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

CALYPSO 2019 Cruise Report: field campaign in the Mediterranean

This cruise aimed to identify transport pathways from the surface into the interior ocean during the late winter in the Alborán sea between the Strait of Gibraltar (5°40’W) and the prime meridian. Theory and previous observations indicated that these pathways likely originated at strong fronts, such as the one that separates salty Mediterranean water and the fresher water in owing from the Atlantic. Our goal was to map such pathways and quantify their transport. Since the outcropping isopycnals at the front extend to the deepest depths during the late winter, we planned the cruise at the end of the Spring, prior to the onset of thermal stratification of the surface mixed layer.Funding was provided by the Office of Naval Research under Contract No. N000141613130

The genetic history of the Southern Arc: a bridge between West Asia and Europe

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra–West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe

The Sadovskii Vortex

The point vortex has been used as a simple model for flows with circulation, and has been desingularized into vortex patches and vortex sheets. In this work, we investigate the steady states of a combination of these two formulations, the Sadovskii vortex. The Sadovskii vortex is a uniform patch of vorticity surrounded by a vortex sheet. Numerical continuation is used to follow families of solutions. In the limiting cases of the vortex patch and vortex sheet cases, we confirm previous research, and in the vortex patch case show new solutions.In the regime where both sources of circulation exist, we show the relationship between the vortex patch and vortex sheet solution families. The more complicated vortex patch solution families lead to the simpler vortex sheet solution family due to a splitting of the vortex patch families at bifurcation points in the presence of the vortex sheet. The more circular elliptical family remains attached to the family with a single pinch off, and this family extends all the way to the pure vortex sheet solutions. More elongated families below this one also split at bifurcation points, and these families do not exist in the vortex sheet regime.In the presence of surface tension, vortex patch shapes are deformed where the background straining flow is into the vortices. This leads to oscillations on the boundary, similar to those found by Tanveer (1986) for bubbles in Hele-Shaw cells. The pinch off cusp for the patch vortex becomes desingularized in the presence of surface tension, and no longer touches. The effects of surface tension on the vortex sheet and Sadovskii vortex shapes are shown to be similar but smaller

The Sadovskii vortex in strain

The point vortex is the simplest model of a two-dimensional vortex with non-zero circulation. The limitations introduced by its lack of core structure have been remedied by using desingularizations such as vortex patches and vortex sheets. We investigate steady states of the Sadovskii vortex in strain, a canonical model for a vortex in a general flow. The Sadovskii vortex is a uniform patch of vorticity surrounded by a vortex sheet. We recover previously known limiting cases of the vortex patch and hollow vortex, and examine the bifurcations away from these families. The result is a solution manifold spanned by two parameters. The addition of the vortex sheet to the vortex patch solutions immediately leads to splits in the solution manifold at certain bifurcation points. The more circular elliptical family remains attached to the family with a single pinch-off, and this family extends all the way to the simpler solution branch for the pure vortex sheet solutions. More elongated families below this one also split at bifurcation points, but these families do not exist in the vortex sheet limit