A Shared Space

Where it divides Arizona and Sonora, the international boundary between Mexico and the United States is both a political reality, literally expressed by a fence, and, to a considerable degree, a cultural illusion. Mexican, Anglo, and Native American cultures straddle the fence; people of various ethnic backgrounds move back and forth across the artificial divide, despite increasing obstacles to free movement. On either side is found a complex cultural mix of ethnic, religious, and occupational groups. In A Shared Space James Griffith examines many of the distinctive folk expressions of this varied cultural region.https://digitalcommons.usu.edu/usupress_pubs/1067/thumbnail.jp

Advances in the delivery of RNA therapeutics: from concept to clinical reality

Abstract - The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic.Juvenile Diabetes Research Foundation (postdoctoral fellowship Grant 3-PDF-2017-383-A-N)National Cancer Institute (U.S.) (Cancer Center Support (core) Grant P30-CA1405

Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension

Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.National Institutes of Health (U.S.) (U54‐CA151884)National Institutes of Health (U.S.) (R01‐DE016516‐06)National Institutes of Health (U.S.) (EB000244

Synergistic Induction of Apoptosis in Primary B-CLL Cells after Treatment with Recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Histone Deacetylase Inhibitors

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently being investigated as a therapeutic agent for a variety of malignancies, as it triggers apoptosis specifically in transformed cells. However, TRAIL use as a stand alone therapeutic is hampered by the fact that many primary tumor cells are resistant to TRAIL-mediated apoptosis. Here, we investigated the extent to which pretreatment of TRAIL-resistant primary B-cell chronic lymphocytic leukemia (B-CLL) cells with histone deacetylase inhibitors (HDACis) could render them susceptible to killing by TRAIL. We found that HDAC inhibition in B-CLL cells led to increased TRAIL receptor expression, increased caspase activation, decreased expression of antiapoptotic regulators such as Bcl-2, and ultimately, enhanced TRAIL-induced apoptosis. Importantly, untransformed peripheral blood mononuclear cells remained largely resistant to TRAIL, even in the presence of HDACis. These results suggest that combination therapies using HDAC inhibition and TRAIL could prove beneficial for the treatment of B-CLL

Peracute Infection of Swine With Salmonella

It has recently been experimentally demonstrated that pigs exposed naturally to Salmonella on the floor of abattoir holding pens can become infected between two and six hours after being placed in the pens. In addition we have demonstrated that tonsillar tissue are almost immediately culture positive following such exposure under experimental conditions. The objective of this study was to determine the shortest amount of time necessary for infection of selected tissues and to determine if the tonsil served as a route for Salmonella entry into lymphoid tissues draining the tonsil. Forty-four Salmonella-negative, market age pigs (90 to 110 kg) were fasted overnight and exposed to approximately 2 X 106 Salmonella enterica serotype Typhimurium strain X4232 (nalidixic acid resistant). The bacteria were mixed with a fecal slurry and the slurry spread on the floor of the pens. Pigs were euthanized at 15, 30, 45, 60 and 120 minutes following initial exposure. Tonsil of the soft palate, medial retropharyngeal lymph node, ileocecal lymph node, a five centimeter section of the terminal ileum, cecal contents and 100 ml of blood were cultured for Salmonella. Strain X4232 was isolated from 98 % (43/44) of tonsils. Strain X4232 was isolated from the ileocecal lymph node within 45 minutes (2/9 pigs), terminal ileum within 15 minutes (1/9 pigs), cecal contents within 15 minutes (1/9 pigs), and blood within 45 minutes (1/9 pigs). Strain X4232 was not recovered from the medial retropharyngeal lymph node, indicating that the organism did not move rapidly into this node from the tonsil of the soft palate. Results of this study indicate that Salmonella can be recovered from selected tissues in market age swine in less than the normal two hour abattoir holding time

Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets.United States. National Institutes of Health (5R01HL75092)National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (MR/J007412/1

The Ursinus Weekly, October 31, 1968

Evaluation favorable; Provincialism assailed • Nixon overwhelms Humphrey; Rightward trend reflected • Founders\u27 Day honors alumni; Honorary degrees conferred • Secret society members elected • Placement Office offers services to \u2769 graduates • Barbara Bruzgo crowned \u2768 Homecoming Queen • Editorial: Activities chaos • Grand Dragon at U.C.; Klan views stated • Grape conspiracy • Letters to the editor • Formation of a fourth party • Editorial: Literary dilemma • Arts forum features four faculty speakers • Opinion: Sulphuric acid + gas • Bears rip Garnet in Homecoming game after humiliating defeat at Muhlenberg • Gillespie and Gane selected as co-captains • Soccer team defeated by Mules and Delaware as Grau is injured • Inside track: And Drexel makes eighteen • Bearettes and West Chester battle here next Thursday • Magicians, Homecoming and R. J. Whatley • Flowers are still undefeated as I.T.F.L. enters fourth week; Beta Sig upsets Sig Rho, 12-7 • Del Valley\u27s QB is man to watch • Hockey team destroys opponents; Cash and Landis star, score 13 • Greek gleaningshttps://digitalcommons.ursinus.edu/weekly/1165/thumbnail.jp