AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK ...targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK and, importantly, also into the sites bound by small molecule activators, thus providing a path for improved drugs.
AMPK is a highly conserved central regulator of cellular and organismal metabolism, which restores energy balance during low-energy conditions such as following starvation or mitochondria stress. Garcia and Shaw review recent advances in AMPK regulation and function, including identification of downstream effectors through which AMPK mechanistically restores metabolic homeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK ...activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.
Trefts and Shaw review the latest advances in studies of the AMPK signaling pathway, a central energy-sensing kinase that promotes catabolism and inhibits anabolism to limit cell growth and promote cell survival under conditions of low nutrients and low cellular energy. Highlights include new intersections with mTOR, lysosomes, and mitochondria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Data Analysis for Precision 21 cm Cosmology Liu, Adrian; Shaw, J. Richard
Publications of the Astronomical Society of the Pacific,
06/2020, Volume:
132, Issue:
1012
Journal Article
Peer reviewed
Open access
The redshifted 21 cm line is an emerging tool in cosmology, in principle permitting three-dimensional surveys of our universe that reach unprecedentedly large volumes, previously inaccessible length ...scales, and hitherto unexplored epochs of our cosmic timeline. Large radio telescopes have been constructed for this purpose, and in recent years there has been considerable progress in transforming 21 cm cosmology from a field of considerable theoretical promise to one of observational reality. Increasingly, practitioners in the field are coming to the realization that the success of observational 21 cm cosmology will hinge on software algorithms and analysis pipelines just as much as it does on careful hardware design and telescope construction. This review provides a pedagogical introduction to state-of-the-art ideas in 21 cm data analysis, covering a wide variety of steps in a typical analysis pipeline, from calibration to foreground subtraction to map making to power spectrum estimation to parameter estimation.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
Highlights • Multiple cell lineages reprogram and migrate in order to heal a wound. • In general, wound healing cell behaviours appear to recapitulate development. • Inflammation evolves over repair ...time-course, promoting repair, angiogenesis and scarring. • Re-epithelialisation involves active participation by follower and suprabasal cells. • Reticular dermal fibroblasts are responsible for early repopulation of the wound bed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•Contemporary review of trends/insights to established/emerging e-waste issues.•Four typical future WEEE management scenarios are identified & discussed.•Emerging concerns: stockpiling; reuse ...standards; obsolescence; IoT, space e-debris.•Key areas of concern & measures to improve WEEE management identified & recommended.•Generation & management data standardisation required alongside political solutions.
Waste electrical and electronic equipment (WEEE) comprises a globally important waste stream due to the scarcity and value of the materials that it contains; annual generation of WEEE is increasing by 3–5% per annum. The effective management of WEEE will contribute critically to progress towards (1) realisation of the United Nations’ Sustainable Development Goals, (2) a circular economy, and (3) resource efficiency. This comprehensive review paper provides a critical and contemporary examination of the current global situation of WEEE management and discusses opportunities for enhancement. Trends in WEEE generation, WEEE-related policies and legislation are exemplified in detail. Four typical future WEEE management scenarios are identified, classified and outlined. The European Community is at the forefront of WEEE management, largely due to the WEEE Directive (Directive 2012/19/EU) which sets high collection and recycling targets for Member States. WEEE generation rates are increasing in Africa though collection and recycling rates are low. WEEE-related legislation coverage is increasing in Asia (notably China and India) and in Latin America. This review highlights emerging concerns, including: stockpiling of WEEE devices; reuse standards; device obsolescence; the Internet of Things, the potential for collecting space e-debris, and emerging trends in electrical and electronic consumer goods. Key areas of concern in regard to WEEE management are identified: the partial provision of formal systems for WEEE collection and treatment at global scale; further escalation of global WEEE generation (increased ownership, and acceleration of obsolescence and redundancy); and absence of regulation and its enforcement. Measures to improve WEEE management at global scale are recommended: incorporation of circular economy principles in EEE design and production, and WEEE management, including urban mining; extension of WEEE legislation and regulation, and improved enforcement thereof; harmonisation of key terms and definitions to permit consistency and meaning in WEEE management; and improvements to regulation and recognition of the informal WEEE management sector.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Mitochondrial dysfunction is one of the earliest pathophysiological events in amyotrophic lateral sclerosis (ALS).•ALS-associated mutant proteins accumulate in mitochondria and cause mitochondrial ...damage.•ALS-associated mitochondrial dysfunction occurs at multiple levels.•ALS affects mitochondrial respiration and ATP production, calcium handling, dynamics, and apoptotic signalling.
Mitochondria are unique organelles that are essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is a prevalent feature of many neurodegenerative diseases including motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption of mitochondrial structure, dynamics, bioenergetics and calcium buffering has been extensively reported in ALS patients and model systems and has been suggested to be directly involved in disease pathogenesis. Here we review the alterations in mitochondrial parameters in ALS and examine the common pathways to dysfunction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core ...autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.
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•ULK1 phosphorylates multiple autophagy components, including VPS34 on Ser249•SBI-0206965 is a highly selective ULK1 kinase inhibitor that blocks autophagy•SBI-0206965 combined with starvation or mTOR inhibition leads to ULK1 degradation•SBI-0206965 synergizes with mTOR inhibition to induce cell death
ULK1 is a serine/threonine kinase that initiates autophagy in response to nutrient deprivation. Egan et al. define ULK1’s consensus phosphorylation motif, demonstrate that ULK1 phosphorylates several autophagy components, and develop a ULK1 small molecule inhibitor (SBI-0206965). SBI-0206965 synergizes with mTOR inhibition to enhance apoptosis in tumor cells, suggesting therapeutic opportunities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction Diabetes is a serious and increasing global health burden and estimates of prevalence are essential for appropriate allocation of resources and monitoring of trends. Methods We ...conducted a literature search of studies reporting the age-specific prevalence for diabetes and used the Analytic Hierarchy Process to systematically select studies to generate estimates for 219 countries and territories. Estimates for countries without available source data were modelled from pooled estimates of countries that were similar in regard to geography, ethnicity, and economic development. Logistic regression was applied to generate smoothed age-specific prevalence estimates for adults 20–79 years which were then applied to population estimates for 2013 and 2035. Results A total of 744 data sources were considered and 174 included, representing 130 countries. In 2013, 382 million people had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle-income countries and these will experience the greatest increase in cases of diabetes over the next 22 years. Conclusion The new estimates of diabetes in adults confirm the large burden of diabetes, especially in developing countries. Estimates will be updated annually including the most recent, high-quality data available.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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