bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer
Authors: Maun Henry R. , Kirchhofer Daniel , Lazarus Robert A. 
Published: June 2010

AbstractProteases represent a large class of enzymes with crucial biological functions. Although targeting various relevant proteases for therapeutic intervention has been widely investigated, structurally related proteins lacking proteolytic activity (pseudo-proteases) have received relatively little attention. Two distinct clinically relevant cancer pathways that contain signaling proteins with pseudo-protease domains include the Met and Hedgehog (Hh) pathways. The receptor tyrosine kinase Met pathway is driven by hepatocyte growth factor (HGF), a plasminogen-related ligand that binds Met and activates intracellular pathways resulting in cell proliferation, angiogenesis, motility and survival. HGF is a disulfide-linked α/β-heterodimer having a trypsin serine protease-like β-chain. The Hh pathway is driven by Sonic hedgehog (Shh), which has a Zn2+metalloprotease fold and binds Patched1 (Ptc1), which de-represses Smoothened and ultimately activates Gli-dependent transcription. Although HGF and Shh differ in structure and function, the pseudo-catalytic sites of both HGF and Shh are crucial for signal transduction. For HGF, this region binds the Met β-propeller domain, which leads to Met dimerization and signaling. For Hh, this region binds to the antagonist receptor Hedgehog-interacting protein (Hhip) and most probably to Ptc1 as well. Thus, for both HGF and Hh pathways, targeting ligand pseudo-active sites represents a new strategy for regulation.
Isolation of genes involved in pancreas regeneration by subtractive hybridization
Authors: Choi Jong-Ho , Lee Min-Young , Kim Yoolee , Shim Jeong-Yun , Han Sang-Moon , Lee Kyung-Ah , Choi Young-Kil , Jeon Hae-Myung , Baek Kwang-Hyun 
Published: June 2010

AbstractThe deterioration of β cells in the pancreas is a crucial factor in the progression of diabetes mellitus; therefore, the recovery of β cells is of vital importance for effective diabetic therapeutic strategies. Partially pancreatectomized rats have been used for the investigation of pancreatic regeneration. Because it was determined that tissue extract from the partially-dissected pancreas induces pancreatic differentiation in embryonic stem cells, paracrine factors were thought to be involved in the regeneration. In this study, we screened for genes that had higher mRNA levels 2 days after 60%-pancreatectomy. The genes were isolated using subtractive hybridization and DNA sequencing. Twelve genes (adipsin,Aplp2,Clu,Col1a2,Glul,Krt8,Lgmn, LOC299907, LOC502894,Pla2g1b,Reg3αandXbp1) were identified, and RT-PCR and real-time PCR analyses were performed to validate their expression levels. Among the genes identified, three genes (Glul,LgmnandReg3a) were selected for further analyses. Assays revealed thatGlulandReg3αenhance cell growth.Glul,LgmnandReg3αchange the expression level of islet marker genes, whereNEUROD,NKX2.2,PAX4andPAX6are up-regulated andsomatostatinis down-regulated. Thus, we believe thatGlul,LgmnandReg3acan serve as novel targets in diabetes mellitus genetic therapy.
Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors
Authors: Heiker John T. , Kosel David , Beck-Sickinger Annette G. 
Published: June 2010

Abstract
The adipocytokine adiponectin and its receptor (AdipoR) comprise a new receptor-ligand system that is involved in a variety of clinically important morbidities such as obesity, type 2 diabetes and cardiovascular diseases. Adiponectin exerts a multitude of beneficial and tissue specific effects depending on its unique, tightly regulated multimerization behavior. Post-translational modifications are essential for the multimer assembly before secretion and protein stability in the circulation. AdipoR1 and 2 have been discovered as a new class of heptahelix receptors structurally and functionally distinct from G-protein-coupled receptors. Both AdipoRs bind adiponectin and the downstream signaling of both AdipoRs is mediated mainly by phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor α, which influence the lipid and glucose metabolism of skeletal muscle and liver cells as well as inflammatory processes and vascular endothelial integrity. Several intracellular binding partners of the AdipoR N-terminus such as APPL1, CK2β and ERp46 have been identified and shown to control receptor signaling. Adiponectin has also been reported to modulate the dimerization and internalization of AdipoRs, which provides new insights into the molecular characteristics of this unusual receptor. The understanding of the functional mechanisms of adiponectin signal transduction is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system.
Nuclear cysteine cathepsin variants in thyroid carcinoma cells
Authors: Tedelind Sofia , Poliakova Kseniia , Valeta Amanda , Hunegnaw Ruth , Yemanaberhan Eyoel Lemma , Heldin Nils-Erik , Kurebayashi Junichi , Weber Ekkehard , Kopitar-Jerala Nataša , Turk Boris , Bogyo Matthew , Brix Klaudia 
Published: June 2010

AbstractThe cysteine peptidase cathepsin B is important in thyroid physiology by being involved in thyroid prohormone processing initiated in the follicular lumen and completed in endo-lysosomal compartments. However, cathepsin B has also been localized to the extrafollicular space and is therefore suggested to promote invasiveness and metastasis in thyroid carcinomas through, e.g., ECM degradation. In this study, immunofluorescence and biochemical data from subcellular fractionation revealed that cathepsin B, in its single- and two-chain forms, is localized to endo-lysosomes in the papillary thyroid carcinoma cell line KTC-1 and in the anaplastic thyroid carcinoma cell lines HTh7 and HTh74. This distribution is not affected by thyroid stimulating hormone (TSH) incubation of HTh74, the only cell line that expresses a functional TSH-receptor. Immunofluorescence data disclosed an additional nuclear localization of cathepsin B immunoreactivity. This was supported by biochemical data showing a proteolytically active variant slightly smaller than the cathepsin B proform in nuclear fractions. We also demonstrate that immunoreactions specific for cathepsin V, but not cathepsin L, are localized to the nucleus in HTh74 in peri-nucleolar patterns. As deduced from co-localization studies andin vitrodegradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.
Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
Authors: Hook Vivian , Hook Gregory , Kindy Mark 
Published: June 2010

Abstract
Beta-amyloid (Aβ) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce Aβ in different mouse models of AD. The inhibitors improve memory and reduce brain Aβ in mice expressing the wild-type (WT) β-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain Aβ in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT β-secretase site, but not the Swe mutant site, of APP for Aβ production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 β-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a β-secretase. Cathepsin B and BACE1 could participate jointly as β-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.
Hydrophilic residues surrounding the S1 and S2 pockets contribute to dimerisation and catalysis in human dipeptidyl peptidase 8 (DP8)
Authors: Pitman Melissa R. , Menz R. Ian , Abbott Catherine A. 
Published: June 2010

Abstract
Dipeptidyl peptidase (DP) 8 belongs to the dipeptidyl peptidase IV gene family. DP8 has been implicated in immune function and asthma, although its biological function is yet unknown. Structures of the homologs, fibroblast activation protein (FAP) and DPIV, are known but the DP8 structure is yet to be resolved. To help characterise the DP8 substrate pocket, mutants of residues lining the pocket were produced at DP8D772, DP8Y315, DP8H434 and DP8D435 and assessed by substrate kinetics and size-exclusion chromatography. Mutations of DP8D772A/E/S/V affected catalysis but did not confer endopeptidase activity. Mutations of DP8H434F, DP8D435F and DP8Y315F reduced catalytic activity. Furthermore, mutations to DP8D772A/E/S/V, DP8H434F, DP8D435F and DP8Y315F affected dimer stabilisation. Homology modelling of DP8 using DPIV and FAP crystal structures suggested that DP8D772, DP8H434 and DP8D435 were located at the edge of the S2 catalytic pocket, contributing to the junction between the alpha-beta hydrolase and beta-propeller domains. This study provides insights into how the DP8 substrate pocket and dimer interface differ from DPIV and FAP which could be utilised for designing more selective DP8 inhibitors.
Adrenaline: communication by electron emission. Effect of concentration and temperature. Product analysis
Authors: Getoff Nikola , Huber Claudia , Hartmann Johannes , Huber Johannes C. , Quint Ruth Maria 
Published: June 2010

Abstract

Background: Based on the recent findings about the ability of sexual hormones to emit electrons (eaq
–) and to act as electron mediator, it was of interest to investigate adrenaline as an important neurotransmitter.

Materials and methods: Highest purity adrenaline (ADR) and chemicals were used for preparation of aqueous solutions (pH ∼7.4). The excitation of ADR in singlet state was achieved by irradiation of airfree aqueous solution with monochromatic UV light at λ=254 nm. The emitted “solvated electrons” (eaq
–) were scavenged by chloroethanol, where the quantum yield of Cl– ions, Q(Cl–)=Q(eaq
–). ADR degradation and formation of photolytic products were followed by HPLC analysis.

Results and conclusion: It was found that Q(eaq
–) values decrease with increasing ADR concentration: for 2.5×10–5 mol/L ADR was determined as Q(eaq
–)=6×10–3, whereas for 1×10–3 mol/L ADR was found to be 0.9×10–3. This is explained by formation of associates in ground state, which consume a part of emitted eaq
–. As a main photolytic product aminochrome was determined.
Congenital adrenal hyperplasia and the function of adrenal medulla
Authors: Lisá Lidka , Bílek Radovan , Vrzalová Zuzana 
Published: June 2010

Abstract

Objective: The most common form of congenital adrenal hyperplasia (CAH) is the deficiency of steroid 21-hydroxylase which results from deletion or mutation of the cytochrome P450 21-hydroxylase gene. The low level of glucocorticoids and in some cases low level of mineralocorticoids has an important pathophysiological influence on the axis of the hypothalamo-pituitary-adrenal cortex.

Design: Using determination of plasmatic metanephrine, normetanephrine and chromogranin A, we wanted to investigate the structure and function of adrenal medulla in patients with CAH, because adrenocortical and adrenomedullary systems are intimately linked anatomically and functionally.

Methods: Levels of plasmatic metanephrine, normetanephrine and chromogranin A were measured in our group of 37 patients (age range: 5–45 years, 18 females and 19 males) with the classic salt-wasting form of CAH.

Results: The reference range was 73% for metanephrine (<10 ng/L, 83.3% females, 63.2% males) and 59.5% for metanephrine (<15 ng/L, 72.2% females, 47.4% males). The concentration of plasmatic nephrines in the first quartile reference range was achieved in the case of metanephrine in all patients (<23 ng/L), and in the case of normetanephrine in 86.5% of patients (<42.5 ng/L). The level in chromogranin A was normal in all patients. No significant differences were found in plasmatic concentrations of nephrines and chromogranin A between males and females with CAH, nor was there a significant correlation with genetic results (severe or moderate salt-wasting form of CAH).

Conclusion: Impaired secretion of glucocorticoids in patients with CAH leads to the structural changes in adrenal medulla which are expressed by low production of metanephrine, and to a lesser extent, normetanephrine.
Modified Direct Shear Apparatus for Unsaturated Sands at Low Suction and Stress
Authors: Likos William J. , Wayllace Alexandra , Godt Jonathan , Lu Ning 
Published: June 2010

AbstractModifications to a conventional laboratory testing system are described for direct shear testing of unsaturated soils at relatively low matric suction and net normal stress. Matric suction ranging from zero (saturated) to about 10 kPa is controlled using a hanging column assembly (ASTM D6836). Net normal stress ranging from about 0.3 to 10 kPa is controlled by directly applying dead loads to the specimen via a series of aluminum top caps machined to varying thicknesses. Precise control of suction and normal stress within these ranges makes the apparatus ideal for examining the shear strength behavior of unsaturated sands, which are characterized by relatively low air-entry pressures and for which the influences of matric suction on mechanical response can be subtle. Soil-water characteristic curves are concurrently obtained during the shear testing program by measuring transient and equilibrium pore water drainage under the imposed suction changes. Testing procedures and recommended protocols are described. Results from a series of tests using saturated and unsaturated specimens of poorly graded fine sand are presented to demonstrate application and performance of the system. Relationships between shear strength and matric suction are non-linear and exhibit peak shear strength at matric suction within the range of the air-entry suction. High friction angles measured for the portions of the failure envelope at low matric suction and normal stress may indicate the effects of dilation on the strength development.
Experimental Investigations of Preheated Jatropha Oil Fuelled Direct Injection Compression Ignition Engine—Part 1: Performance, Emission, and Combustion Characteristics
Authors: Agarwal Avinash Kumar , Dhar Atul 
Published: June 2010

Abstract
Vegetable oils demonstrate several problems as fuel for compression ignition engines due to their high viscosity and low volatility characteristics. Viscosity can be brought down by heating or blending them with mineral diesel. In the first part of the present investigations, a novel method of preheating straight vegetable oils with the waste heat of the engine exhaust is presented. Experimental investigations were carried out for combustion, performance, and emission properties of preheated and unhealed jatropha oil in a direct injection engine at different loads at constant engine speed (1500 r/min). Brake specific fuel consumption and exhaust gas temperatures for preheated jatropha oil were found to be higher compared to mineral diesel. Thermal efficiency was lower for preheated jatropha oil compared to mineral diesel. The vegetable oil preheating reduced the CO2, CO, and HC emissions but increased the NOx emissions. Analysis of cylinder pressure rise, heat release rate, and cumulative heat release was carried out. Preheated jatropha oil shows lower combustion delay but slower heat release rate compared to mineral diesel. Combustion duration for both preheated and unheated jatropha oils is higher than mineral diesel, but heating was found to increase the combustion duration of jatropha oil. Maximum in-cylinder pressure was observed for mineral diesel for higher load conditions, but at lower load, relatively higher peak cylinder pressure was obtained with preheated jatropha oil. Detailed combustion analysis suggests that preheated jatropha oil gives identical combustion as that of mineral diesel. Hence, waste heat of exhaust gas can be effectively utilized to preheat the jatropha oil for improving its combustion properties as a diesel engine fuel.
Fatigue Crack Propagation Behavior of an Inertia Friction Welded α/β Titanium Alloy
Authors: Pardhi Y. , Dungey C. , Baxter G. , Bowen P. , Halford T. P. 
Published: June 2010

Abstract
The inertia friction welding process is being extensively investigated for the joining of high strength titanium alloys for aerospace applications. Although it offers solid state joining, the thermal cycle and deformation involved results in microstructural inhomogeneity across the weld interface. In this paper, the fatigue crack propagation behavior in an inertia welded microstructure in a high strength, high temperature α/β titanium alloy is considered. The fatigue crack propagation behavior in corner notched weld specimens at varying stress ratios is studied at room and elevated temperatures and compared with that of the parent material. Fatigue crack growth rates at lower stress intensity ranges are comparable with those in the parent material. However, in weld specimens tested at room temperature, unstable crack growth occurs at lower stress intensity range values compared to that at high temperature. Fracture surface observations show that this difference is related to a change in fracture mode from transgranular to intergranular/mixed mode during room temperature tests. This change in fatigue crack growth mechanism is deduced to be due to low ductility intergranular failure of grain boundary α in the refined transformed beta microstructure across the weld interface.
La παλαιὰ συμμαχία fra Atene e Leontini nel quadro della politica occidentale ateniese
Authors: Maddoli Gianfranco 
Published: June 2010

Riassunto
Tucidide (3,86), in riferimento alla prima spedizione ateniese in Sicilia (427 a. C.), menziona una “antica alleanza” fra Atene e Leontini la cui datazione è stata ed è oggetto di un lungo dibattito e di diverse ipotesi. Il testo di questa alleanza – insieme a quello di un′alleanza fra Atene e Reggio – è conservato in forma epigrafica (rispettivamente IG I3 54 = ML 64 e IG I3 54 = ML 63) ed è databile al 433/2, ma si tratta di un “rinnovo” delle alleanze. L′autore propone di collegare la stipula originaria con la ribellione dei Siculi di Ducezio (fine anni ′50) e con la spedizione di Diotimos in Occidente che, in accordo con una recente ricerca, deve essere datata intorno al 452 a. C. L′intervento ateniese è il primo segnale di quella politica di presenza nell′area occidentale che fu additata da Temistocle, perseguita da Cimone e consolidata da Pericle con la fondazione di Turii.
Ricerche sulle tradizioni di fondazione di Magnesia al Meandro. Un aggiornamento
Authors: Biagetti Claudio 
Published: June 2010

Riassunto
Il presente lavoro propone un quadro aggiornato sulle tradizioni di fondazione di Magnesia al Meandro a partire dal racconto epigrafico di IMagn. 17, che conserva una ktisis anonima della città. Dall′analisi testuale dell′iscrizione e dal confronto di questa con la documentazione letteraria su Magnesia è possibile individuare tre distinti filoni di tradizione: quello magnesio-tessalo, quello cretese e quello licio. Ulteriori leggende emergono dall′esame delle fonti letterarie ed epigrafiche relative a Magnesia: si tratta delle tradizioni delfiche, di quelle spartane e di quelle indigene. Una piena comprensione della genesi e dello sviluppo delle tradizioni magnesie passa però attraverso l′inquadramento delle stesse nel panorama più ampio delle colonie greche d′Asia Minore.
Rom und Jerusalem – Kaiserherrschaft und herodische Dynastie. Beobachtungen und Fragen zur neueren Forschung
Authors: Bernett Monika 
Published: June 2010

Zusammenfassung
Der Beitrag gibt einen Überblick über die neuere Forschung zur jüdischen Geschichte zur Zeit der herodischen Dynastie bis Anfang des 2. Jh. n. Chr. Er setzt sich dabei intensiver mit Art und Bedeutung der Beziehungen zwischen lokalen Herrschern, römischen Autoritäten und dem Kaiserhaus auseinander. Zur Debatte steht insbesondere die Frage, inwiefern die herodischen Dynasten politische Vermittlungsfunktionen zwischen Rom und den Juden in Judäa sowie im Rest des Römischen Reichs wahrnahmen und welcher politische Einfluß ihnen deshalb attestiert werden kann. Schlußfolgerung ist, daß die Formen und Inhalte symbolischer Kommunikation in diesem Beziehungsfeld zu wenig bedacht und deshalb Annahmen zu Macht und Einfluß von Mitgliedern des herodischen Hauses nicht ausreichend differenziert getroffen werden.
Les seuiri augustales dans les Germanies: Etude des inscriptions
Authors: Amiri Bassir 
Published: June 2010

Rsum
Le rôle social, économique et religieux des *Augustales dans l′Empire n′est plus à démontrer. Moins attestée que dans d′autres provinces, leur présence en Germanie n′en soulève pas moins des questions capitales relatives à leur rôle dans la transmission des valeurs issues de l′Empire. Quelles informations les sources épigraphiques livrent-elles sur leur intégration sociale, sur leur relation avec le pouvoir municipal et l′élite? Reposant sur des fondements instaurés par Auguste, leur autorité est renforcée par des aspects qui relèvent de l′idéologie et de la représentation sociale. Comment les sévirs des Germanies ont-ils voulu présenter leur relation avec le pouvoir et se mettre au service de ce pouvoir en devenant un instrument de l′acculturation des provinces au modèle romain?
A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings
Authors: Pugliese-Pires Patricia N , Tonelli Carlos A , Dora Jose M , Silva Paulo C A , Czepielewski Mauro , Simoni Genoir , Arnhold Ivo J P , Jorge Alexander A L 
Published: June 2010

BackgroundGH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported.ObjectivesTo report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation.Subjects and methodsHormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 μg/kg BID.ResultsBoth siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder.ConclusionGHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.