl)-2,3-dihydroxyphenylsulfanyl]acetic acid (IV) have been synthesized and characterized by elemental analysis, TG/DTA, FT-IR, ESR, XPS, XPD and conductivity measurements. Compounds I–III can coordinate in their singly deprotonated forms and act as bidentate ligands. These compounds yield Cu (II) complexes of the stoichiometry Cu(L)2, which have square planar geometry (g| > g⊥ > ge). Unlike them, compound IV behaves as a terdentate ligand, and its complex Cu(LIV)2 has distorted octahedral geometry. According to ESR data, only the Cu(LII)2 complex contains a very small amount of phenoxyl radicals. Antimicrobial activities of these ligands and their respective Cu (II) complexes have been determined with respect to Gram-positive and Gram-negative bacteria, as well as on yeasts. Their phytotoxic properties against Chlorella vulgaris 157 were also examined.