Reading nuggets from this week (for scientists)

My favourite occupation is to read scientific papers and here is a biassed list of what I have come across recently.. Unfortunately, it would require technical knowledge, so probably most appropriate for scientists themselves.

My favourites because they are relevant for my stuff: 

A very important contribution in Nature Cell Biology by Liu et al.: G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Demonstration that multiple cells are actually capable of proliferating in the absence of any of the G1 cyclins (D + E) – contrary to the prevailing model; however, pluripotent stem cells lose their pluripotent proficiency and acquire a trophectodermal cell fate (as well as a propensity to generate neural tissue in chimerism studies). The underlying mechanism comprises G1 Cyclin/CDK-mediated phosphorylation of the core transcription factors NANOG, OCT4 and SOX2. This is suggested as a potential contributing mechanism to the acquisition of pluripotency traits in malignant cells. Very interesting given the link between PI3K/AKT activation and Cyclin D + CDK2 upregulation. Note that individual loss of either Cyclin D or E doesn’t result in pluripotency loss. Also, the studies are performed in MEFs isolated from genetically engineered mice of the right genotype.

Review in Nature Communication by Dejana et al.: The molecular basis of endothelial cell plasticity. Covers early endothelial development, and the remarkable cell fate plasticity exhibited by endothelial cells. Essentially, all aspects of endothelial cell commitment and their ability to transition into haematopoietic stem cells or cardiac mesenchyme are dependent on the same set of pathways, which include VEGFR1/VEGFR2 and c-KIT signalling, i.e. PI3K activation.

A Stem Cell paper from Harding et al.: Highly Efficient Differentiation of Endothelial Cells from Pluripotent Stem Cells Requires the MAPK and the PI3K Pathways. The most useful bit of this paper is the development of an efficient endothelial cell differentiation protocol from human pluripotent stem cells that doesn’t require cell sorting. As of the claim that PI3K and MAPK pathways are essential, I would like to see more detailed evidence beyond the use of broad-spectrum inhibitors.

Signalling studies and molecular biology

The Yudushkin lab (same guy who recently published a nice Molecular Cell paper PIP3-dependent restriction of AKT activity to cell membranes) have contributed a paper to JCB, examining the localisation of mTORC2 activity (Ebner et al. 2017: Localization of mTORC2 activity inside cells). The starting question was how growth factors couple to mTORC2 in order to induce downstream phosphorylation of AKT. Previous studies had provided some evidence that mTORC2 associates with mitochondria, ribosomes, endosomal compartments and the plasma membrane. However, not much known regarding which of these membranes link to mTORC2 activity in a cellular context and whether there are pool-specific contributions to AKT activation. One outcome of the current study is, therefore, the development of a tool that allows tracking of mTORC2 enzymatic activity towards AKT within the cell. Important findings from this paper include: PM-associated mTORC2 is constitutively active towards AKT; hence neither growth factors nor PI3K inhibition has an effect on mTORC2 activity at this cellular site – however, PI3K activity is required for mTORC2 activity at early and late endosomes. Studies performed in HEK293s, so will be interesting to see if this is replicated in additional cell types in the future.

Metabolism, T2D, obesity incl. adipocyte studies 

Nature paper by Wong et al. The role of fatty acid β-oxidation in lymphangiogenesis. Haven’t read beyond abstract and discussion, but interesting concept! Turns out that β-oxidation, as expected, contributed to energy generation and nucleotide synthesis, as well as epigenetic regulation through Acetyl-CoA-dependent p300-mediated histone acetylation of the PROX1 gene, which is important for VEC to LEC differentiation. Multiple reports out recently that elegantly demonstrate the integration of metabolism and cell fate commitment.

Cell Metabolism paper by Mauro et al. 2017 (K. Okkenhaug is a co-author): Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals. Haven’t read it in detail, but this is the summary provided by the journal (seems relevant!): “Lymphocyte infiltration of non-lymphoid tissues, including adipose and vascular tissues, is a prominent feature of chronic inflammation in diet obesity. Mauro et al. find that the saturated fatty-acid palmitate activates a PI3K p110δ-Akt pathway leading to CD4+ T cell differentiation into effector memory-like T cells upon priming in obese mice and humans.”

A nice Cell Metabolism review on ketogenesis and alternative functions of ketone bodies; Puchalska, P. & Crawford, P. 2017: Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

A paper in Diabetes (Ehrlund et al. 2017: Transcriptional Dynamics During Human Adipogenesis and Its Link to Adipose Morphology and Distribution), published a few a weeks ago, explores the transcriptional dynamics of adipocytes subjected to differentiation in vitro. Unfortunately, I can’t get access to the paper even when I login. From the abstract, however, I gather that it might be relevant as the study profiles the expressional changes of genes, enhancers, and long noncoding RNAs and demonstrates that enhancers expressed during adipogenesis overlap with SNPs associated with white adipose tissue distribution. The paper should contain useful time courses with important distinctions between downregulated, transient and late-induced transcripts, such as relationships to hypertrophy and insulin sensitivity.

Another report in Diabetes by Ralph de Fronzo (big name in the field I believe; Gastaldelli et al. 2017: Role of Adipose Tissue Insulin Resistance in the Natural History of T2DM: Results from the San Antonio Metabolism Study) investigates the role of adipose tissue insulin resistance in the natural progression to Type 2 Diabetes in humans. Specifically, they recruited 302 subjects varying glucose tolerance (normal, impaired, Type 2 Diabetes), subjected them to an OGTT (oral glucose tolerance test) and an euglycaemic insulin clamp and profiled their insulin sensitivity alongside plasma free-fatty acids (FFAs). A progressive decline in insulin sensitivity was accompanied by impaired FFA suppression, but overt hyperglycaemia was only established with the progression to T2D. Results are kind of expected in light of the burgeoning mouse literature on the topic as well as epidemiological studies, but I suppose it had not been formally demonstrated in human beings.

PIK3CD papers that might be relevant

Compagno et al. Phosphatidylinositol 3-kinase δ blockade increases genomic instability in B cells (Nature 2017); mechanism relies on the ability of PIK3CD to suppress activation-induced cytidine deaminase (AID) in B cells, where this enzyme promotes class switching of immunoglobulin genes.

 

 

Just out of interest…

The Biochemical Society’s recent Biochemist issue focussed on Gender Medicine. All too often, the variable “sex” is ignored in biomedical research, and that needs to change. Personally, I can see why it can be difficult to always include XX and XY in your research – after all, this doubles the resources required for your study. I suppose funders need to be more supportive in this respect! The issue also contains additional interesting reads on science policy and outreach, so have a look if you can gain access to it via the following link (not sure if you are not a member): http://www.biochemistry.org/Portals/0/Biochemist/February2017Biochemist-smaller2.pdf?utm_medium=email&utm_campaign=Biochemist%20Online%20-%20February%202017&utm_content=Biochemist%20Online%20-%20February%202017+CID_4dbf76701bce671026dc91550506090f&utm_source=Campaign%20Monitor&utm_term=pdf

One step closer to understanding consciousness? A group in the U.S. discovered the existence of mouse neurons that seem to wrap around the whole brain; the group believes that this might underlie the mechanism of consciousness as the three neurons seemed to connect to most or all of the outer parts of the brain that take in sensory  information and control behaviour. Furthermore, the Read the Nature News & Views here: http://www.nature.com/news/a-giant-neuron-found-wrapped-around-entire-mouse-brain-1.21539?WT.ec_id=NEWS-20170302&spMailingID=53538106&spUserID=MTExMDUzNjM3NTkxS0&spJobID=1120320868&spReportId=MTEyMDMyMDg2OAS2

 

 

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