An intact C-terminal end of albumin is required for its long half-life in humans.

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics

Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus

Background: Individual patients show a large variability in albuminuria response to angiotensin receptor blockers (ARB). Identifying novel biomarkers that predict ARB response may help tailor therapy. We aimed to discover and validate a serum metabolite classifier that predicts albuminuria response to ARBs in patients with diabetes mellitus and micro- or macroalbuminuria. Methods: Liquid chromatography-tandem mass spectrometry metabolomics was performed on serum samples. Data from patients with type 2 diabetes and microalbuminuria (n = 49) treated with irbesartan 300 mg/day were used for discovery. LASSO and ridge regression were performed to develop the classifier. Improvement in albuminuria response prediction was assessed by calculating differences in R-2 between a reference model of clinical parameters and a model with clinical parameters and the classifier. The classifier was externally validated in patients with type 1 diabetes and macroalbuminuria (n = 50) treated with losartan 100 mg/day. Molecular process analysis was performed to link metabolites to molecular mechanisms contributing to ARB response. Results: In discovery, median change in urinary albumin excretion (UAE) was -42 % [Q1-Q3: -69 to -8]. The classifier, consisting of 21 metabolites, was significantly associated with UAE response to irbesartan (p <0.001) and improved prediction of UAE response on top of the clinical reference model (R2 increase from 0.10 to 0.70; p <0.001). In external validation, median change in UAE was -43 % [Q1-Q35: -63 to -23]. The classifier improved prediction of UAE response to losartan (R2 increase from 0.20 to 0.59; p <0.001). Specifically ADMA impacting eNOS activity appears to be a relevant factor in ARB response. Conclusions: A serum metabolite classifier was discovered and externally validated to significantly improve prediction of albuminuria response to ARBs in diabetes mellitus

A Distant Fast Radio Burst Associated with Its Host Galaxy by the Very Large Array

We present the discovery and subarcsecond localization of a new fast radio burst (FRB) by the Karl G. Jansky Very Large Array (VLA) and realfast search system. The FRB was discovered on 2019 June 14 with a dispersion measure of 959 pc cm⁻³. This is the highest DM of any localized FRB and its measured burst fluence of 0.6 Jy ms is less than nearly all other FRBs. The source is not detected to repeat in 15 hr of VLA observing and 153 hr of CHIME/FRB observing. We describe a suite of statistical and data quality tests we used to verify the significance of the event and its localization precision. Follow-up optical/infrared photometry with Keck and Gemini associate the FRB with a pair of galaxies with r ∼ 23 mag. The false-alarm rate for radio transients of this significance that are associated with a host galaxy is roughly 3×10⁻⁴ hr⁻¹. The two putative host galaxies have similar photometric redshifts of z_(phot) ∼ 0.6, but different colors and stellar masses. Comparing the host distance to that implied by the dispersion measure suggests a modest (~ 50 pc/cm⁻³) electron column density associated with the FRB environment or host galaxy/galaxies