Some recent reads.. So much new science!

Metabolism and physiology

An adipo-biliary-uridine axis that regulates energy homeostasis (Deng et al. 2017 Science Signaling)

Copied lay description: “The nucleoside uridine is well known for its role in critical cellular functions such as nucleic acid synthesis. Its role in whole-animal physiology has received comparatively little attention. In mammals, plasma uridine levels are tightly regulated, but the underlying mechanisms are unclear. Studying mouse models, Deng et al. show that plasma uridine levels are controlled by feeding behavior (see the Perspective by Jastroch and Tschöp). Fasting causes an adipocyte-mediated rise in plasma uridine, which triggers a lowering of body temperature. Feeding causes a bile-mediated drop in plasma uridine, which enhances insulin sensitivity in a leptin-dependent manner. Thus, uridine is part of a complex regulatory loop that affects energy balance and potentially contributes to metabolic disease.” – read through it briefly, and it is quite interesting!

Pik3r1 is required for glucocorticoid-induced perilipin 1 phosphorylation in lipid dropled for adipocyte lipolysis (in press in Diabetes; by Kuo et al.)

  • Not read in detail, but claims to demonstrate a role of p85a independent of its regulatory function as class IA PI3K components.. Would be worth reading in detail as I can imagine multiple confounding factors given the deinhibition of the catalytic p110 subunit in the absence of p85a.

Stem cell and developmental biology

Autophagy maintains the metabolism and function of young and old stem cells (Ho et al. 2017 Nature)

  • Aim of study: to identify how autophagy controls hematopoietic stem cell function, and how changes in autophagy levels control HSC ageing.
  • Results: autophagy plays a critical role in preserving HSC functionality by clearing aged mitochondria. This maintains HSC quiescience and stemness. Decreased autophagy with age, resulting in lower regeneration potential.

Human haematopoietic stem cell lineage commitment is a continuous process (Velten et al. Nature 2017)

  • This is an interesting topic, particularly because I recently attended a talk by Dr Ana Cvejic who talked about the current debate about the accuracy of the current haematopoietic lineage tree. Are there distinct intermediate steps from a multipotent stem cell to a unipotent cell? Or does the transition occur directly? This confusion largely stems from the reliance on cell surface markers to identify distinct cell populations. Instead, a call was made to incorporate single-cell transcriptional analyses as part of future studies.
  • This is exactly what this study has done and it describes that the tree-like structure of haematopoiesis is incorrect as haematopoietic stem cells appear to acquire differentiation biases in a gradual manner without passing through discrete intermediate states.

 PI3K/AKT/mTORC signalling pathway

mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide (Matsumoto et al. Nature 2017) – from January but only got around to looking at it now. The second long non-coding RNA that seems to play a role in regulating this signalling pathway (see Lin et al. Nature Cell Biology 2017 for another example). What’s special about this one is that its regulatory role depends not on its non-coding properties, but on a hidden protein-coding sequence. The peptide that is produced by LINC00961 is expressed in a tissue-specific manner and restricts mTORC1 activation in response to amino acids.  It is demonstrated that this mechanism has a functional importance in muscle regeneration in mouse model organisms.

 PARK2 depletion connects energy and oxidative stress to PI3K/Akt activation via PTEN S-Nitrosylation (Gupta et al. Molecular Cell 2017; Lewis Cantley one of the last authors)

  • PARK2 is commonly deleted in cancer, and this paper demonstrates a novel regulatory mechanism that involves indirect PARK2-induced activation (via decreased removal of damaged mitochondria) of eNOS. Activation of eNOS in this setting promotes S-nitrosylation of PTEN and its subsequent Ubiquitin-dependent degradation. This mechanism was demonstrated in specific cancer cell lines and other immortalised cell models. Supporting its pathological importance, PARK2 and PTEN loss occur together in many cancers – if one PTEN allele is lost, the protein product of the remaining allele will suffer increased degradation upon concomitant PARK2 The only thing that is missing from this paper is a clear statement of the number of independent experimental replicates that they produced!

Amino acid – insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells (Kalaitzidis et al. 2017 JCI; Sabatini as one of the last authors)

  • Interesting paper because of increasing evidence in the stem cell worls that mTORC signalling is carefully regulated, partly to maintain low protein synthesis rate.
  • The authors suggest that a nutrient-insensitive mTORC1 in HSCs is part of a protective mechanism against variable nutrient availability and oncogenes due to excess nutrient stimulation.

A key leading edge review from Sabatini: mTOR signalling in growth and disease (Cell 2017)

 

 Technical

GuideScan software for improved single and paired CRISPR guide RNA design (Perez et al. 2017 Nat Biotechnology)

  • For the CRISPR users out there, the Ventura lab offer a new and superior tool for CRISPR gRNA design with improved specificity compared to commonly used competitor tools. Utility demonstrated for non-coding DNA regions.

Optimized labeling of membrane proteins for applications to super-resolution imaging in confined cellular environments using monomeric streptavidin (Chamma et al. 2017 Nature Protocols)

  • This seems quite cool and relevant if you want to perform cell imaging experiments with the aim to define target-specific trafficking events. The monomeric streptavidin labelling method has the advantage that the tag is very small, hence the fluorescent probe will be right in the vicinity what you want to study which is important for reliable superresolution results. The tag is only 15 aa big.

I came across an “older” paper from 2015 on CRISPR sgRNA designs by Farboud, B. and Meyer, B. (Genetics 2015); they describe improved targeting efficiency if the sgRNAs have a 3’ GG motif in addition to the 3’ terminal NGG PAM site. Worth a read..

Diet/exercise and other interesting bits and pieces

Went back to read Raubenheimer and Simpson’s review in Annual Rev Nutr 2016 which describes their nutritional geometry framework that advocates a holistic approach to nutrition science. Instead of focusing on the effects of a single nutrient in isolation, we should explore how different food components interact and how an animal’s behaviour, including foraging, is dependent on multiple environmental variables that are often left out in reductionist-type nutrient science. It is also worth having a look at the same authors’ Cell Metabolism paper from 2014: The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice.

 Dieting, independent of genetic factors, has been shown to result in long-term weight gain – by yet another study (International Journal of Obesity, Pietiläinen et al. Does dieting make you fat? A Twin Study).

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