In this brief obituary, we celebrate the life and achievements of Professor Roger Williams, who set up the UK's first liver transplant programme and championed excellence in hepatology for six decades.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539739 | PMC |
| http://dx.doi.org/10.7861/clinmed.obit.20.5 | DOI Listing |
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Paradoxical dominant negative activity of an immunodeficiency-associated activating variant.
Elife
January 2025
The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom.
encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction.
View Article and Find Full Text PDFPersistent Short Sleep Duration From Pregnancy to 2 to 7 Years After Delivery and Metabolic Health.
JAMA Netw Open
December 2024
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Importance: Short sleep duration during pregnancy and the perimenopausal period has been associated with adverse cardiometabolic outcomes. However, it remains unclear how sleep duration changes after delivery and whether such changes are associated with the cardiometabolic health of birthing people.
Objective: To investigate whether persistently short sleep during pregnancy and after delivery is associated with incident hypertension and metabolic syndrome.
Making PI3K superfamily enzymes run faster.
Adv Biol Regul
November 2024
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. Electronic address:
Article Synopsis
- The phosphoinositide 3-kinase (PI3K) superfamily consists of lipid kinases and PI3K-like protein kinases that share a conserved C-terminal kinase domain, characterized by low basal activity that can be significantly enhanced by various regulatory factors.
- Activators induce conformational changes in the kinase domain that improve ATP-binding and catalysis efficiency, specifically through realignment of the active site and changes in a region known as the PIKK regulatory domain.
- A recent discovery of a small-molecule activator for PI3Kα may lead to the development of specific PI3K activators, with potential applications in wound healing, neurodegeneration treatment, and anti-stroke therapies.
Epidural steroid injection technique.
Tech Vasc Interv Radiol
September 2024
Quantum Radiology, University of Alabama at Birmingham Hospital and Quantum Radiology, Atlanta, GA. Electronic address:
An epidural steroid injection (ESI) is a minimally invasive, image guided procedure for the treatment of back pain. Pain originating in the lumbar spine is the most common referral for ESI but the entire spine may be targeted. ESI can provide temporary but meaningful relief for patients who may have failed conservative management with oral analgesics and physical therapy.
View Article and Find Full Text PDFATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding.
Biochem J
December 2024
Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown.
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