Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau.

Small heat shock proteins (sHSPs) are a class of oligomeric molecular chaperones that limit protein aggregation. However, it is often not clear where sHSPs bind on their client proteins or how these protein-protein interactions (PPIs) are regulated. Here, we map the PPIs between human Hsp27 and the microtubule-associated protein tau (MAPT/tau). We find that Hsp27 selectively recognizes two aggregation-prone regions of tau, using the conserved β4-β8 cleft of its alpha-crystallin domain. The β4-β8 region is also the site of Hsp27-Hsp27 interactions, suggesting that competitive PPIs may be an important regulatory paradigm. Indeed, we find that each of the individual PPIs are relatively weak and that competition for shared sites seems to control both client binding and Hsp27 oligomerization. These findings highlight the importance of multiple, competitive PPIs in the function of Hsp27 and suggest that the β4-β8 groove acts as a tunable sensor for clients

Diagnosing Frontal Dynamics From Observations Using a Variational Approach

Intensive hydrographic and horizontal velocity measurements collected in the Alboran Sea enabled us to diagnose the three-dimensional dynamics of a frontal system. The sampled domain was characterized by a 40 km diameter anticyclonic eddy, with an intense front on its eastern side, separating the Atlantic and Mediterranean waters. Here, we implemented a multi-variate variational analysis (VA) to reconstruct the hydrographic fields, combining the 1-km horizontal resolution of the Underway Conductivity-Temperature-Depth (CTD) system with information on the flow shape from the Acoustic Doppler Current Profiler velocities. One advantage of the VA is given by the physical constraint, which preserves fine-scale gradients better than the classical optimal interpolation (OI). A comparison between real drifter trajectories and virtual particles advected in the mapping quantified the improvements in the VA over the OI, with a 15% larger skill score. Quasi-geostrophic (QG) and semi-geostrophic (SG) omega equations enabled us to estimate the vertical velocity (w) which reached 40 m/day on the dense side of the front. How nutrients and other passive tracers leave the mixed-layer and subduct is estimated with 3D advection from the VA, which agreed with biological sampling from traditional CTD casts at two eddy locations. Downwelling warm filaments are further evidence of subduction, in line with the w from SG, but not with QG. SG better accounted for the along-isopycnal component of w in agreement with another analysis made on isopycnal coordinates. The multi-platform approach of this work and the use of variational methods improved the characterization and understanding of (sub)-mesoscale frontal dynamics.This research was supported by the Office of Naval Research Departmental Research Initiative CALYPSO under program officers Terri Paluszkiewicz and Scott Harper. The authors' ONR Grant are as follows: N000141613130 (AP, SR and AM), N000141812418 (PMP), S. Johnston N000141812416 (TMSJ), N000141812138 (TO), N000141712517 and N00014191269 (LRC), N000141812139 and N000141812420 (AS) and N000141812139and (EDA). This article is also a contribution to the PRE-SWOT project funded by the Spanish Research Agency and the European Regional Development Fund (AEI/FEDER, UE) under grant agreement (CTM2016-78607-P)

Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study

[EN] The photoinduced cycloreversion of oxetanes has been thoroughly investigated in connection with the photorepair of the well-known DNA (6-4) photoproducts. In the present work, the direct photolysis of the two regioisomers arising from the irradiation of benzophenone (BP) and 1,3-dimethylthymine (DMT), namely the head-to-head (HH-1) and head-to-tail (HT-1) oxetane adducts, has been investigated by combining ultrafast spectroscopy and theoretical multiconfigurational quantum chemistry analysis. Both the experimental and computational results agree with the involvement of an excited triplet exciplex(3)[BPMIDLINE HORIZONTAL ELLIPSISDMT]* for the photoinduced oxetane cleavage to generate(3)BP* and DMT through an adiabatic photochemical reaction. The experimental signature of(3)[BPMIDLINE HORIZONTAL ELLIPSISDMT]* is the appearance of an absorption band atca.400 nm, detected by femtosecond transient absorption spectroscopy. Its formation is markedly regioselective, as it is more efficient and proceeds faster for HH-1 (similar to 2.8 ps) than for HT-1 (similar to 6.3 ps). This is in line with the theoretical analysis, which predicts an energy barrier to reach the triplet exciplex for HT-1, in contrast with a less hindered profile for HH-1. Finally, the more favorable adiabatic cycloreversion of HH-1 compared to that of HT-1 is explained by its lower probability to reach the intersystem crossing with the ground state, which would induce a radiationless deactivation process leading either to a starting adduct or to a dissociated BP and DMT.Financial support from the Spanish Government (RYC-2015-17737, CTQ2017-89416-R, RYC-2015-19234, CTQ2017-87054-C2-2-P, and MDM-2015-0538), from the Conselleria d'Educacio, Investigacio, Cultura i Esport (PROMETEO/2017/075 and GRISOLiAP/2017/005) and from the Universitat de Valencia (postdoctoral grant within the "Atraccio de Talent 2019" Program for A. G.) is gratefully acknowledged. This work was also supported by a 2019 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation. The Foundation takes no responsibility for the opinions, statements, and contents of this project, which are entirely the responsibility of its authors.Blasco-Brusola, A.; Navarrete-Miguel, M.; Giussani, A.; Roca-Sanjuan, D.; Vayá Pérez, I.; Miranda Alonso, MÁ. (2020). Regiochemical memory in the adiabatic photolysis of thymine-derived oxetanes. A combined ultrafast spectroscopic and CASSCF/CASPT2 computational study. Physical Chemistry Chemical Physics. 22(35):20037-20042. https://doi.org/10.1039/d0cp03084hS2003720042223

Toward a Surrogate Marker of Malaria Exposure: Modeling Longitudinal Antibody Measurements under Outbreak Conditions

Background: Biomarkers of exposure to Plasmodium falciparum would be a useful tool for the assessment of malaria burden and analysis of intervention and epidemiological studies. Antibodies to pre-erythrocytic antigens represent potential surrogates of exposure. Methods and Findings: In an outbreak cohort of U.S. Marines deployed to Liberia, we modeled pre- and post-deployment IgG against P. falciparum sporozoites by immunofluorescence antibody test, and both IgG and IgM against the P. falciparum circumsporozoite protein by enzyme-linked immunosorbant assay. Modeling seroconversion thresholds by a fixed ratio, linear regression or nonlinear regression produced sensitivity for identification of exposed U.S. Marines between 58-70% and specificities between 87-97%, compared with malaria-naïve U.S. volunteers. Exposure was predicted in 30-45% of the cohort. Conclusion: Each of the three models tested has merits in different studies, but further development and validation in endemic populations is required. Overall, these models provide support for an antibody-based surrogate marker of exposure to malaria

Inertial Oscillations and Frontal Processes in an Alboran Sea Jet: Effects on Divergence and Vertical Transport

Vertical transport pathways in the ocean are still only partially understood despite their importance for biogeochemical, pollutant, and climate applications. Detailed measurements of a submesoscale frontal jet in the Alboran Sea (Mediterranean Sea) during a period of highly variable winds were made using cross-frontal velocity, density sections and dense arrays of surface drifters deployed across the front. The measurements show divergences as large as ±f implying vertical velocities of order 100 m/day for a ≈ 20 m thick surface layer. Over the 20 hr of measurement, the divergences made nearly one complete oscillation, suggesting an important role for near-inertial oscillations. A wind-forced slab model modified by the observed background frontal structure and with initial conditions matched to the data produces divergence oscillations and pattern compatible with that observed. Significant differences, though, are found in terms of mean divergence, with the data showing a prevalence of negative, convergent values. Despite the limitations in data sampling and model uncertainties, this suggests the contribution of other dynamical processes. Turbulent boundary layer processes are discussed, as a contributor to enhance the observed convergent phase. Water mass properties suggest that symmetric instabilities might also be present but do not play a crucial role, while downward stirring along displaced isopycnals is observed.This work has been supported and co-financed by the CALYPSO project, within the Office of Naval Research Departmental Research Initiative, under the following grants: N00014-18-1-2782 and N00014-22-1-2039 (GE,SD,MB,AG), N00014-18-1-2139 (AYS,EAD), N00014-18-1-2138 (TO), N00014-18-1-2418 and N00014-20-1-2754 (PMP), N00014-19-1-2692 and N00014-19-1-2380 (LC and part of the drifter data collection/analysis), N00014-18-1-2431 (JTF), N00014-18-1-2416 (TMSJ), N00014-16-1-3130 (AP,DRT,SR), N00014-21-1-2702 (AM). MF was supported by the Scripps Institutional Postdoctoral Fellowship (MAF). Investigation of front dynamics in the Mediterranean Sea from multiplatform observations is supported as well by the European Union's JERICO-S3 project through Grant 871153. Open Access Funding provided by Consiglio Nazionale delle Ricerche within the CRUI-CARE Agreement.Peer reviewe