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Interstitial oxygen embrittles titanium, particularly at cryogenic temperatures, which necessitates a stringent control of oxygen content in fabricating titanium and its alloys. Here, we propose a structural strategy, via grain refinement, to alleviate this problem. Compared to a coarse-grained counterpart that is extremely brittle at 77 K, the uniform elongation of an ultrafine-grained (UFG) microstructure (grain size ~ 2.0 µm) in Ti-0.3wt.%O is successfully increased by an order of magnitude, maintaining an ultrahigh yield strength inherent to the UFG microstructure. This unique strength-ductility synergy in UFG Ti-0.3wt.%O is achieved via the combined effects of diluted grain boundary segregation of oxygen that helps to improve the grain boundary cohesive energy and enhanced dislocation activities that contribute to the excellent strain hardening ability. The present strategy will not only boost the potential applications of high strength Ti-O alloys at low temperatures, but can also be applied to other alloy systems, where interstitial solution hardening results into an undesirable loss of ductility.

Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of leptin signaling whose disruption protects against diet-induced obesity in mice. We investigated whether structural characterization of human PTP1B variant proteins might reveal precise mechanisms to target for weight loss therapy. We selected 12 rare variants for functional characterization from exomes from 997 people with persistent thinness and 200,000 people from UK Biobank. Seven of 12 variants impaired PTP1B function by increasing leptin-stimulated STAT3 phosphorylation in cells. Using room-temperature X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, and computational modeling, we determined that human variants modulate the 3-dimensional structure of PTP1B through distinct allosteric conduits that energetically link distal, highly ligandable structural regions to the active site. These studies inform the design of allosteric PTP1B inhibitors for the treatment of obesity., Competing Interests: Competing interests: ISF has consulted for a number of companies developing weight loss drugs including Eli Lilly, Novo Nordisk and Rhythm Pharmaceuticals. The other authors declare no competing interests.

The key characteristic (KCs) framework has been used previously to assess the carcinogenicity and cardiotoxicity of various chemical and pharmacological agents. Here, the 12 KCs of cardiotoxicity are used to evaluate the previously reported cardiotoxicity of phenanthrene (Phe), a tricyclic polycyclic aromatic hydrocarbon (PAH), and major component of fossil fuel-derived air pollution. Phe is a semi-volatile pollutant existing in both the gas phase and particle phase through adsorption onto or into particulate matter (PM). Phe can translocate across the airways and gastrointestinal tract into the systemic circulation, enabling body-wide effects. Our evaluation based on a comprehensive literature review, indicates Phe exhibits 11 of the 12 KCs for cardiotoxicity. These include adverse effects on cardiac electromechanical performance, the vasculature and endothelium, immunomodulation and oxidative stress, and neuronal and endocrine control. Environmental agents that have similarly damaging effects on the cardiovascular system are heavily regulated and monitored, yet globally there is no air quality regulation specific for PAHs like Phe. Environmental monitoring of Phe is not the international standard with benzo[a]pyrene being frequently used as a proxy despite the two PAH species exhibiting significant differences in sources, concentration variations and toxic effects. The evidence summarised in this evaluation highlights the need to move away from proxied PAH measurements and develop a monitoring network capable of measuring Phe concentration. It also stresses the need to raise awareness amongst the medical community of the potential cardiovascular impact of PAH exposure. This will allow the production of mitigation strategies and possibly the development of new policies for the protection of the societal groups most vulnerable to cardiovascular disease., Competing Interests: Declaration of Competing Interest Authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)