Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal

Accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been proposed to be responsible for human aging and age-associated mitochondrial respiration defects. However, our previous findings suggested an alternative hypothesis of human aging—that epigenetic changes but not mutations regulate age-associated mitochondrial respiration defects, and that epigenetic downregulation of nuclear-coded genes responsible for mitochondrial translation [e.g., glycine C-acetyltransferase (GCAT), serine hydroxymethyltransferase 2 (SHMT2)] is related to age-associated respiration defects. To examine our hypothesis, here we generated mice deficient in Gcat or Shmt2 and investigated whether they have respiration defects and premature aging phenotypes. Gcat-deficient mice showed no macroscopic abnormalities including premature aging phenotypes for up to 9 months after birth. In contrast, Shmt2-deficient mice showed embryonic lethality after 13.5 days post coitum (dpc), and fibroblasts obtained from 12.5-dpc Shmt2-deficient embryos had respiration defects and retardation of cell growth. Because Shmt2 substantially controls production of N-formylmethionine-tRNA (fMet-tRNA) in mitochondria, its suppression would reduce mitochondrial translation, resulting in expression of the respiration defects in fibroblasts from Shmt2-deficient embryos. These findings support our hypothesis that age-associated respiration defects in fibroblasts of elderly humans are caused not by mtDNA mutations but by epigenetic regulation of nuclear genes including SHMT2

Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, butmight be useful for various other physical symptoms, including nausea, fatigue,dyspnea, and constipation. However, few studies have used TENS for treating thephysical symptoms of patients with advanced cancer. In this crossover trial, we assessthe effects of TENS on pain and other physical symptoms in 20 in-patients withadvanced cancer receiving palliative care. For 5-day phases between wash out periodsof 5 days, patients received TENS or non-TENS. TENS was delivered at four points: thecenter of the back for mainly nausea and dyspnea, on the back at the same dermatomallevel as the origin of the pain (100 Hz), and on both ankle joints for constipation (10Hz). The intensity of pain and the total opioid dose used during phases were recorded.Physical symptoms were evaluated using the European Organization for Research andTreatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care(QLQ-C15-PAL). Hematological and biochemical data were recorded before and afterthe TENS phase. The average pain and total number of opioid rescue doses weresignificantly reduced by TENS. TENS tended to improve nausea and appetite loss, butnot constipation. There were no effects on hematological and biochemical parameters.Use of TENS could safely improve pain, nausea, and appetite loss in patients withadvanced cancer. Although it cannot be used as a substitute for opioids and otherpharmaceutical treatment, it may be useful to support palliative care

Probing the universal role of Sec1/Munc18 proteins by mutagenesis of yeast Sec1

The Sec1/Munc18 (SM) family of proteins is essential for intracellular vesicle trafficking in eukaryotic cells. Sec1, the SM protein at the yeast plasma membrane, is required for membrane fusion leading to secretion and cell growth. Fusion of exocytic vesicles targeted to the plasma membrane occurs in two stages. The vesicle is first tethered to the membrane by a protein complex called the exocyst. Essential membrane-associated proteins known as the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) located on both the plasma membrane and the vesicle assemble together to form a stable four-helix bundle called the SNARE complex. In the second step, Sec1 binds to the assembled SNARE complex and there is fusion of the two membranes. Sec1 has been shown to bind the SNARE complex, but the exact role and mechanism of Sec1 function remains unknown. In this study, site-directed mutagenesis was used to investigate the significance of highly conserved salt bridges in SM proteins and define the SNARE complex binding surface on Sec1 with data from random mutants studied by Yi-Shan Cheng and Jenna Hutton. In addition, Sec1 mutants with a novel phenotype were generated that may support a role for Sec1 in vesicle tethering.M.S.Includes bibliographical references (p. 64-68)

Effects of transcutaneous electrical nerve stimulation on physical symptoms in advanced cancer patients receiving palliative care

Transcutaneous electrical nerve stimulation (TENS) is primarily used for pain, but might be useful for various other physical symptoms, including nausea, fatigue, dyspnea, and constipation. However, few studies have used TENS for treating the physical symptoms of patients with advanced cancer. In this crossover trial, we assess the effects of TENS on pain and other physical symptoms in 20 in-patients with advanced cancer receiving palliative care. For 5-day phases between wash out periods of 5 days, patients received TENS or non-TENS. TENS was delivered at four points: the center of the back for mainly nausea and dyspnea, on the back at the same dermatomal level as the origin of the pain (100 Hz), and on both ankle joints for constipation (10 Hz). The intensity of pain and the total opioid dose used during phases were recorded. Physical symptoms were evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative Care (QLQ-C15-PAL). Hematological and biochemical data were recorded before and after the TENS phase. The average pain and total number of opioid rescue doses were significantly reduced by TENS. TENS tended to improve nausea and appetite loss, but not constipation. There were no effects on hematological and biochemical parameters. Use of TENS could safely improve pain, nausea, and appetite loss in patients with advanced cancer. Although it cannot be used as a substitute for opioids and other pharmaceutical treatment, it may be useful to support palliative care