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"Taylor, Robert"
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Mutations causing mitochondrial disease: What is new and what challenges remain?
Mitochondrial diseases are among the most common and most complex of all inherited genetic diseases. The involvement of both the mitochondrial and nuclear genome presents unique challenges, but despite this there have been some remarkable advances in our knowledge of mitochondrial diseases over the past few years. A greater understanding of mitochondrial genetics has led to improved diagnosis as well as novel ways to prevent transmission of severe mitochondrial disease. These and other advances have had a major impact on patient care, but considerable challenges remain, particularly in the areas of therapies for those patients manifesting clinical symptoms associated with mitochondrial dysfunction and the tissue specificity seen in many mitochondrial disorders. This review highlights some important recent advances in mitochondrial disease but also stresses the areas where progress is essential.
Journal Article
Overdispersion in COVID-19 increases the effectiveness of limiting nonrepetitive contacts for transmission control
Increasing evidence indicates that superspreading plays a dominant role in COVID-19 transmission. Recent estimates suggest that the dispersion parameter k for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is on the order of 0.1, which corresponds to about 10% of cases being the source of 80% of infections. To investigate how overdispersion might affect the outcome of various mitigation strategies, we developed an agent-based model with a social network that allows transmission through contact in three sectors: “close” (a small, unchanging group of mutual contacts as might be found in a household), “regular” (a larger, unchanging group as might be found in a workplace or school), and “random” (drawn from the entire model population and not repeated regularly). We assigned individual infectivity from a gamma distribution with dispersion parameter k. We found that when k was low (i.e., greater heterogeneity, more superspreading events), reducing random sector contacts had a far greater impact on the epidemic trajectory than did reducing regular contacts; when k was high (i.e., less heterogeneity, no superspreading events), that difference disappeared. These results suggest that overdispersion of COVID-19 transmission gives the virus an Achilles’ heel: Reducing contacts between people who do not regularly meet would substantially reduce the pandemic, while reducing repeated contacts in defined social groups would be less effective.
Journal Article
Making hard decisions with DecisionTools
Teaching the fundamental ideas of decision analysis, this text avoids an overly technical explanation of the mathematics used in management science. This new version incorporates and implements the powerful Decision Tools Suite, a toolkit for risk and decision analysis.
Book
Mitochondrial OXPHOS Biogenesis: Co-Regulation of Protein Synthesis, Import, and Assembly Pathways
The assembly of mitochondrial oxidative phosphorylation (OXPHOS) complexes is an intricate process, which—given their dual-genetic control—requires tight co-regulation of two evolutionarily distinct gene expression machineries. Moreover, fine-tuning protein synthesis to the nascent assembly of OXPHOS complexes requires regulatory mechanisms such as translational plasticity and translational activators that can coordinate mitochondrial translation with the import of nuclear-encoded mitochondrial proteins. The intricacy of OXPHOS complex biogenesis is further evidenced by the requirement of many tightly orchestrated steps and ancillary factors. Early-stage ancillary chaperones have essential roles in coordinating OXPHOS assembly, whilst late-stage assembly factors—also known as the LYRM (leucine–tyrosine–arginine motif) proteins—together with the mitochondrial acyl carrier protein (ACP)—regulate the incorporation and activation of late-incorporating OXPHOS subunits and/or co-factors. In this review, we describe recent discoveries providing insights into the mechanisms required for optimal OXPHOS biogenesis, including the coordination of mitochondrial gene expression with the availability of nuclear-encoded factors entering via mitochondrial protein import systems.
Journal Article
Emerging roles of ATG7 in human health and disease
The cardinal stages of macroautophagy are driven by core autophagy‐related (ATG) proteins, whose ablation largely abolishes intracellular turnover. Disrupting ATG genes is paradigmatic of studying autophagy deficiency, yet emerging data suggest that ATG proteins have extensive biological importance beyond autophagic elimination. An important example is ATG7, an essential autophagy effector enzyme that in concert with other ATG proteins, also regulates immunity, cell death and protein secretion, and independently regulates the cell cycle and apoptosis. Recently, a direct association between ATG7 dysfunction and disease was established in patients with biallelic
ATG7
variants and childhood‐onset neuropathology. Moreover, a prodigious body of evidence supports a role for ATG7 in protecting against complex disease states in model organisms, although how dysfunctional ATG7 contributes to manifestation of these diseases, including cancer, neurodegeneration and infection, in humans remains unclear. Here, we systematically review the biological functions of ATG7, discussing the impact of its impairment on signalling pathways and human pathology. Future studies illuminating the molecular relationship between ATG7 dysfunction and disease will expedite therapies for disorders involving ATG7 deficiency and/or impaired autophagy.
Graphical Abstract
In this review, R. Taylor, J. Collier & colleagues discuss the biological functions of the autophagy protein ATG7, and the impact of its impairment on signalling pathways and human pathology
Journal Article
Rise of the robot army
Reluctant superhero Miles Taylor battles an army of deadly robots, but struggles to dominate eighth grade at Chapman Middle School, where bullies and unrequited love await.
Book
Mitochondrial disease in adults: recent advances and future promise
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
Journal Article