Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging

Autophagy is a constitutive lysosomal catabolic pathway that degrades damaged organelles and protein aggregates. Stem cells are characterized by self-renewal, pluripotency, and quiescence; their long life span, limited capacity to dilute cellular waste and spent organelles due to quiescence, along with their requirement for remodeling in order to differentiate, all suggest that they require autophagy more than other cell types. Here, we review the current literature on the role of autophagy in embryonic and adult stem cells, including hematopoietic, mesenchymal, and neuronal stem cells, highlighting the diverse and contrasting roles autophagy plays in their biology. Furthermore, we review the few studies on stem cells, lysosomal activity, and autophagy. Novel techniques to detect autophagy in primary cells are required to study autophagy in different stem cell types. These will help to elucidate the importance of autophagy in stem cells during transplantation, a promising therapeutic approach for many diseases.     

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.     

Short-circuiting of the overturning circulation in the Antarctic Circumpolar Current

The oceanic overturning circulation has a central role in the Earth's climate system and in biogeochemical cycling, as it transports heat, carbon and nutrients around the globe and regulates their storage in the deep ocean. Mixing processes in the Antarctic Circumpolar Current are key to this circulation, because they control the rate at which water sinking at high latitudes returns to the surface in the Southern Ocean. Yet estimates of the rates of these processes and of the upwelling that they induce are poorly constrained by observations. Here we take advantage of a natural tracer-release experiment-an injection of mantle helium from hydrothermal vents into the Circumpolar Current near Drake Passage-to measure the rates of mixing and upwelling in the current's intermediate layers over a sector that spans nearly one-tenth of its circumpolar path. Dispersion of the tracer reveals rapid upwelling along density surfaces and intense mixing across density surfaces, both occurring at rates that are an order of magnitude greater than rates implicit in models of the average Southern Ocean overturning. These findings support the view that deep-water pathways along and across density surfaces intensify and intertwine as the Antarctic Circumpolar Current flows over complex ocean-floor topography, giving rise to a short circuit of the overturning circulation in these regions.     

族人与外人:一个中国宗族的收养

根据有关宗族的族谱 ,以及通过实地调查获取的第一手资料 ,在分析很多收养案例后得出结论 :宗族内部的分支争斗是导致收养外人这一异常形式存在的根本原因。