Submerged arc welding (SAW) is often the method of choice in pressure vessel fabrication. This process features high production rates, welding energy and/or welding speed and requires minimal operator skill. The selection of appropriate parameters in SAW is essential, not only to optimize the welding process in order to maintain the highest level of productivity, but also to obtain the most desirable mechanical properties of the weld.<p> The focus of this study was to investigate the effect of welding speed on the properties of SA516 Grade 70. Plates of SA516 Gr. 70 steel 17 mm x 915 mm x 122 mm were submerged arc welded with a welding current of 700 A and welding speeds of 15.3, 12.3 and 9.3 mm/s. Following the welding; strength, microstructure, hardness and impact toughness of the specimens were examined. Charpy impact testing was performed according to ASTM E 23 on specimens notched in the weld metal (WM) and in the heat-affected zone (HAZ), to measure the impact toughness. Fractography was performed on broken specimens using optical and scanning electron microscopy in order to correlate the mechanisms of fracture with the impact toughness values.<p> The highest hardness values were in the coarse-grained HAZ followed by the WM with the lowest hardness in the parent metal (PM). The HAZ had higher impact toughness than the WM and PM for all welding speeds. The slowest welding speed (9.3 mm/s) obtained complete penetration and therefore produced the most visually sound weld. The fastest welding speed (15.3 mm/s) had the narrowest HAZ and showed good ductile-to-brittle transition behaviour for both the WM and HAZ specimens, but produced incomplete penetration defects. Welding speed had little affect on the notch toughness of the HAZ with only a 9 J rise in upper shelf energy and an 8 °C drop in the impact transition temperature (ITT) with increased welding speed from 9.3 to 15.3 mm/s. However, for the WM, there was a 63 J drop in the upper shelf energy but also a 41 °C improvement of the ITT between the 9.3 and 15.3 mm/s welding speeds.

Purpose: Excessive day time sleepiness, sleep disorders and neurobehavior changes are common clinical observations in the patients with epilepsy. From literature review, they were highly related with epilepsy risk characteristics (age of onset, types or numbers of drugs, seizure frequency), co-morbidities or neuronal network changes. The serological biomarkers have been reported to reflect the phenomenon of seizure, while their correlations with neurobehavior changes were still not concluded. There were two purposes of this thesis. (1) To understand the relationship between sleep disturbance with day time performances (2) To understand the relationships between serological biomarkers, neurobehavior performances and neuronal networks in patients with temporal lobe epilepsy. Material and Methods: The study enrolled patients from epilepsy outpatient clinic. By using self-appreciated questionnaire (The Pittsburgh Sleep Quality Index, The Epworth Sleepiness Scale, Euroqol Quality of Life Scale-5D), we collected the characteristics of sleep related behavior and life quality changes and explored the relationship with epilepsy risk characteristics. In patients with temporal lobe epilepsy, we assessed the neurobehavior performances, measured the serological biomarkers (heat shock protein 70, S100£]protein, neuron specific enolase, brain derived neurotrophic factor, plasma and mitochondrial DNA) and brain magnetic resonance imaging. In statistical analysis, we compared the differences with age matched controls or performed correlation analysis among the parameters Result: One hundred and seventeen patients with epilepsy completed the sleep quality questionnaires. The results showed that 20 percent of patients had day time sleepiness, while the sleep disorder was prolong sleep latency and impaired sleep efficiency. In epilepsy characteristics, patients with complex partial seizure, intractable seizure or with multi-pharmacy were related with poor sleep quality. A total of 34 patients completed the serological, neurobehavior and brain magnetic resonance analysis. The results showed that patients with temporal lobe epilepsy had higher heat shock protein 70 and S100£]protein levels, while those with attacks more than twice per month had significant higher heat shock protein 70, S100£]protein and neuron specific enolase levels. Compared with the matched controls, the regions showing atrophy included hippocampus and parahippocampus, putamen, thalamus and supplementary motor areas. In correlation study, only heat shock protein 70 showed an inverse correlation with hippocampal volume (R square = 0.22, p = 0.007) after controlling for the effect of age. Conclusion: The study suggested that epilepsy risk characteristics, serological biomarkers, brain atrophic regions were important factors for day time sleepiness, sleep disturbances and neurobehavior changes in patients with epilepsy.

In eukaryotic cells, most proteins in the cytosol and nucleus are degraded via the ubiquitin-proteasome pathway. Ubiquitin is best known for its role in targeting proteins for degradation by the proteasome. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is found specifically in central and peripheral neurons, and is responsible for the removal of small peptide fragments from the ubiquitin chain and for co-translational processing of ubiquitin gene products to generate free monomeric ubiquitin. In response to extreme conditions, cells exhibit an up-regulation of heat shock protein (HSP) expression, which contributes to repair and protective mechanisms. Within the HSP family, HSP70 is the major inducible member that protects against cell death. Based on the pharmacologic property of organophosphates as an inhibitor of cholinesterase, it is generally contended that manifestations of organophosphate poisoning, including secretion and muscle fasciculation, stupor, cardiopulmonary collapse, respiratory failure, coma or death, result from accumulation of, and over-stimulation by acetylcholine at peripheral of central synapses. One approach in furthering our understanding on organophosphate poisoning is delineation of its potential protective mechanisms. In this regard, the information on the cellular and molecular mechanisms that underlie organophosphate poisoning has received attention. Our laboratory demonstrated previously that a crucial brain site via which mevinphos (Mev), an organophosphate insecticide of the P=O type, acts is the rostral ventrolateral medulla (RVLM), the medullary origin of premotor sympathetic neurons that are responsible for the maintenance of vasomotor tone. The phasic changes in cardiovascular events over the course of acute Mev intoxication also parallel fluctuations of the ¡§life-and-death¡¨ signals that emanate form the RVLM. Based on a rat model of organophosphate poisoning that provides continuous information on cellular and molecular mechanisms in the RVLM, the present study was undertaken to evaluate whether changes in protein level of UCH-L1 or HSP70 are associated with death arising from Mev intoxication. We also evaluated the efficacy of both of them in the neuroprotection against fatality during Mev intoxication. The first part of this study investigated whether UCH-L1 plays a neuroprotective role at the RVLM, where Mev acts to elicit cardiovascular toxicity. In Sprague-Dawley rats maintained under propofol anesthesia, Mev (960 &#x00B5;g/kg, i.v.) induced a parallel and progressive augmentation in UCH-L1 or ubiquitin expression at the ventrolateral medulla during the course of Mev intoxication. The increase in UCH-L1 level was significantly blunted on pretreatment with microinjection bilaterally into the RVLM of a transcription inhibitor, actinomycin D (5 nmol) or a translation inhibitor, cycloheximide (20 nmol). Compared to artificial cerebrospinal fluid (aCSF) or sense uch-L1 oligonucleotide (100 pmol) pretreatment, microinjection of an antisense uch-L1 oligonucleotide (100 pmol) bilaterally into the RVLM significantly increased mortality, reduced the duration of the phase I (¡§pro- life¡¨ phase), blunted the increase in ubiquitin expression in ventrolateral medulla, and augmented the induced hypotension in rats that received Mev. The second part of this study investigated whether HSP70 plays a neuroprotective role at the RVLM. Intravenous administration of Mev (960

This thesis analyzes the cohesiveness, and voting likeliness of the political groups in the European Parliament on Turkey between 1980-1996. The thesis consists of two main parts: in the first part the structure, and historical evoluation of the European Parliament has been analyzed. In the second part, the changes in Turkish politics between 1980-96, and the cohesiveness, and voting alliances of the political groups have been analyzed by using roll call vote data.

(理学療法基礎系7, 第42回日本理学療法学術大会)

<p>Inducible Heat shock protein (Hsp70i) is a protein chaperone that is utilized during tumorigenesis and viral infections for efficient propagation. Overexpression of Hsp70i is observed in a wide spectrum of human tumors, and this overexpression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Hsp70i aids in cancer cell propagation through regulation of anti-apoptotic and cell survival pathways. Furthermore, Hsp70i is induced following infection for several viruses and aids viral propagation, in part through regulation of anti-apoptotic pathways as well as promoting the folding of newly synthesized proteins. Due to the parallel role of Hsp70i in both cancer and viral pathogenesis, identification of small-molecule inhibitors selective for Hsp70i could provide tools for the development of novel therapeutics and further elucidate the role of Hsp70i in both cancer and viral infections.</p><p>To date, few Hsp70 inhibitors have been identified and characterized, and their efficacy in clinical settings is unknown. Through the fluorescence-linked enzyme chemoproteomic strategy (FLECS) screen, an allosteric inhibitor selective for Hsp70i was identified, called HS-72. We show that HS-72 is highly selective for Hsp70i, over the broader purinome and other Hsp70 family members, in particular the closely related constitutively active Hsp70 family member, Hsc70. Additionally, HS-72 acts as an allosteric inhibitor to induce a conformational change and inhibit Hsp70i activity. HS-72 displays hallmarks of Hsp70i inhibition in vitro by promoting Hsp70i substrate protein degradation, protein aggregation, and selective growth inhibition of cancer cells. In wild type mice HS-72 is well tolerated and a limited PK study shows HS-72 is bioavailable. Furthermore, in a MMTV-neu breast cancer mouse model, HS-72 shows efficacy to inhibit tumor growth and promote survival.</p><p>Due to the similar utilization of Hsp70i in cancer and viral pathogenesis, this suggests the potential for HS-72 as an antiviral agent. Dengue virus (DENV) is of great public health importance due to estimates of up to 400 million infections per year, coupled with the geographic distribution of the virus, which is now endemic in over 100 countries worldwide. There is also a pressing need for DENV interventions, owing to the lack of approved vaccines or antiviral therapies. DENV is reliant on host factors throughout the viral life cycle and Hsp70i has been implicated as a host factor in DENV pathogenesis. Additionally, the complete role of Hsp70i in DENV pathogenesis remains to be elucidated, highlighting a unique opportunity to use HS-72 as a tool to specifically probe Hsp70i function. In monocytes, Hsp70i is expressed at low levels preceding DENV infection, but Hsp70i expression is induced upon DENV infection. Furthermore, inducing Hsp70i expression prior to infection, correlates with an increase in DENV infection. Targeting Hsp70i with HS-72, results in a dose dependent reduction in DENV infected monocytes, while cell viability was maintained, through inhibiting the entry stage of the viral life cycle. Following infection, Hsp70i localizes to the cell surface and interacts with the DENV receptor complex to mediate viral entry. While, HS-72 treatment results in a disruption of the interaction of Hsp70i with the DENV receptor complex, yielding a reduction in infected cells. </p><p>Collectively this work further supports Hsp70i as an anticancer and anti-dengue virus target, and identifies HS-72, a chemical scaffold that is amenable to resynthesis and iteration, as an ideal starting point for a new generation of therapeutics targeting Hsp70i.</p> / Dissertation

No description available.

La protéine Nef du VIH-1 joue un rôle important dans la pathogenèse du VIH-1 en modulant les voies de signalisation de la cellule hôte. La signalisation par le TcR est essentielle à la sélection positive pour générer les cellules simples positives (SP) CD4+ et simples positives (SP) CD8+, processus largement dépendant de l’activité de la Src kinase Lck et de son habileté à lier la queue cytoplasmique des corécepteurs CD4 et CD8. Nous avons précédemment trouvé que l’expression de Nef dans le VIH ou VIS peut induire une sévère déplétion des thymocytes et une baisse d’expression du corécepteur CD4 à la membrane. Nous avons également montré que Nef bloque la génération des thymocytes doubles positifs (DP) CD4+ CD8+ en plus d’altérer la transition des cellules DP vers CD4+ SP. Par contre, ce phénotype est récupérable par plusieurs approches dont le croisement d’une souris transgéniques exprimant Nef avec une souris exprimant la forme constitutivement active de Lck Y505F. Les résultats indiquent que la maturation des cellules CD4+ est altérée par le dysfonctionnement de la signalisation CD4-Lck. Toutefois, les mécanismes moléculaires par lesquels Nef contribue au bloc de la génération des cellules CD4+ dans le thymus demeurent très imprécis. Dans cette étude, en utilisant des approches biochimiques et de microscopie confocale, nous avons trouvé que les thymocytes transgéniques Nef+ expriment plus de Lck que les thymocytes Nef-. Malgré cette augmentation, une partie significative de Lck est incapable d’atteindre la membrane plasmique. Cette fraction était significativement accumulée dans un compartiment intracellulaire des thymocytes transgéniques exprimant Nef. Également, en utilisant la technique d’essai kinase in vitro, nous avons trouvé que l’activité kinase de Lck est significativement augmentée dans les thymocytes transgéniques mais demeure stable suite à une stimulation par un α-CD3ε + α-CD4. Également, comparativement aux thymocytes Nef-, la kinase Lck dans les thymocytes transgéniques était résistante à la dégradation suite à une stimulation. En examinant le statut de c-Cbl, le principal régulateur négatif de Lck, nous avons montré que c-Cbl colocalise faiblement avec Lck, malgré son hyperphosphorylation constitutive. Ceci pourrait expliquer l’échec de la dégradation de Lck. En plus, nous avons trouvé que suite à une stimulation par un α-CD3ε + α-CD4, la phosphorylation de Zap-70 en tyrosine 493 par Lck est diminuée, résultant d’une importante baisse de l’activité kinase de Zap-70 et d’un bloc des premiers évènements de la voie de signalisation par le TcR. Ces données indiquent que la signalisation CD4-Lck est interrompue par la présence de Nef. / HIV-1 Nef protein plays an essential role in the HIV-1 pathogenesis by modulating the host signaling transduction pathways. TcR signalling is important for the thymic selection process to CD4 and CD8 single positive T cells and is greatly dependent on the activity of Src kinase Lck and its ability to bind to CD4 and CD8 cytoplasmic tail. We previously found that expression of HIV or SIV Nef can induce severe thymocytes depletion and downregulation of CD4 expression in Nef+ mice. We also recently showed that Nef blocks generation of double positive thymocytes and impairs DP to CD4+ SP T cells transition. The reversal of this phenotype was accomplished by several approaches, among them by crossing Nef+ mice with mice expressing constitutively active Lck Y505F. These results imply that the maturation of CD4+ T cells is disrupted due to impairment of Lck-mediated CD4 receptor signaling. However, the molecular mechanisms by which Nef contributes to the impairment in thymic CD4 generation remains largely unclear. In this study, using confocal microscopy and biochemical approaches, we found that Nef+ thymocytes express more Lck than the Nef- control. Despite of this increase, a significant portion of Lck molecules were unable to reach to the plasma membrane. It was significantly accumulated in the intracellular endosomal compartment of the Nef+ thymocytes. Moreover, using IVKA we found that the activity of Lck is significantly increased in Nef+ thymocytes but was not further increased upon stimulation by α-CD3ε, α-CD4 or α-CD3ε + α-CD4. Moreover, compared to Nef- controls, Lck kinase in Nef+ thymocytes was resistant to degradation upon stimulation. Examining the status of c-Cbl, the main negative regulator of Lck, showed that c-Cbl localized with Lck poorly, despite his constitutive hyperphosphorylation. This explains the failure of Lck degradation. In addition, we found that upon stimulation, Zap-70 phosphorylation at tyrosine 493 by Lck is decreased, resulting by a decrease of Zap-70 kinase activity and TcR proximal event block. These data indicate that CD4-Lck signaling was interrupted by the presence of Nef.

This study undertakes two major issues concerning the authenticity of Nahj al-Balaghah, namely, the compilation and composition of the book. Shii scholars, with almost no exception, have credited the compilation of Nahj al-Balaghah to al-Sharif al-Radi In contrast, Sunni scholars and Orientalists hold different opinions about the matter. The early scholars among Sunnis and their western counterparts mostly credited Murtada with Nahj al-Balaghah, while later scholars generally vacillate between the two brothers. This study attempts to resolve misconceptions concerning the compilation of the book. It also suggests that in all probability Radi is the compiler while there is hardly any evidence to credit Murtada. / The problem of the composition of Nahj al-Balaghah, namely, the attribution of its contents to Ali ibn Abi Talib is more problematic. Unlike the Sunni scholars, the Shiis believe that the contents of the book represent Alis discourses. This thesis examines the most important arguments of both opponents and proponents of the authenticity of Nahj al-Balaghah and suggests that since a large portion of the book is present in the earlier sources, the generalization of some Sunni scholars in doubting the entire book cannot be sustained. (Abstract shortened by UMI.)

ISRAELITE INTERACTIONS WITH GENTILES IN THE OLD TESTAMENT AND THE IMPLICATIONS REGARDING MISSIONS Nancy Jane Eavenson, Ph.D. The Southern Baptist Theological Seminary, 2011 Chair: Dr. Russell T. Fuller This dissertation examines the missional implications of teaching regarding Israelite interactions with Gentiles found in the Hebrew Scriptures. Chapter 1 defines what is meant in this study concerning mission and Israelite interactions with Gentiles. In addition, foundation is laid for the study by detailing presuppositions, history of perspectives on the topic, and the methodology. Chapter 2 surveys the witness present in the Hebrew Scriptures concerning God's expectations for Israel's interactions with Gentiles. First, principles are highlighted for interactions from the Torah narratives and legislation. Next principles are identified in passages outside of the Torah. Finally, principles are outlined that are derived from key phrases and overall themes spanning the entire body of Hebrew Scriptures. Chapter 3 studies specific examples of Israelite and Gentile interactions throughout the Hebrew Scriptures. Analysis is provided of the interactions in view of the foundational principles identified in chapter 2. Chapter 4 examines how the intertestamental Jews interpreted and applied teaching from the Hebrew Scriptures concerning their interactions with Gentiles. Primary attention is given to the Jewish writings of the Apocrypha, Pseudepigrapha, Josephus, and the Tannaim with references to NT opinion. Chapter 5 synthesizes the data from the Hebrew Scriptures and intertestamental witness and draws conclusions about God's intention for Israel in relation to the Gentiles. In addition, observations are made concerning Israel's application of principles from the Hebrew Scriptures concerning their interactions with Gentiles. Finally, implications of the study are drawn for current application. This work maintains that although many Israelites in the Hebrew Scriptures were unaware of God's intention for mission to Gentiles, some existed who understood God's desire and cooperated with God's mission. In addition, during the intertestamental period while many Jews failed to understand and act on God's mission to have His name glorified by Gentiles, others felt called to intentionally interact with Gentiles and actively sought to bring Gentiles to know and worship Yahweh as God.