The Sheddase Activity of ADAM10/ADAM17 on CXCL16 Increases Proliferation and Survival of Colorectal Cancer Cells

CXCL16 is an interferon-inducible chemokine of the CXC-subfamily and functions as an adhesion molecule, when membrane bound, and a chemoattractant when soluble. Upregulation of cell associated CXCL16 (cCXCL16) in colorectal cancer is associated with increased tumor infiltrating lymphocytes and good prognosis. ADAM10 and ADAM17 are metalloproteinases responsible for cleaving CXCL16, releasing soluble CXCL16 (sCXCL16) and contributing to proliferation and migration of mesangial cells, in kidney inflammatory disease. We hypothesize that cCXCL16 is a substrate for ADAM10 and ADAM17 cleavage in colorectal cancer, releasing sCXCL16, which mediates cell proliferation. To this end, we first identified CXCL16 in the human colon carcinoma cell line, RKO, by immunohistochemistry. cCXCL16 was found in the membrane, cytoplasm and nucleus. We treated RKO, in vitro, with an inflammatory cytokine mix containing 1.4 nM rhIFN[gamma], 2.0 nM rhTNF[alpha] and 2.0 nM rhIL1[beta] to increase the cleavage of cCXCL16 to sCXCL16. Overnight incubation with the cytokine mix significantly (P=.004) increased the release of sCXCL16 compared to normal conditions. To confirm that a metalloproteinase is responsible for the cleavage of cCXCL16, we used a broad spectrum metalloproteinase inhibitor, GM6001, in combination with inflammatory stimulation, in cell culture. We assayed the supernatant using ELISA for sCXCL16. GM6001 at 100 [mu]M decreased sCXCL16 to levels indistinguishable from the background. Using siRNA, we knocked down the expression of ADAM10 and ADAM17, independently, to determine if the activity of each on cCXCL16 was mediated by inflammatory stimulation. It was shown that ADAM10 constitutively cleaved cCXCL16, and ADAM17 cleavage activity was induced by inflammatory stimulation. To determine if sCXCL16 increased colorectal cancer cell (CRC) proliferation through ligand-receptor binding, we treated cells with a range of rhCXCL16 from 3.125-100 ng/mL. rhCXCL16 did not increase RKO proliferation at doses up to 100 ng/mL. We used GM6001, to inhibit the cleavage of cCXCL16 into sCXCL16 then performed an ATPase assay and 6 day cell cycle analysis, under inflammatory stimulation. Increased cleavage of cCXCL16 induced by inflammatory stimulation with the cytokine mix containing 1.4 nM rhIFN[gamma], 2.0 nM rhTNF[alpha] and 2.0 nM rhIL1[beta], increased RKO proliferation and reduced apoptosis. We conclude that ADAM10 and ADAM17 cleavage of cCXCL16 to sCXCL16 is increased by ADAM17 activation with inflammatory stimulation. The cleavage of the extracellular portion from cCXCL16 is associated with increased proliferation and decreased apoptosis of colorectal cancer cells

Alien Registration- Talton, Jasper J. (Portland, Cumberland County)

https://digitalmaine.com/alien_docs/21334/thumbnail.jp

An Investigation Of Elementary Guidance In Pickens County

It was the purpose of this study (1) to investigate the status of elementary guidance as it exists today through historical research; (2) to survey the members of the elementary faculty of Pickens County, Georgia, with regard to their opinion of the value of the various guidance and counseling activities conducted under a pilot study; and (3) to reach a conclusion regarding the organization and administration of an elementary guidance program that would meet the needs of the students and the community

Factors of inclusive education for children with autism (UK experience)

This article identifies factors, which influence the successful inclusion of children and young people with ASD in mainstream schools in the UK. The results present seven themes that are identified from the literature as factors that influence the successful inclusion of individuals with ASD within mainstream schools. The identified themes are: Support Staff, Communication, Staff Training, Relationships with Peers, Interventions and Teaching Strategies, Organisational Culture and Attitudes and Relationships with Teacher. The implications associated with these factors are then discussed

Models of gestational diabetes and offspring outcomes in mice

Gestational diabetes mellitus (GDM) is the most common pregnancy disorder. GDM pregnancies result in offspring that are more likely to develop metabolic syndrome in adolescence than the background population. As offspring experience these adverse effects during their reproductive years, GDM has the potential to propagate disease for many generations. Hyperleptinemia, a key characteristic of both GDM and maternal obesity has not been studied in isolation to determine its role in programming offspring outcomes. Hyperglycemia in the absence of obesity has also not been widely modeled without surgical or chemical means. My research goal was to study the offspring outcomes of these two facets of GDM in C57B6 mice. We observed that maternal hyperleptinemia improved offspring insulin sensitivity, and protected the offspring from developing glucose intolerance. These outcomes were partly mediated by reduced fatty acid accumulation in the liver. Our findings suggest that maternal hyperleptinemia is protective of offspring glucose control. Maternal hyperglycemia in lean dams increased offspring adiposity while glucose tolerance was unchanged. This effect was mediated by a preference for glucose over lipids for substrate utilization, and multiple gene expression changes in the male adipose tissue and liver. Our results indicate that lean maternal hyperglycemia results in metabolically healthy obesity in offspring. This work demonstrates that GDM in lean women may not negatively affect glucose tolerance, and that maternal hyperleptinemia may mediate this, through improving insulin sensitivity. It supports other data that suggest that the liver and adipose tissue are key regulators of whole body metabolism.Includes biblographical reference

Developmental Origins of Ovarian Disorder: Impact of Maternal Lean Gestational Diabetes on the Offspring Ovarian Proteome in Mice

Gestational diabetes mellitus (GDM) is an obstetric disorder affecting approximately 10% of pregnancies. The 4HFHS (High Fat High Sucrose) mouse model emulates GDM in lean women. Dams are fed a HFHS diet one week prior to mating and throughout gestation resulting in inadequate insulin response to glucose in mid-late pregnancy. The offspring of HFHS dams have increased adiposity, thus, we hypothesized that maternal metabolic alterations during lean GDM would compromise ovarian function in offspring both basally and in response to a control or HFHS diet in adulthood. Briefly, DLPL were lean dams and control diet pups; DLPH were lean dams and HFHS pups; DHPL were HFHS dams and control diet pups and DHPH were HFHS dams and HFHS pups. A HFHS challenge in the absence of maternal GDM (DLPL vs. DLPH) increased 3 and decreased 30 ovarian proteins. Maternal GDM in the absence of a dietary stress (DLPL vs. DHPL) increased abundance of 4 proteins and decreased abundance of 85 proteins in the offspring ovary. Finally, 87 proteins increased, and 4 proteins decreased in offspring ovaries due to dietary challenge and exposure to maternal GDM in utero (DLPL vs. DHPH). Canopy FGF signaling regulator 2 (CNPY2), Deleted in azoospermia-associated protein 1 (DAZAP1), Septin 7 (SEPT7), and Serine/arginine rich splicing factor 2 (SRSF2) were altered across multiple offspring groups. Together, these findings suggest a possible impact on fertility and oocyte quality in relation to GDM exposure in utero as well as in response to a western diet in later life

Sino-Soviet relations, 1968-1973 as illustrated by the official Soviet press

The change which occurred from 1949 to 1973 in the relations between the Union of Soviet Socialist Republics and the People’s Republic of China (P. R. C.) was not foreseen by most scholars in the field. Only when the two nations had all but come to blows did the western world discover what the eastern world had already known: the “monolithic� bloc was something less than monolithic. In spite of the common ideology, China and Russia had serious differences of opinion on a wide variety of questions. To understand modern trends, which are usually the end result of past events, the scholar must examine the background of a problem. Beginning in 1634, and even earlier, the Chinese were inundated with adventurous Russian settlers, who, encouraged by their ambitious Tsars, endeavored to turn the Amur River area and Mongolia into Russian provinces. The decaying Manchu Empire tried desperately to turn back the tide of Russian expansion but failed. The unequal treaties of Aigun, Peking, and Tientsin, to name only a few, remained in the minds of the Chinese to color their attitudes in later days. The emergence of the P. R. C. appeared to have created a monolithic bloc of socialist nations. The first few years of their relations were generally calm and gave little hint of the trouble to come. Then, in 1956, the revelation of Khrushchev’s speech to the Twentieth CPSU congress, with its programs of “peaceful coexistence� with the West and “de-Stalinization,� led China to seek her own path to socialism, the Great Leap Forward. Following the failure of the Great Leap, China fell into the turmoil of the Cultural Revolution, which was mostly designed to purge the party of “anti-Maoist� elements. The Cultural Revolution gave rise to some of the most vicious exchanges of polemics between the two governments. And indirectly, affected relations on the border. The Czechoslovakian crisis of August, 1968, found the Soviets trying to justify their brutal suppression of Czech liberties to the Chinese. The Soviet Union suffered a serious loss of trust in the socialist bloc countries, who wondered if they would be next. China gained in prestige because of her severe criticism of the Soviets. The war in Vietnam held dangers for both nations. Neither could afford to allow the United States to win, but both feared the emergence of a rival socialist nation in Asia should the Vietnamese gain a decisive victory. Therefore, both China and the U. S. S. R. supplied the Vietnamese in a limited manner, accused the U. S. of imperialism and each other of holding back aid, and worked toward limiting the conflict. The emergence of détente with the West offered China and the Soviet Union an opportunity to ease tensions with the U. S., but increased competition between the two for the allegiance of the non-aligned nations. The Soviets were slow to react to the onset of “ping-pong� diplomacy, possibly not realizing the extent of change which had occurred in Peking and Washington. Moscow treated Nixon’s trip to China as a “show� and was shocked to discover that Peking and Washington were really coming to a form of limited rapprochement. Criticism of the Cultural Revolution continued to be a main-stay of Soviet polemics. The tensions of the Spring of 1969 led to deaths on the river borders, intermittent conferences on “consolidation� on existing borders, and a running dispute on what constituted an “unequal treaty.� Finally, the India-Pakistan War of 1971 gave the first opportunity for the Chinese to expand their attacks on the Soviets in the framework of the United Nations. They took the side of Pakistan with the U. S., in opposition to India and the Soviet Union. The observations made during the study of Chinese and Russian Relations led to the conclusion that the dispute cannot be attributed to one factor only. Both sides use ideology more as a tool than anything else, and territorial claims appear to be matters of principle to the Chinese, rather than a true cause for war. If the recent history of their relations is indicative of future trends, the likelihood of war between China and Russia appears remote. The vast differences of society and outlook between the two and the inescapable factor of national interest, however, will not allow a true reconciliation for some time and may lead to a worsening of their relations before they improve, if indeed any improvement is possible