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Background: To investigate the mechanisms driving regulatory evolution across tissues, we experimentally mapped promoters, enhancers, and gene expression in the liver, brain, muscle, and testis from ten diverse mammals., Results: The regulatory landscape around genes included both tissue-shared and tissue-specific regulatory regions, where tissue-specific promoters and enhancers evolved most rapidly. Genomic regions switching between promoters and enhancers were more common across species, and less common across tissues within a single species. Long Interspersed Nuclear Elements (LINEs) played recurrent evolutionary roles: LINE L1s were associated with tissue-specific regulatory regions, whereas more ancient LINE L2s were associated with tissue-shared regulatory regions and with those switching between promoter and enhancer signatures across species., Conclusions: Our analyses of the tissue-specificity and evolutionary stability among promoters and enhancers reveal how specific LINE families have helped shape the dynamic mammalian regulome.

Background: Necrotizing enterocolitis (NEC) involves impaired ileal blood flow due to alterations in vascular tone control and intestinal angiogenesis. Platelet-derived growth factor (PDGF) is a mediator of normal angiogenesis in intestinal epithelium. We hypothesized that gene dysregulation during experimental NEC results in altered PDGF expression., Methods: Sprague-Dawley rats were randomized to groups by litter. Controls were delivered vaginally and dam-fed. NEC groups were delivered prematurely by cesarean section and subjected to an established NEC protocol. Ileum was obtained at 0, 12, 24, 48, 72, and 96 h of life from all animals (N = 108 animals). Western blot analysis was carried out for every time point, and samples were evaluated by immunohistochemistry. Antibodies against PDGF-A, PDGF-B, and their receptors, PDGFR-α and PDGFR-β, were used. Statistical analysis was performed using two-way analysis of variance with a priori P < 0.05., Results: Ileal PDGF-A concentration was higher in controls versus NEC from 24-96 h of life. Its receptor, PDGFR-α, was low in concentration in both groups at all time points. PDGF-B concentration was increased in controls at 24 and 72 h of life but decreased at the 48-h mark. Its receptor, PDGFR-β, was also low in both groups at 12 and 24 h but increased in controls at 48 and 72 h., Conclusions: These data support our hypothesis that PDGF and PDGF receptor expression are altered in experimental NEC. Dysregulation of PDGF during intestinal maturation could contribute to the development of NEC. Further investigation into this pathway could yield new therapeutic targets for this devastating disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Major histocompatibility complex (MHC) class I molecules are ligands for T-cell receptors of CD8(+) T cells and inhibitory receptors of natural killer cells. Assembly of the heavy chain, light chain, and peptide components of MHC class I molecules occurs in the endoplasmic reticulum (ER). Specific assembly factors and generic ER chaperones, collectively called the MHC class I peptide loading complex (PLC), are required for MHC class I assembly. Calreticulin has an important role within the PLC and induces MHC class I cell surface expression, but the interactions and mechanisms involved are incompletely understood. We show that interactions with the thiol oxidoreductase ERp57 and substrate glycans are important for the recruitment of calreticulin into the PLC and for its functional activities in MHC class I assembly. The glycan and ERp57 binding sites of calreticulin contribute directly or indirectly to complexes between calreticulin and the MHC class I assembly factor tapasin and are important for maintaining steady-state levels of both tapasin and MHC class I heavy chains. A number of destabilizing conditions and mutations induce generic polypeptide binding sites on calreticulin and contribute to calreticulin-mediated suppression of misfolded protein aggregation in vitro. We show that generic polypeptide binding sites per se are insufficient for stable recruitment of calreticulin to PLC substrates in cells. However, such binding sites could contribute to substrate stabilization in a step that follows the glycan and ERp57-dependent recruitment of calreticulin to the PLC.

Methamphetamine, called meth, crystal, or speed, is a central nervous system stimulant that can be injected, smoked, snorted, or ingested orally; prolonged use at high levels results in dependence. Methamphetamine (MA) is a derivative of amphetamine, which was widely prescribed in the 1950s and 1960s as a medication for depression and obesity, reaching a peak of 31 million prescriptions in the United States in 1967. Until the late 1980s, illicit use and manufacture of MA was endemic to California, but the MA user population has recently broadened in nature and in regional distribution, with increased use occurring in midwestern states. An estimated 4.7 million Americans (2.1% of the U.S. population) have tried MA at some time in their lives. Short- and long-term health effects of MA use include stroke, cardiac arrhythmia, stomach cramps, shaking, anxiety, insomnia, paranoia, hallucinations, and structural changes to the brain. Children of MA abusers are at risk of neglect and abuse, and the use of MA by pregnant women can cause growth retardation, premature birth, and developmental disorders in neonates and enduring cognitive deficits in children. MA-related deaths and admissions to hospital emergency rooms are increasing. Although inpatient hospitalization may be indicated to treat severe cases of long-term MA dependence, optimum treatment for MA abusers relies on an intensive outpatient setting with three to five visits per week of comprehensive counseling for at least the first three months. The burgeoning problems of increased MA use must be addressed by adequate treatment programs suitable for a variety of user types.

The results of the fourth anesthesia morbidity and mortality survey of the members of the Southern California Society of Oral and Maxillofacial Surgeons is presented. A questionnaire was mailed to 203 active members in February 1988. All responded or were contacted by Society staff and a response obtained. Results were compared with the three previous studies and revealed trends in training, length of time in practice, modes of practice, equipment used, medications used, numbers of anesthetic procedures performed, and specific instances of morbidity and mortality. Over the 20-year period from 1968 through 1987, seven deaths occurred in more than 4,700,000 anesthetics given, a rate of one death in each 673,000 anesthetics administered.