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"Gray, Michael"
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Mosaic nature of the mitochondrial proteome: Implications for the origin and evolution of mitochondria
Comparative studies of the mitochondrial proteome have identified a conserved core of proteins descended from the α-proteobacterial endosymbiont that gave rise to the mitochondrion and was the source of the mitochondrial genome in contemporary eukaryotes. A surprising result of phylogenetic analyses is the relatively small proportion (10–20%) of the mitochondrial proteome displaying a clear α-proteobacterial ancestry. A large fraction of mitochondrial proteins typically has detectable homologs only in other eukaryotes and is presumed to represent proteins that emerged specifically within eukaryotes. A further significant fraction of the mitochondrial proteome consists of proteins with homologs in prokaryotes, but without a robust phylogenetic signal affiliating them with specific prokaryotic lineages. The presumptive evolutionary source of these proteins is quite different in contending models of mitochondrial origin.
Journal Article
Superman. Vol. 4, Black dawn
\"Though Superman and his family have found a measure of peace in their adopted town of Hamilton, they've also sensed a sinister presence lurking beneath its idyllic rural facade--something, as a visiting Batman and Robin are about to discover, that is stripping young Jonathan Kent of his powers and pitting neighbor against neighbor, hero against hero, father against son. Soon the time will come for Jonathan to choose: Will he follow his father into the light of truth and justice? Or will this Boy of Steel be forever warped by the corrupting powers of darkness?\"-- Provided by publisher.
Book
Role of CFTR in epithelial physiology
Salt and fluid absorption and secretion are two processes that are fundamental to epithelial function and whole body fluid homeostasis, and as such are tightly regulated in epithelial tissues. The CFTR anion channel plays a major role in regulating both secretion and absorption in a diverse range of epithelial tissues, including the airways, the GI and reproductive tracts, sweat and salivary glands. It is not surprising then that defects in CFTR function are linked to disease, including life-threatening secretory diarrhoeas, such as cholera, as well as the inherited disease, cystic fibrosis (CF), one of the most common life-limiting genetic diseases in Caucasian populations. More recently, CFTR dysfunction has also been implicated in the pathogenesis of acute pancreatitis, chronic obstructive pulmonary disease (COPD), and the hyper-responsiveness in asthma, underscoring its fundamental role in whole body health and disease. CFTR regulates many mechanisms in epithelial physiology, such as maintaining epithelial surface hydration and regulating luminal pH. Indeed, recent studies have identified luminal pH as an important arbiter of epithelial barrier function and innate defence, particularly in the airways and GI tract. In this chapter, we will illustrate the different operational roles of CFTR in epithelial function by describing its characteristics in three different tissues: the airways, the pancreas, and the sweat gland.
Journal Article
Superman : Rebirth deluxe edition
\"After the stunning events of DC REBIRTH, the world is left without Superman! Luckily, there is another Man of Steel to fill his shoes: the pre-Flashpoint Kal-El! However, can this new Superman protect the world while raising a super-son with his wife, Lois Lane? And should they help their boy use his new and rapidly increasing abilities, or hide them from the world?\"-- Provided by publisher.
Book
Inorganic polyphosphate and the stringent response coordinately control cell division and cell morphology in Escherichia coli
Cell division is a fundamental biological process, and the mechanisms that control it in Escherichia coli have been the subject of intense research scrutiny for many decades. Similarly, both the (p)ppGpp-dependent stringent response and inorganic polyphosphate (polyP) synthesis are well-studied, evolutionarily ancient, and widely conserved pathways in diverse bacteria. Our results indicate that these systems, normally studied as stress-response mechanisms, play a coordinated and novel role in regulating cell division, morphology, and metabolism even under non-stress conditions.
Journal Article
Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial
Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound.
We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment.
Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3–4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred.
The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy.
Oxford Biomedical Research Centre, National Institute for Health Research.
Journal Article
Star destroyers : big ships blowing things up
\"In space, size matters. Boomers. Ships of the Line. Star Destroyers. The bigger the ship, the better the bang. From the dawn of history onward, commanding the most powerful ship around has been a dream of admirals, sultans, emperors, kings, generalissimos, and sea captains everywhere. For what the intimidation factor alone doesn't achieve, a massive barrage from super-weapons probably will. Thus it was, and ever shall be, even into the distant future. From the oceans of Earth, to beneath the ice of Europa, to the distant reaches of galactic empires, it is the great warships and their crews that sometimes keep civilization safe for the rest of us -- but sometimes become an extinction-level event in and of themselves\"--Back cover.
Book
Recent expansion of metabolic versatility in Diplonema papillatum, the model species of a highly speciose group of marine eukaryotes
Abstract Background Diplonemid flagellates are among the most abundant and species-rich of known marine microeukaryotes, colonizing all habitats, depths, and geographic regions of the world ocean. However, little is known about their genomes, biology, and ecological role. Results We present the first nuclear genome sequence from a diplonemid, the type species Diplonema papillatum . The ~ 280-Mb genome assembly contains about 32,000 protein-coding genes, likely co-transcribed in groups of up to 100. Gene clusters are separated by long repetitive regions that include numerous transposable elements, which also reside within introns. Analysis of gene-family evolution reveals that the last common diplonemid ancestor underwent considerable metabolic expansion. D. papillatum -specific gains of carbohydrate-degradation capability were apparently acquired via horizontal gene transfer. The predicted breakdown of polysaccharides including pectin and xylan is at odds with reports of peptides being the predominant carbon source of this organism. Secretome analysis together with feeding experiments suggest that D. papillatum is predatory, able to degrade cell walls of live microeukaryotes, macroalgae, and water plants, not only for protoplast feeding but also for metabolizing cell-wall carbohydrates as an energy source. The analysis of environmental barcode samples shows that D. papillatum is confined to temperate coastal waters, presumably acting in bioremediation of eutrophication. Conclusions Nuclear genome information will allow systematic functional and cell-biology studies in D. papillatum . It will also serve as a reference for the highly diverse diplonemids and provide a point of comparison for studying gene complement evolution in the sister group of Kinetoplastida, including human-pathogenic taxa.
Journal Article