Spontaneous emergence of topologically robust grid cell modules: A multiscale instability theory

Modular structures in the brain play a central role in compositionality and intelligence, however the general mechanisms driving module emergence have remained elusive. Studying entorhinal grid cells as paradigmatic examples of modular architecture and function, we demonstrate the spontaneous emergence of a small number of discrete spatial and functional modules from an interplay between continuously varying lateral interactions generated by smooth cortical gradients. We derive a comprehensive analytic theory of modularization, revealing that the process is highly generic with its robustness deriving from topological origins. The theory generates universal predictions for the sequence of grid period ratios, furnishing the most accurate explanation of grid cell data to date. Altogether, this work reveals novel principles by which simple bottom-up dynamical interactions lead to macroscopic modular organization.

In situ Alphavirus Assembly and Budding Mechanism Revealed by Cellular CryoET

Chikungunya virus (CHIKV) is an alphavirus and the etiological agent for debilitating arthritogenic disease in humans. Previous studies with purified virions or budding mutants have not resolved the structural mechanism of alphavirus assembly in situ. Here we used cryogenic electron tomography (cryoET) imaging of CHIKV-infected human cells and subvolume classification to resolve distinct assembly intermediate conformations. These structures revealed that particle formation is driven by the spike envelope layer. Additionally, we showed that asymmetric immature nucleocapsids (NCs) provide scaffolds to trigger assembly of the icosahedral spike lattice, which progressively transforms immature NCs into icosahedral cores during virus budding. Further, cryoET of the infected cells treated with neutralizing antibodies (NAbs) showed that NAb-induced blockage of CHIKV assembly was achieved by preventing spike-spike lateral interactions that are required to bend the plasma membrane around NC cores. These findings provide molecular mechanisms for designing antivirals targeting spike-driven assembly/budding of viruses.

Interpretation of the adsorption of metals on quartz crystal based-macromolecule via advanced modeling of equilibrium isotherms

In this article, new insights about the metals-porphyrin complexes are proved by analyzing the zinc, nickel and chromium adsorption process over the well-known porphyrin macromolecule. The use of the quartz crystal microbalance (QCM) apparatus allows the control of the complexation systems’ experimental adsorption data operating at four temperatures. The experimental results and the physical models reveal that the zinc and nickel complexation processes are to be examined using the mono layer adsorption model. While, the double layer model describes the interaction between the chromium compound and the porphyrin. Actually, the three metals are shown to be adsorbed by a multi-docking process in the physicochemical description. The endothermic character of the investigated processes is shown through the appropriate data of the principal parameter adsorbent sites’ density. Hence, several porphyrin sites are exclusively stimulated at high temperature. The parameters of van del Waals, depicting the influences of the lateral interactions, explain the nickel isotherms down trend. The chemical bonds are shown to be carried out between the zinc and the porphyrin through the calculated adsorption energies. Considering the thermodynamic study, and referring to the configurational entropy and the free enthalpy, it is to be noted that the disorder peak of the three mechanisms is reached when the equilibrium concentration is equal to the energetic parameters’ values for each system. The nickel enthalpy revealed for high concentration that the adsorbates’ lateral interactions disapproved the nickel chloride adsorption. The free enthalpy trends, that observed two stability states of the chromium compound, confirmed the chromium double layer mechanism.

Protein Adsorbate Biohybrids and Sequential Hystallosteric Protein Adsorption

Protein adsorption on solid surfaces is characterized by multivalence, binding-unit overlap, sequential adsorption, surface allosterics, lateral interactions and pronounced adsorption-desorption hysteresis, giving rise to the sequential, hystallosteric, adsorption model ("SHA model"). Adsorption isotherms of fibrinogen on a titanium miniplates and of the growth factors rhBMP-2 and rhVEGF165 on PDLLA nanofiber fleeces are presented. Controversial Langmuir type isotherms of fibrinogen and rhVEGF165 can be understood on the basis of singular long-lived metastable states central to the SHA-model.

Learning of biased representations in LIP through interactions between recurrent connectivity and Hebbian plasticity

When monkeys learn to group visual stimuli into arbitrary categories, lateral intraparietal area (LIP) neurons become category-selective. Surprisingly, the representations of learned categories are overwhelmingly biased: nearly all LIP neurons in a given animal prefer the same category over other behaviorally equivalent categories. We propose a model where such biased representations develop through the interplay between Hebbian plasticity and the recurrent connectivity of LIP. In this model, two separable processes of positive feedback unfold in parallel: in one, category selectivity emerges from competition between prefrontal inputs; in the other, bias develops due to lateral interactions among LIP neurons. This model reproduces the levels of category selectivity and bias observed under a variety of conditions, as well as the redevelopment of bias after monkeys learn redefined categories. It predicts that LIP receptive fields would spatially cluster by preferred category, which we experimentally confirm. In summary, our model reveals a mechanism by which LIP learns abstract representations and assigns meaning to sensory inputs.

Bending-torsional elasticity and energetics of the plus-end microtubule tip

Microtubules (MTs), mesoscopic cellular filaments, grow primarily by the addition of GTP-bound tubulin dimers at their dynamic flaring plus-end tips. They operate as chemomechanical energy transducers with stochastic transitions to an astounding shortening motion upon hydrolyzing GTP to GDP. Time-resolved dynamics of the MT tip - a key determinant of this behavior - as a function of nucleotide state, internal lattice strain, and stabilizing lateral interactions have not been fully understood. Here, we use atomistic simulations to study the spontaneous relaxation of complete GTP-MT and GDP-MT tip models from unfavorable straight to relaxed splayed conformations and to comprehensively characterize the elasticity of MT tips. Our simulations reveal the dominance of viscoelastic dynamics of MT protofilaments during the relaxation process, driven by the stored bending-torsional strain and counterbalanced by the inter-protofilament interactions. We show that the post-hydrolysis MT tip is exposed to higher activation energy barriers for straight lattice formation, which translates into its inability to elongate. Our study provides an 'information ratchet' mechanism for the elastic energy conversion and release by MT tips and offers new insights into the mechanoenzymatics of MTs.

Chromatic Induction in Migraine

The human visual system is not a colorimeter. The perceived colour of a region does not only depend on its colour spectrum, but also on the colour spectra and geometric arrangement of neighbouring regions, a phenomenon called chromatic induction. Chromatic induction is thought to be driven by lateral interactions: the activity of a central neuron is modified by stimuli outside its classical receptive field through excitatory–inhibitory mechanisms. As there is growing evidence of an excitation/inhibition imbalance in migraine, we compared chromatic induction in migraine and control groups. As hypothesised, we found a difference in the strength of induction between the two groups, with stronger induction effects in migraine. On the other hand, given the increased prevalence of visual phenomena in migraine with aura, we also hypothesised that the difference between migraine and control would be more important in migraine with aura than in migraine without aura. Our experiments did not support this hypothesis. Taken together, our results suggest a link between excitation/inhibition imbalance and increased induction effects.

Distinct axial and lateral interactions within homologous filaments dictate the signaling specificity and order of the AIM2-ASC inflammasome

Inflammasomes are filamentous signaling platforms integral to innate immunity. Currently, little is known about how these structurally similar filaments recognize and distinguish one another. A cryo-EM structure of the AIM2PYD filament reveals that the architecture of the upstream filament is essentially identical to that of the adaptor ASCPYD filament. In silico simulations using Rosetta and molecular dynamics followed by biochemical and cellular experiments consistently demonstrate that individual filaments assemble bidirectionally. By contrast, the recognition between AIM2 and ASC requires at least one to be oligomeric and occurs in a head-to-tail manner. Using in silico mutagenesis as a guide, we also identify specific axial and lateral interfaces that dictate the recognition and distinction between AIM2 and ASC filaments. Together, the results here provide a robust framework for delineating the signaling specificity and order of inflammasomes.