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Human phosphoglycerate kinase 1(hPGK1) is a key glycolytic enzyme that regulates the balance between ADP and ATP concentrations inside the cell. Phosphorylation of hPGK1 at S203 and S256 has been associated with enzyme import from the cytosol to the mitochondria and the nucleus respectively. These changes in subcellular locations drive tumorigenesis and are likely associated with site‐specific changes in protein stability. In this work, we investigate the effects of site‐specific phosphorylation on thermal and kinetic stability and protein structural dynamics by hydrogen–deuterium exchange (HDX) and molecular dynamics (MD) simulations. We also investigate the binding of 3‐phosphoglycerate and Mg‐ADP using these approaches. We show that the phosphomimetic mutation S256D reduces hPGK1 kinetic stability by 50‐fold, with no effect of the mutation S203D. Calorimetric studies of ligand binding show a large decrease in affinity for Mg‐ADP in the S256D variant, whereas Mg‐ADP binding to the WT and S203D can be accurately investigated using protein kinetic stability and binding thermodynamic models. HDX and MD simulations confirmed the destabilization caused by the mutation S256D (with some long‐range effects on stability) and its reduced affinity for Mg‐ADP due to the strong destabilization of its binding site (particularly in the apo‐state). Our research provides evidence suggesting that modifications in protein stability could potentially enhance the translocation of hPGK1 to the nucleus in cancer. While the structural and energetic basis of its mitochondrial import remain unknown. [ABSTRACT FROM AUTHOR]

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS). Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years. Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison. Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7–42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56–10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1–3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7–52.7] pg/ml and 158.9 [IQR, 126.9–255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03–8.54] pg/ml and 91.0 [72.6–109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values. Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values. [ABSTRACT FROM AUTHOR]

Andean glaciers are losing mass rapidly but a centennial‐scale context to those rates is lacking. Here we show the extent of >5,500 glaciers during the Little Ice Age chronozone (LIA; c. 1,400 to c. 1,850) and compute an overall area change of −25% from then to year 2000 at an average rate of −36.5 km2 yr−1 or −0.11% yr−1. Glaciers in the Tropical Andes (Peru, Bolivia) have depleted the most; median −56% of LIA area, and the fastest; median −0.16% yr−1. Up to 10 × acceleration in glacier area loss has occurred in Tropical mountain sub‐regions comparing LIA to 2,000 rates to post‐2000 rates. Regional climate controls inter‐regional variability, whereas local factors affect intra‐region glacier response time. Analyzing glacier area change by river basins and by protected areas leads us to suggest that conservation and environmental management strategies should be re‐visited as proglacial areas expand. Plain Language Summary: Andean glaciers are melting fast but how that rate compares in a longer‐term context is unknown. In this study we mapped the extent of >5,500 glaciers during the Little Ice Age, which was the last major glacial advance culminating about c. 150 years ago. We analyzed the change in glacier size and computed overall area change of −25% from the LIA to year 2000 at a rate of −36.5 km2 per year or −0.11% per year. Glaciers within Peru and Bolivia have shrunk the most by median −56% of LIA area, and the fastest by median −0.16% per year. We discuss that these glaciers are depleting and retreating due to climate change but that response is compounded by glacier size, shape and terminus environment effects. As glaciers melt they reveal proglacial landscapes that tend to be highly unstable, impacting water resources, natural hazards and terrestrial and aquatic ecology. Key Points: Little Ice Age (LIA) chronozone extent of >5,500 glaciers mapped from geomorphological evidenceOverall glacier area change of −25% to year 2000 at a rate of −36.5 km2 yr−1 or −0.11% yr−1Up to 10 × acceleration in glacier area loss for Tropical sub‐regions comparing LIA to 2,000 with post‐2000 rates [ABSTRACT FROM AUTHOR]

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