Research Roundup #2 – aHUS and iPSCs, schizophrenia, and GETIs

By Alomone Team • September 2021

Welcome back to Research Roundup. This time we’ve got quite a spread, from stem cells in kidney disease patients through to cell thermobiology.

Patient-specific iPSC-derived endothelial cells reveal aberrant p38 MAPK signaling in atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening disease that can lead to acute renal failure, yet the molecular mechanisms behind its development are mostly unknown. Research here built upon suspicions that endothelial damage might be at the heart of aHUS’ pathogenesis. With induced pluripotent stem cell-derived endothelial cells (iPSC-ECs), reprogrammed from skin fibroblasts, they showed that there is indeed a global impairment of endothelial function. These aHUS iPSC-ECs had dysfunctional endothelial phenotypes with decreased migration and tube formation capacity as well as impaired cell proliferation. Also, p38 was highlighted as a novel signaling pathway in this dysfunction and could be a potential therapeutic target.

Get the whole story at Stem Cell Reports

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Anisomycin (A-520) as a p38-specific activator.

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

It looks like disruption of the excitation/inhibition (E/I) balance, via N-methyl-d-aspartate receptor (NMDAR) hypofunction alongside GABAergic neurotransmission dysfunction, may contribute to schizophrenia. To unravel the relationship between NMDAR hypofunction and GABAergic inhibition, the team from the University of California used racemase knockout (SRKO) mice as a model of reduced NMDAR activity. What they saw was a reduced number of inhibitory synapses onto CA1 pyramidal neurons in these mice. And with a reduction in inhibition, there’s an increase in the E/I ratio, which in turn enhances synaptically driven neuronal excitability.

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Tetrodotoxin (T-500) in whole-cell voltage-clamp recordings to block action potential-dependent neurotransmitter release.

A highly-sensitive genetically encoded temperature indicator exploiting a temperature-responsive elastin-like polypeptide

Fluorescence nanothermometry (FNT) uses temperature-sensitive fluorescent indicators, like a fluorescent probe (FP), to measure temperature through the resulting fluorescence. It lets us look at really intriguing stuff like the low thermal conductivity in cells and discrepancies between theoretical and experimental measurements of intracellular temperature changes. For the very fine sensitivity measures needed in live-cell work, we need a better version of the existing genetically encoded temperature indicators (GETIs). New research here is doing just that. The researchers have created a new GETI for Förster resonance energy transfer (FRET) comprised of a temperature-responsive elastin-like polypeptide (ELP) fused with a cyan FP, an mTurquoise2 (mT) donor, and a mVenus (mV) acceptor. They called this the ELP-TEMP and it achieved the highest temperature sensitivity ever seen in fluorescent nanothermometers!

To see ELP-TEMP in action, head over to Nature’s Scientific Reports.