Quantifying the Effects of Elastic Collisions and Non-Covalent Binding on Glutamate Receptor Trafficking in the Post-Synaptic Density

One mechanism of information storage in neurons is believed to be determined by the strength of synaptic contacts. The strength of an excitatory synapse is partially due to the concentration of a particular type of ionotropic glutamate receptor (AMPAR) in the post-synaptic density (PSD). AMPAR concentration in the PSD has to be plastic, to allow the storage of new memories; but it also has to be stable to preserve important information. Although much is known about the molecular identity of synapses, the biophysical mechanisms by which AMPAR can enter, leave and remain in the synapse are unclear. We used Monte Carlo simulations to determine the influence of PSD structure and activity in maintaining homeostatic concentrations of AMPARs in the synapse. We found that, the high concentration and excluded volume caused by PSD molecules result in molecular crowding. Diffusion of AMPAR in the PSD under such conditions is anomalous. Anomalous diffusion of AMPAR results in retention of these receptors inside the PSD for periods ranging from minutes to several hours in the absence of strong binding of receptors to PSD molecules. Trapping of receptors in the PSD by crowding effects was very sensitive to the concentration of PSD molecules, showing a switch-like behavior for retention of receptors. Non-covalent binding of AMPAR to anchored PSD molecules allowed the synapse to become well-mixed, resulting in normal diffusion of AMPAR. Binding also allowed the exchange of receptors in and out of the PSD. We propose that molecular crowding is an important biophysical mechanism to maintain homeostatic synaptic concentrations of AMPARs in the PSD without the need of energetically expensive biochemical reactions. In this context, binding of AMPAR with PSD molecules could collaborate with crowding to maintain synaptic homeostasis but could also allow synaptic plasticity by increasing the exchange of these receptors with the surrounding extra-synaptic membrane

On the Zwitterionic Nature of Gas-Phase Peptides and Protein Ions

Determining the total number of charged residues corresponding to a given value of net charge for peptides and proteins in gas phase is crucial for the interpretation of mass-spectrometry data, yet it is far from being understood. Here we show that a novel computational protocol based on force field and massive density functional calculations is able to reproduce the experimental facets of well investigated systems, such as angiotensin II, bradykinin, and tryptophan-cage. The protocol takes into account all of the possible protomers compatible with a given charge state. Our calculations predict that the low charge states are zwitterions, because the stabilization due to intramolecular hydrogen bonding and salt-bridges can compensate for the thermodynamic penalty deriving from deprotonation of acid residues. In contrast, high charge states may or may not be zwitterions because internal solvation might not compensate for the energy cost of charge separation

Global satellite-observed daily vertical migrations of ocean animals

Every night across the world’s oceans, numerous marine animals arrive at the surface of the ocean to feed on plankton after an upward migration of hundreds of metres. Just before sunrise, this migration is reversed and the animals return to their daytime residence in the dark mesopelagic zone (at a depth of 200–1,000 m). This daily excursion, referred to as diel vertical migration (DVM), is thought of primarily as an adaptation to avoid visual predators in the sunlit surface layer1,2 and was first recorded using ship-net hauls nearly 200 years ago3. Nowadays, DVMs are routinely recorded by ship-mounted acoustic systems (for example, acoustic Doppler current profilers). These data show that night-time arrival and departure times are highly conserved across ocean regions4 and that daytime descent depths increase with water clarity4,5, indicating that animals have faster swimming speeds in clearer waters4. However, after decades of acoustic measurements, vast ocean areas remain unsampled and places for which data are available typically provide information for only a few months, resulting in an incomplete understanding of DVMs. Addressing this issue is important, because DVMs have a crucial role in global ocean biogeochemistry. Night-time feeding at the surface and daytime metabolism of this food at depth provide an efficient pathway for carbon and nutrient export6,7,8. Here we use observations from a satellite-mounted light-detection-and-ranging (lidar) instrument to describe global distributions of an optical signal from DVM animals that arrive in the surface ocean at night. Our findings reveal that these animals generally constitute a greater fraction of total plankton abundance in the clear subtropical gyres, consistent with the idea that the avoidance of visual predators is an important life strategy in these regions. Total DVM biomass, on the other hand, is higher in more productive regions in which the availability of food is increased. Furthermore, the 10-year satellite record reveals significant temporal trends in DVM biomass and correlated variations in DVM biomass and surface productivity. These results provide a detailed view of DVM activities globally and a path for refining the quantification of their biogeochemical importance

Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis.

To access publisher's full text version of this article click on the hyperlink belowWe performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10(-12), odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10(-18), OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts