SummaryA fundamental rule of cell division is that daughter cells inherit half the DNA complement and an appropriate proportion of cellular organelles. The highly asymmetric cell divisions of female meiosis present a different challenge because one of the daughters, the polar body, is destined to degenerate, putting at risk essential maternally inherited organelles such as mitochondria. We have therefore investigated mitochondrial inheritance during the meiotic divisions of the mouse oocyte. We find that mitochondria are aggregated around the spindle by a dynein-mediated mechanism during meiosis I, and migrate together with the spindle towards the oocyte cortex. However, at cell division they are not equally segregated and move instead towards the oocyte-directed spindle pole and are excluded from the polar body. We show that this asymmetrical inheritance in favour of the oocyte is not caused by bias in the spindle itself but is dependent on an intact actin cytoskeleton, spindle-cortex proximity, and cell cycle progression. Thus, oocyte-biased inheritance of mitochondria is a variation on rules that normally govern organelle segregation at cell division, and ensures that essential maternally inherited mitochondria are retained to provide ATP for early mammalian development.
Mitochondria provide the primary source of ATP in the oocyte and early embryo and mitochondrial dysfunction and deficit of mitochondria-derived ATP has been linked to suboptimal developmental competence. We have undertaken a study of ATP in the maturing mouse oocyte using a novel recombinant FRET based probe, AT1.03. We show that AT1.03 can be successfully used to monitor cytosolic ATP levels in single live oocytes over extended time periods. We find that ATP levels undergo dynamic changes associated with specific maturational events and that oocytes display altered rates of ATP consumption at different stages of maturation. Cumulus enclosed oocytes have a higher ATP level during maturation than denuded oocytes and this can be abolished by inhibition of gap junctional communication between the oocyte and cumulus cells. Our work uses a new approach to shed light on regulation of ATP levels and ATP consumption during oocyte maturation.
The COVID‐19 pandemic potentially makes treatment of acute leukaemia more difficult. Most induction chemotherapy regimens for acute leukaemia lead to extended periods of cytopaenia and immunosuppression rendering patients vulnerable to opportunistic infections. As with many aspects of SARS‐CoV‐2, there is no universally accepted way of treating patients who present with acute leukaemia and associated infection.
While changes in SARS-CoV-2 viral load over time have been documented, detailed information on the impact of remdesivir and how it might alter intra-host viral evolution is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 recovered from the upper respiratory tract of hospitalised children revealed that remdesivir treatment suppressed viral RNA levels in one patient but not in a second infected with an identical strain. Evidence of drug resistance to explain this difference was not found. Reduced levels of subgenomic (sg) RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication that is independent of viral RNA levels. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. We conclude that these are likely to have arisen from within-host evolution, and not co-transmission, although superinfection cannot be excluded in one case. Sample-to-sample heterogeneity in the abundances of variant genotypes is best explained by the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalisation is well described in serious lung infections caused by influenza and Mycobacterium tuberculosis and has been associated with poor drug penetration, suboptimal treatment and drug resistance. Our data provide evidence that remdesivir is able to suppress SARS-CoV-2 replication in vivo but that its efficacy may be compromised by factors reducing penetration into the lung. Based on data from influenza and Mycobacterium tuberculosis lung infections we conclude that early use of remdesivir combined with other agents should now be evaluated.Summary SentenceDeep sequencing of longitudinal samples from SARS-CoV-2 infected paediatric patients identifies evidence of remdesivir-associated inhibition of viral replication in vivo and uncovers evidence of within host evolution of distinct viral genotypes.
Detailed information on intrahost viral evolution in SARS‐CoV‐2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS‐CoV‐2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS‐CoV‐2 variant genotypes in four patients. These likely arose from within‐host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample‐to‐sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.
A fit-looking 23-year-old male participant in a summer mountain trail run collapses 3 km from the end of the 25 km race. Despite the altitude, ambient temperatures are warm, and the participants have been exposed to the full sun for several hours. On your first assessment, he is very confused, with a weak, rapid pulse (160 beats per minute). His skin is wet and cool. A passing member of the same running club alleges that he is not known to have any medical conditions. You notice that his water bottles are both empty. As fellow runners help you carry him to the nearby medical-aid station, a rapidly expanding differential diagnosis fills your thoughts. BackgroundWilderness heat-related illnesses span a continuum of medical problems caused by the generation of, and/or exposure to, excessive heat in the wilderness environment. They can range from minor annoyances to life-threatening conditions. Endogenous heat production is directly dependent on the sum of that from inescapable sources, such as basal cellular metabolism and cardiorespiratory work, and heat generated by physical exertion. All heat exchange (gain or loss) occurs through four mechanisms: conduction, convection, radiation and evaporation. Conduction refers to the direct transfer of heat from one object to another through contact. Convection is heat gain or loss due to movement of a fluid (such as air); a convection oven or wind chill from an Antarctic breeze are similar examples. Radiation describes transfer of heat through electromagnetic waves, epitomised by the heat of the sun on skin. Evaporation is the loss of heat induced by the phase change from liquid to gas, which is dramatically affected by ambient vapour pressure or relative humidity.Many animals have developed ingenious strategies to adapt their physiology to control heat gain or loss. Indeed, it is hypothesised that particular human traits -our upright stance, complex bony structure of the foot, nuchal ligament, relatively hairless skin and copious capacity for perspiration -evolved to give us an advantage in chasing down prey in the prehistorical African heat.[1] Today, however, humans are unique in their ability to adapt the environment to control their physiology through behaviour and material means: use of clothing, shelter, and devices such as heaters and air conditioners. Despite this, we cannot alter the laws of thermodynamics, and people in the wilderness are subject to the same exposure and thermal exchange mechanisms as our primitive ancestors. Fortunately, the development of modern science, clothing technology, and an understanding of physiology allow us to function successfully in environments of extreme heat under many adverse circumstances (Fig. 1).Risk factors traditionally considered to increase our susceptibility to the deleterious effects of heat stress include obesity, lack of acclimatisation to hot environments, poor physical fitness, extremes of age, underlying illness (e.g. cardiac conditions, hyperthyroidism), dehydration, certain medications (e.g. beta blockers, anti...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.