Global Structure of the Intrinsically Disordered Protein Tau Emerges from Its Local Structure

The paradigmatic disordered protein tau plays an important role in neuronal function and neurodegenerative diseases. To disentangle the factors controlling the balance between functional and disease-associated conformational states, we build a structural ensemble of the tau K18 fragment containing the four pseudorepeat domains involved in both microtubule binding and amyloid fibril formation. We assemble 129-residue-long tau K18 chains with atomic detail from an extensive fragment library constructed with molecular dynamics simulations. We introduce a reweighted hierarchical chain growth (RHCG) algorithm that integrates experimental data reporting on the local structure into the assembly process in a systematic manner. By combining Bayesian ensemble refinement with importance sampling, we obtain well-defined ensembles and overcome the problem of exponentially varying weights in the integrative modeling of long-chain polymeric molecules. The resulting tau K18 ensembles capture nuclear magnetic resonance (NMR) chemical shift and J-coupling measurements. Without further fitting, we achieve very good agreement with measurements of NMR residual dipolar couplings. The good agreement with experimental measures of global structure such as single-molecule Förster resonance energy transfer (FRET) efficiencies is improved further by ensemble refinement. By comparing wild-type and mutant ensembles, we show that pathogenic single-point P301L, P301S, and P301T mutations shift the population from the turn-like conformations of the functional microtubule-bound state to the extended conformations of disease-associated tau fibrils. RHCG thus provides us with an atomically detailed view of the population equilibrium between functional and aggregation-prone states of tau K18, and demonstrates that global structural characteristics of this intrinsically disordered protein emerge from its local structure

Eradication of invasive species: science, attitude and understanding. The beaver in Tierra del Fuego

El manejo de especies invasoras presenta desafíos, que incluyen la necesidad de generar conocimiento aplicado y capacidades de gestión, así como modificar actitudes y comportamientos de la sociedad. El caso de la especie invasora castor canadiense, Castor canadensis, ejemplifica enfoques que pueden aplicarse para tratar otras especies invasoras. Repasamos la historia de manejo del castor y el cambio de enfoque que derivó en un acuerdo binacional inédito para restaurar los ecosistemas afectados por la especie mediante su erradicación, acuerdo que avanza mediante un proceso de generación de capacidades y escalamiento en la complejidad del trabajo, desde áreas piloto hacia todo el rango de distribución actual de la especie. Destacamos cómo la investigación aporta al manejo del castor, presentando detalles de la investigación en marcha en algunos ejes principales: 1) la factibilidad de erradicar en áreas piloto; 2) la estimación de tasas vitales y de dispersión y la construcción de modelos predictivos de expansión de la invasión, y 3) la determinación de criterios objetivos para declarar la erradicación del castor en sectores bajo manejo. La generación de capacidades es crucial para este complejo proceso. La construcción del capital social necesario para manejar el problema requiere de un diálogo continuo entre los diversos sectores involucrados y la construcción de agendas consensuadas. El sector científico puede asistir este proceso, pero sin imponer agendas unilaterales, sino identificando y contribuyendo a resolver las preguntas correctas y entendiendo las particularidades de los demás sectores, la cultura de las organizaciones y los tiempos para dar respuestas prácticas para lograr conservación basada en ciencia.The management of invasive species involves several challenges, ranging from the need to generate applied knowledge and capacity building abilities to a change in perceptions and behaviors in society. The case of the invasive Canadian beaver, Castor canadensis, illustrates possible approaches to address other invasive species. We reviewed the management history of the beaver and the change of approach that led to an unprecedented bi-national agreement to restore the affected ecosystems by means of the eradication of the species. This agreement advances by means of a training process of capacity building and a gradual scaling in the complexity of the work, from pilot areas to the whole current distribution of the species. We highlight how scientific research contributes to the management of the species, presenting details of the ongoing research in three major areas: 1) feasibility of eradication in pilot areas; 2) assessment of vital and dispersion rates and building predictive models of the spread of the invasion, and 3) determination of objective criteria to declare beaver eradication in areas under management. Capacity building is critical for this complex process. Assembling the social capital needed to manage the problem requires a continuous dialogue and agreed agendas among various stakeholders. The scientific sector can assist in this process without imposing unilateral agendas, but identifying the right questions and understanding the particularities of other sectors, the culture of organizations and the time frames needed for practical responses to achieve science-based conservation.Fil: Schiavini, Adrian Carlos Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Carranza, M. L.. Secretaria de Desarrollo Sustentable y Ambiente; ArgentinaFil: Deferrari, Guillermo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Escobar, Julio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Malmierca, Laura Margarita Elvira. Administración de Parques Nacionales. Delegación Regional Patagonia; ArgentinaFil: Pietrek, A.. University of Duke; Estados Unido

Self-Organization and Regulation of Intrinsically Disordered Proteins with Folded N-Termini

How do mostly disordered proteins coordinate the specific assembly of very large signal transduction protein complexes? A newly emerging hypothesis may provide some clues towards a molecular mechanism

SH3 Domain-Mediated Recruitment of Host Cell Amphiphysins by Alphavirus nsP3 Promotes Viral RNA Replication

Among the four non-structural proteins of alphaviruses the function of nsP3 is the least well understood. NsP3 is a component of the viral replication complex, and composed of a conserved aminoterminal macro domain implicated in viral RNA synthesis, and a poorly conserved carboxyterminal region. Despite the lack of overall homology we noted a carboxyterminal proline-rich sequence motif shared by many alphaviral nsP3 proteins, and found it to serve as a preferred target site for the Src-homology 3 (SH3) domains of amphiphysin-1 and -2. Nsp3 proteins of Semliki Forest (SFV), Sindbis (SINV), and Chikungunya viruses all showed avid and SH3-dependent binding to amphiphysins. Upon alphavirus infection the intracellular distribution of amphiphysin was dramatically altered and colocalized with nsP3. Mutations in nsP3 disrupting the amphiphysin SH3 binding motif as well as RNAi-mediated silencing of amphiphysin-2 expression resulted in impaired viral RNA replication in HeLa cells infected with SINV or SFV. Infection of Balb/c mice with SFV carrying an SH3 binding-defective nsP3 was associated with significantly decreased mortality. These data establish SH3 domain-mediated binding of nsP3 with amphiphysin as an important host cell interaction promoting alphavirus replication

Analysis of a storm situation over the southern Baltic Sea using direct hydrometeorological and remote sensing measurements results

The paper presents results of research concerning meteorological and hydrological conditions in the storm related with the Xaver cyclone moving fast over the Baltic Sea. The analyses were based on remote sensing data from radars in Świdwin and Gdańsk-Rębiechowo and hydrometeorological data from direct measurements conducted at the coastal stations of the Polish Navy, marine stations of the Institute of Meteorology and Water Management, hydrometeorological station on the “Baltic Beta” oil rig and the Coastal Research Station of the Institute of Hydroengineering of the Polish Academy of Sciences in Lubiatowo. The assessment of the synoptic situation was made using surface weather charts, satellite images of cloud cover and meteorological radars products. The measurement data were used to analyze the surface and upper air wind fields for assessment of the hydrological situation (water condition, height and direction of the significant and maximum waves) and evaluation of threats to sea navigation and coastal infrastructure