Strangers in blood Feerick, Jean
Strangers in blood,
c2010, 20101002, 2010, 2010-10-02, 2010-01-01
eBook
Strangers in Bloodexplores, in a range of early modern literature, the association between migration to foreign lands and the moral and physical degeneration of individuals.
Epithelial-mesenchymal transition (EMT) is important during embryonic cell layer movement and tumor cell invasiveness. EMT converts adherent epithelial cells to motile mesenchymal cells, favoring ...metastasis in the context of cancer progression. Transforming growth factor-β (TGF-β) triggers EMT via intracellular Smad transducers and other signaling proteins. We previously reported that the high mobility group A2 (HMGA2) gene is required for TGF-β to elicit EMT in mammary epithelial cells. In the present study we investigated the molecular mechanisms by which HMGA2 induces EMT. We found that HMGA2 regulates expression of many important repressors of E-cadherin. Among these, we analyzed in detail the zinc-finger transcription factor SNAIL1, which plays key roles in tumor progression and EMT. We demonstrate that HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. Furthermore, we observed that HMGA2 cooperates with the TGF-β/Smad pathway in regulating SNAIL1 gene expression. The mechanism behind this cooperation involves physical interaction between these factors, leading to an increased binding of Smads to the SNAIL1 promoter. SNAIL1 seems to play the role of a master effector downstream of HMGA2 for induction of EMT, as SNAIL1 knock-down partially reverts HMGA2-induced loss of epithelial differentiation. The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program.
One mechanism by which communication between the endoplasmic reticulum (ER) and mitochondria is achieved is by close juxtaposition between these organelles via mitochondria-associated membranes ...(MAM). The MAM consist of a region of the ER that is enriched in several lipid biosynthetic enzyme activities and becomes reversibly tethered to mitochondria. Specific proteins are localized, sometimes transiently, in the MAM. Several of these proteins have been implicated in tethering the MAM to mitochondria. In mammalian cells, formation of these contact sites between MAM and mitochondria appears to be required for key cellular events including the transport of calcium from the ER to mitochondria, the import of phosphatidylserine into mitochondria from the ER for decarboxylation to phosphatidylethanolamine, the formation of autophagosomes, regulation of the morphology, dynamics and functions of mitochondria, and cell survival. This review focuses on the functions proposed for MAM in mediating these events in mammalian cells. In light of the apparent involvement of MAM in multiple fundamental cellular processes, recent studies indicate that impaired contact between MAM and mitochondria might underlie the pathology of several human neurodegenerative diseases, including Alzheimer's disease. Moreover, MAM has been implicated in modulating glucose homeostasis and insulin resistance, as well as in some viral infections.
•Mitochondria-associated membranes (MAM) are part of the endoplasmic reticulum (ER).•MAM are reversibly tethered to mitochondria.•Import of some lipids into mitochondria occurs via the MAM.•MAM regulate calcium homeostasis, mitochondrial function, autophagy and apoptosis.•MAM are implicated in neurodegenerative diseases and glucose homeostasis in humans.
Cholesterol is required for the growth and viability of mammalian cells and is an obligate precursor for steroid hormone synthesis. Using a loss-of-function screen for mutants with defects in ...intracellular cholesterol trafficking, a Chinese hamster ovary cell mutant with haploinsufficiency of the U17 snoRNA was isolated. U17 is an H/ACA orphan snoRNA, for which a function other than ribosomal processing has not previously been identified. Through expression profiling, we identified hypoxia-upregulated mitochondrial movement regulator (HUMMR) mRNA as a target that is negatively regulated by U17 snoRNA. Upregulation of HUMMR in U17 snoRNA-deficient cells promoted the formation of ER-mitochondrial contacts, decreasing esterification of cholesterol and facilitating cholesterol trafficking to mitochondria. U17 snoRNA and HUMMR regulate mitochondrial synthesis of steroids in vivo and are developmentally regulated in steroidogenic tissues, suggesting that the U17 snoRNA-HUMMR pathway may serve a previously unrecognized, physiological role in gonadal tissue maturation.
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•Haploinsufficiency of U17 snoRNA alters intracellular cholesterol trafficking•HUMMR acts downstream of U17 snoRNA to regulate cholesterol delivery to mitochondria•U17 snoRNA and HUMMR developmentally regulate steroidogenesis in vivo
Through a genetic screen, Jinn et al. identify the small nucleolar RNA U17 as a regulator of cellular cholesterol homeostasis. U17, via its target mRNA encoding HUMMR, an outer mitochondrial membrane adaptor protein, modulates ER-mitochondria contacts to regulate cholesterol flux to mitochondria and steroid hormone synthesis in vivo.
Arguing that the commercial stage depended on the unprecedented demographic growth and commercial vibrancy of London to fuel its own development, Jean E. Howard posits a particular synergy between ...the early modern stage and the city in which it flourished. In London comedy, place functions as the material arena in which social relations are regulated, urban problems negotiated, and city space rendered socially intelligible. Rather than simply describing London, the stage participated in interpreting it and giving it social meaning. Each chapter of this book focuses on a particular place within the city-the Royal Exchange, the Counters, London's whorehouses, and its academies of manners-and examines the theater's role in creating distinctive narratives about each. In these stories, specific locations are transformed into venues defined by particular kinds of interactions, whether between citizen and alien, debtor and creditor, prostitute and client, or dancing master and country gentleman. Collectively, they suggest how city space could be used and by whom, and they make place the arena for addressing pressing urban problems: demographic change and the influx of foreigners and strangers into the city; new ways of making money and losing it; changing gender roles within the metropolis; and the rise of a distinctive "town culture" in the West End. Drawing on a wide range of familiar and little-studied plays from four decades of a defining era of theater history,Theater of a Cityshows how the stage imaginatively shaped and responded to the changing face of early modern London.
This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including ...the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events. Moreover, mitochondrial function is severely impaired when the PE content of mitochondria is reduced below a threshold level. The discovery and implications of the existence of membrane contact sites between the endoplasmic reticulum and mitochondria and their relevance for PS and PE metabolism, as well as for mitochondrial function, are also discussed. Many of the recent advances in these fields are due to the use of isotope labeling for tracing biochemical pathways. In addition, techniques for disruption of specific genes in mice are now widely used and have provided major breakthroughs in understanding the roles and metabolism of PS and PE in vivo.
Pelvic floor muscle training (PFMT) is the most commonly used physical therapy treatment for women with stress urinary incontinence (SUI). It is sometimes also recommended for mixed urinary ...incontinence (MUI) and, less commonly, urgency urinary incontinence (UUI).This is an update of a Cochrane Review first published in 2001 and last updated in 2014.
To assess the effects of PFMT for women with urinary incontinence (UI) in comparison to no treatment, placebo or sham treatments, or other inactive control treatments; and summarise the findings of relevant economic evaluations.
We searched the Cochrane Incontinence Specialised Register (searched 12 February 2018), which contains trials identified from CENTRAL, MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, ClinicalTrials.gov, WHO ICTRP, handsearching of journals and conference proceedings, and the reference lists of relevant articles.
Randomised or quasi-randomised controlled trials in women with SUI, UUI or MUI (based on symptoms, signs or urodynamics). One arm of the trial included PFMT. Another arm was a no treatment, placebo, sham or other inactive control treatment arm.
At least two review authors independently assessed trials for eligibility and risk of bias. We extracted and cross-checked data. A third review author resolved disagreements. We processed data as described in the Cochrane Handbook for Systematic Reviews of Interventions. We subgrouped trials by diagnosis of UI. We undertook formal meta-analysis when appropriate.
The review included 31 trials (10 of which were new for this update) involving 1817 women from 14 countries. Overall, trials were of small-to-moderate size, with follow-ups generally less than 12 months and many were at moderate risk of bias. There was considerable variation in the intervention's content and duration, study populations and outcome measures. There was only one study of women with MUI and only one study with UUI alone, with no data on cure, cure or improvement, or number of episodes of UI for these subgroups.Symptomatic cure of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were eight times more likely to report cure (56% versus 6%; risk ratio (RR) 8.38, 95% confidence interval (CI) 3.68 to 19.07; 4 trials, 165 women; high-quality evidence). For women with any type of UI, PFMT groups were five times more likely to report cure (35% versus 6%; RR 5.34, 95% CI 2.78 to 10.26; 3 trials, 290 women; moderate-quality evidence).Symptomatic cure or improvement of UI at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT groups were six times more likely to report cure or improvement (74% versus 11%; RR 6.33, 95% CI 3.88 to 10.33; 3 trials, 242 women; moderate-quality evidence). For women with any type of UI, PFMT groups were two times more likely to report cure or improvement than women in the control groups (67% versus 29%; RR 2.39, 95% CI 1.64 to 3.47; 2 trials, 166 women; moderate-quality evidence).UI-specific symptoms and quality of life (QoL) at the end of treatment: compared with no treatment or inactive control treatments, women with SUI who were in the PFMT group were more likely to report significant improvement in UI symptoms (7 trials, 376 women; moderate-quality evidence), and to report significant improvement in UI QoL (6 trials, 348 women; low-quality evidence). For any type of UI, women in the PFMT group were more likely to report significant improvement in UI symptoms (1 trial, 121 women; moderate-quality evidence) and to report significant improvement in UI QoL (4 trials, 258 women; moderate-quality evidence). Finally, for women with mixed UI treated with PFMT, there was one small trial (12 women) reporting better QoL.Leakage episodes in 24 hours at the end of treatment: PFMT reduced leakage episodes by one in women with SUI (mean difference (MD) 1.23 lower, 95% CI 1.78 lower to 0.68 lower; 7 trials, 432 women; moderate-quality evidence) and in women with all types of UI (MD 1.00 lower, 95% CI 1.37 lower to 0.64 lower; 4 trials, 349 women; moderate-quality evidence).Leakage on short clinic-based pad tests at the end of treatment: women with SUI in the PFMT groups lost significantly less urine in short (up to one hour) pad tests. The comparison showed considerable heterogeneity but the findings still favoured PFMT when using a random-effects model (MD 9.71 g lower, 95% CI 18.92 lower to 0.50 lower; 4 trials, 185 women; moderate-quality evidence). For women with all types of UI, PFMT groups also reported less urine loss on short pad tests than controls (MD 3.72 g lower, 95% CI 5.46 lower to 1.98 lower; 2 trials, 146 women; moderate-quality evidence).Women in the PFMT group were also more satisfied with treatment and their sexual outcomes were better. Adverse events were rare and, in the two trials that did report any, they were minor. The findings of the review were largely supported by the 'Summary of findings' tables, but most of the evidence was downgraded to moderate on methodological grounds. The exception was 'participant-perceived cure' in women with SUI, which was rated as high quality.
Based on the data available, we can be confident that PFMT can cure or improve symptoms of SUI and all other types of UI. It may reduce the number of leakage episodes, the quantity of leakage on the short pad tests in the clinic and symptoms on UI-specific symptom questionnaires. The authors of the one economic evaluation identified for the Brief Economic Commentary reported that the cost-effectiveness of PFMT looks promising. The findings of the review suggest that PFMT could be included in first-line conservative management programmes for women with UI. The long-term effectiveness and cost-effectiveness of PFMT needs to be further researched.
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are metabolically related membrane aminophospholipids. In mammalian cells, PS is required for targeting and function of several intracellular ...signaling proteins. Moreover, PS is asymmetrically distributed in the plasma membrane. Although PS is highly enriched in the cytoplasmic leaflet of plasma membranes, PS exposure on the cell surface initiates blood clotting and removal of apoptotic cells. PS is synthesized in mammalian cells by two distinct PS synthases that exchange serine for choline or ethanolamine in phosphatidylcholine (PC) or PE, respectively. Targeted disruption of each PS synthase individually in mice demonstrated that neither enzyme is required for viability whereas elimination of both synthases was embryonic lethal. Thus, mammalian cells require a threshold amount of PS. PE is synthesized in mammalian cells by four different pathways, the quantitatively most important of which are the CDP-ethanolamine pathway that produces PE in the ER, and PS decarboxylation that occurs in mitochondria. PS is made in ER membranes and is imported into mitochondria for decarboxylation to PE via a domain of the ER mitochondria-associated membranes (MAM) that transiently associates with mitochondria. Elimination of PS decarboxylase in mice caused mitochondrial defects and embryonic lethality. Global elimination of the CDP-ethanolamine pathway was also incompatible with mouse survival. Thus, PE made by each of these pathways has independent and necessary functions. In mammals PE is a substrate for methylation to PC in the liver, a substrate for anandamide synthesis, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Thus, PS and PE participate in many previously unanticipated facets of mammalian cell biology. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
► The biosynthesis and functions of PS in mammalian cells are reviewed. ► The transport of PS to mitochondria via mitochondria-associated membranes is discussed. ► 4 Pathways for mammalian PE biosynthesis are reviewed.
Dysregulation of cholesterol homeostasis in the brain is increasingly being linked to chronic neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's ...disease (PD), Niemann-Pick type C (NPC) disease and Smith-Lemli Opitz syndrome (SLOS). However, the molecular mechanisms underlying the correlation between altered cholesterol metabolism and the neurological deficits are, for the most part, not clear. NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively. However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases. Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD. Moreover, inheritance of the E4 isoform of apolipoprotein E (APOE), a cholesterol-carrying protein, markedly increases the risk of developing AD. Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to anti-inflammatory properties of the drug. Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established. Some important considerations for treatment of neurodegenerative diseases are the impermeability of the blood-brain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred. This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are two aminophospholipids whose metabolism is interrelated. Both phospholipids are components of mammalian cell membranes and play important ...roles in biological processes such as apoptosis and cell signaling. PS is synthesized in mammalian cells by base-exchange reactions in which polar head groups of preexisting phospholipids are replaced by serine. PS synthase activity resides primarily on mitochondria-associated membranes and is encoded by two distinct genes. Studies in mice in which each gene has been individually disrupted are beginning to elucidate the importance of these two synthases for biological functions in intact animals. PE is made in mammalian cells by two completely independent major pathways. In one pathway, PS is converted into PE by the mitochondrial enzyme PS decarboxylase. In addition, PE is made via the CDP-ethanolamine pathway, in which the final reaction occurs on the endoplasmic reticulum and nuclear envelope. The relative importance of these two pathways of PE synthesis has been investigated in knockout mice. Elimination of either pathway is embryonically lethal, despite the normal activity of the other pathway. PE can also be generated from a base-exchange reaction and by the acylation of lyso-PE. Cellular levels of PS and PE are tightly regulated by the implementation of multiple compensatory mechanisms.
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