A switch from α‐helical to β‐strand conformation during co‐translational protein folding

Cellular proteins begin to fold as they emerge from the ribosome. The folding landscape of nascent chains is not only shaped by their amino acid sequence but also by the interactions with the ribosome. Here, we combine biophysical methods with cryo‐EM structure determination to show that folding of a β‐barrel protein begins with formation of a dynamic α‐helix inside the ribosome. As the growing peptide reaches the end of the tunnel, the N‐terminal part of the nascent chain refolds to a β‐hairpin structure that remains dynamic until its release from the ribosome. Contacts with the ribosome and structure of the peptidyl transferase center depend on nascent chain conformation. These results indicate that proteins may start out as α‐helices inside the tunnel and switch into their native folds only as they emerge from the ribosome. Moreover, the correlation of nascent chain conformations with reorientation of key residues of the ribosomal peptidyl‐transferase center suggest that protein folding could modulate ribosome activity.     

A network-based approach to integrate nutrient microenvironment in the prediction of synthetic lethality in cancer metabolism

Synthetic Lethality (SL) is currently defined as a type of genetic interaction in which the loss of function of either of two genes individually has limited effect in cell viability but inactivation of both genes simultaneously leads to cell death. Given the profound genomic aberrations acquired by tumor cells, which can be systematically identified with -omics data, SL is a promising concept in cancer research. In particular, SL has received much attention in the area of cancer metabolism, due to the fact that relevant functional alterations concentrate on key metabolic pathways that promote cellular proliferation. With the extensive prior knowledge about human metabolic networks, a number of computational methods have been developed to predict SL in cancer metabolism, including the genetic Minimal Cut Sets (gMCSs) approach. A major challenge in the application of SL approaches to cancer metabolism is to systematically integrate tumor microenvironment, given that genetic interactions and nutritional availability are interconnected to support proliferation. Here, we propose a more general definition of SL for cancer metabolism that combines genetic and environmental interactions, namely loss of gene functions and absence of nutrients in the environment. We extend our gMCSs approach to determine this new family of metabolic synthetic lethal interactions. A computational and experimental proof-of-concept is presented for predicting the lethality of dihydrofolate reductase (DHFR) inhibition in different environments. Finally, our approach is applied to identify extracellular nutrient dependences of tumor cells, elucidating cholesterol and myo-inositol depletion as potential vulnerabilities in different malignancies.     

GlialCAM,a CLC-2 Cl- Channel Subunit,Activates the Slow Gate of CLC Chloride Channels

GlialCAM, a glial cell adhesion molecule mutated in megalencephalic leukoencephalopathy with subcortical cysts, targets the CLC-2 Cl^- channel to cell contacts in glia and activates CLC-2 currents in vitro and in vivo. We found that GlialCAM clusters all CLC channels at cell contacts in vitro and thus studied GlialCAM interaction with CLC channels to investigate the mechanism of functional activation. GlialCAM slowed deactivation kinetics of CLC-Ka/barttin channels and increased CLC-0 currents opening the common gate and slowing its deactivation. No functional effect was seen for common gate deficient CLC-0 mutants. Similarly, GlialCAM targets the common gate deficient CLC-2 mutant E211V/H816A to cell contacts, without altering its function. Thus, GlialCAM is able to interact with all CLC channels tested, targeting them to cell junctions and activating them by stabilizing the open configuration of the common gate. These results are important to better understand the physiological role of GlialCAM/CLC-2 interaction.     

Weather effect on widely distributed seabirds through migration flyways: a case study with the Northern Gannet Morus bassanus in the Bay of Biscay

Capsule: Northern Gannet Morus bassanus counts obtained from a coastal monitoring network in northern Spain were highly determined by wind conditions.

Aims: To determine how external factors including weather conditions affect seabird counts in a land-based seabird monitoring project (Red de observación de Aves y Mamíferos marinos, RAM project; Seabird & Marine Mammal Observation Network).

Methods: Seabird counts were obtained from four study capes situated in the southeastern part of the Bay of Biscay in northern Spain. Counts were conducted on a monthly-basis for a period of 3 hours starting at dawn on each sampling day. Data used here were compiled over a 10-year period (2006–15).

Results: Northern Gannet numbers were chiefly influenced by meteorological conditions at a local spatial scale. Northwesterly winds were found to positively influence gannet abundance, whereas high relative humidity caused a decrease in abundance. Moreover, gannets were more abundant during the non-breeding period as compared to breeding period.

Conclusion: We recommend considering the effect of the wind and relative humidity on land-based seabird counts in the Bay of Biscay when handling data from the RAM protocol in order to avoid biases and misinterpretation of data. Since seabirds approach the coast during harsh weather conditions, the RAM protocol should be improved in order to better account for the distance at which the birds are seen.     

Microglial immune response is impaired against the neurotropic fungus Lomentospora prolificans

Lomentospora (Scedosporium) prolificans is an opportunistic pathogen capable of causing invasive infections in immunocompromised patients. The fungus is able to disseminate via the bloodstream finally arriving at the central nervous system producing neurological symptoms and, in many cases, patient death. In this context, microglial cells, which are the resident immune cells in the central nervous system, may play an important role in these infections. However, this aspect of anti‐L. prolificans immunity has been poorly researched to date. Thus, the interactions and activity of microglial cells against L. prolificans were analysed, and the results show that there was a remarkable impairment in their performance regarding phagocytosis, the development of oxidative burst, and in the production of pro‐inflammatory cytokines, compared with macrophages. Interestingly, L. prolificans displays great growth also when challenged with immune cells, even when inside them. We also proved that microglial phagocytosis of the fungus is highly dependent on mannose receptor and especially on dectin‐1. Taken together, these data provide evidence for an impaired microglial response against L. prolificans and contribute to understanding the pathobiology of its neurotropism.     

Food availability as a potential source of bias in the egg production method for copepods

The measurement of copepod adult female fecundity as an estimateof adult growth (production) rates has been an approach widelyused in both laboratory and field studies. Here we demonstratethat the basic assumption of this approach, i.e. that estimatedegg production during the incubation reflects the ‘insitu’ conditions, is not always legitimate and that itis temperature dependent. The enhancement of metabolic ratesinduced by high temperatures induces a more accented bias ofthe method. We also provide guidelines on how to conduct theincubations in order to obtain more reliable estimates.     

Sea-level dynamics and palaeoecological factors affecting trace fossil distribution in Eocene turbiditic deposits (Gorrondatxe section,N Spain)

Ichnological analysis of the upper Ypresian–lower Lutetian interval at the Gorrondatxe section (W Pyrenees, N Spain), reveals a relationship between sea-level dynamics and the eco-sedimentary factors influencing trace fossil assemblages. The 600 m thick section of deep-sea turbiditic deposits contains 41 ichnospecies belonging to 28 ichnogenera, which are typical of the Nereites ichnofacies, and mostly of the Paleodictyon ichnosubfacies, suggesting deposition in a basin plain to fan-fringe setting. The trace fossil diversity and abundance fluctuate, irrespective of turbidite frequency. These ichnological features are strongly affected by trophic level changes related partly to sea-level dynamics according to the sequence stratigraphic interpretations for the studied section. Temperature, oxygenation and substrate changes are also considered as relevant factors. Increased ichnodiversity, particularly among graphoglyptids, coincides with moderate oligotrophy and stable ecological conditions. Eutrophisation, lowered oxygenation and drop of temperature, typical of low sea level, can reduce ichnodiversity.