Aquaglyceroporin AQP7's affinity for its substrate glycerol

AQP7 is one of the four human aquaglyceroporins that facilitate glycerol transport across the cell membrane, a biophysical process that is essential in human physiology. Therefore, it is interesting to compute AQP7s affinity for its substrate (glycerol) with reasonable certainty to compare with the experimental data suggesting high affinity in contrast with most computational studies predicting low affinity. In this study aimed at computing the AQP7-glycerol affinity with high confidence, we implemented a direct computation of the affinity from unbiased equilibrium molecular dynamics (MD) simulations of three all-atom systems constituted with 0.16M, 4.32M, and 10.23M atoms, respectively. These three sets of simulations manifested a fundamental physics law that the intrinsic fluctuations of pressure in a system are inversely proportional to the system size (the number of atoms in it). These simulations showed that the computed values of glycerol-AQP7 affinity are dependent upon the system size (the inverse affinity estimations were, respectively, 47.3 mM, 1.6 mM, and 0.92 mM for the three model systems). In this, we obtained a lower bound for the AQP7-glycerol affinity (an upper bound for the dissociation constant). Namely, the AQP7-glycerol affinity is stronger than 1087/M (the dissociation constant is less than 0.92 mM). Additionally, we conducted hyper steered MD (hSMD) simulations to map out the Gibbs free-energy profile. From the free-energy profile, we produced an independent computation of the AQP7-glycerol dissociation constant being approximately 0.18 mM.

Stretching and squeezing of neuronal log firing rate distribution by psychedelic and intrinsic brain state transitions

How psychedelic drugs change the activity of cortical neuronal populations and whether such changes are specific to transition into the psychedelic brain state or shared with other brain state transitions is not well understood. Here, we used Neuropixels probes to record from large populations of neurons in prefrontal cortex of mice given the psychedelic drug TCB-2. Drug ingestion significantly stretched the distribution of log firing rates of the population of recorded neurons. This phenomenon was previously observed across transitions between sleep and wakefulness, which suggested that stretching of the log-rate distribution can be triggered by different kinds of brain state transitions and prompted us to examine it in more detail. We found that modulation of the width of the log-rate distribution of a neuronal population occurred in multiple areas of the cortex and in the hippocampus even in awake drug-free mice, driven by intrinsic fluctuations in their arousal level. Arousal, however, did not explain the stretching of the log-rate distribution by TCB-2. In both psychedelic and naturally occurring brain state transitions, the stretching or squeezing of the log-rate distribution of an entire neuronal population reflected concomitant changes in two subpopulations, with one subpopulation undergoing a downregulation and often also stretching of its neurons’ log-rate distribution, while the other subpopulation undergoes upregulation and often also a squeeze of its log-rate distribution. In both subpopulations, the stretching and squeezing were a signature of a greater relative impact of the brain state transition on the rates of the slow-firing neurons. These findings reveal a generic pattern of reorganisation of neuronal firing rates by different kinds of brain state transitions.

Spontaneous Chiral Symmetry Breaking in a Random, Driven Chemical System

Living systems have evolved to efficiently consume available energy sources using an elaborate circuitry of chemical reactions, which are puzzlingly restricted to specific chiral configurations. While autocatalysis is known to induce such chiral symmetry breaking, whether this might also arise in a more general class of non-autocatalytic chemical networks--by mere virtue of energy source exploitation--is a sensible yet underappreciated possibility. In this work, we examine this question within a model of randomly-generated complex chemical networks and show that chiral symmetry breaking may occur spontaneously and generically by harnessing energy sources from external environmental drives. Key to this transition are intrinsic fluctuations of achiral-to-chiral reactions and tight matching of system configurations to the environmental drive which, together, amplify and sustain diverged enantiomer distributions. The results thus demonstrate a generic mechanism in which energetic drives may give rise to homochirality in an otherwise totally symmetrical environment.

Aberrant Temporal-Spatial Complexity of Intrinsic Fluctuations in Major Depression

Accumulating evidence suggested that the brain is highly dynamic, thus investigation of brain dynamics especially in brain connectivity would provide crucial information that stationary functional connectivity could miss. This study investigated temporal expressions of spatial modes within the default mode network (DMN), salience network (SN) and cognitive control network (CCN) using a reliable data-driven co-activation pattern (CAP) analysis. We found reduced number of CAPs, as well as transitions between different CAPs of the DMN and CCN, in patients with MDD. These results suggested reduced variability and flexibility of these two brain networks in the patients. By contrast, we also found increased number of CAPs of the SN in the patients, indicating enhanced variability of the SN in individuals with MDD. In addition, the patients were characterized by prominent activation of mPFC and insula. More importantly, we showed that our findings were robust and reproducible with another independent data set. Our findings suggest that functional connectivity in the patients may not be simply attenuated or potentiated, but just alternating faster or slower among more complex patterns. The aberrant temporal-spatial complexity of intrinsic fluctuations reflects functional diaschisis of resting-state networks as characteristic of patients with MDD.

Intrinsic Fluctuations in Transpiration Induce Photorespiration to Oxidize P700 in Photosystem I

Upon exposure to environmental stress, the primary electron donor in photosystem I (PSI), P700, is oxidized to suppress the production of reactive oxygen species that could oxidatively inactivate the function of PSI. The illumination of rice leaves with actinic light induces intrinsic fluctuations in the opening and closing of stomata, causing the net CO2 assimilation rate to fluctuate. We examined the effects of these intrinsic fluctuations on electron transport reactions. Under atmospheric O2 conditions (21 kPa), the effective quantum yield of photosystem II (PSII) (Y(II)) remained relatively high while the net CO2 assimilation rate fluctuated, which indicates the function of alternative electron flow. By contrast, under low O2 conditions (2 kPa), Y(II) fluctuated. These results suggest that photorespiration primarily drove the alternative electron flow. Photorespiration maintained the oxidation level of ferredoxin (Fd) throughout the fluctuation of the net CO2 assimilation rate. Moreover, the relative activity of photorespiration was correlated with both the oxidation level of P700 and the magnitude of the proton gradient across the thylakoid membrane in 21 kPa O2 conditions. These results show that photorespiration oxidized P700 by stimulating the proton gradient formation when CO2 assimilation was suppressed by stomatal closure.

Statistics of Lifetimes for Transient Bursting States in Coupled Noisy Excitable Systems

In ensembles of oscillators, intrinsic fluctuations often enable nontrivial dynamics in seemingly simple situations. One of such effects occurs in coupled FitzHugh–Nagumo oscillators subjected to external noise. At the considered parameter values, the global deterministic attractor is the resting state. Additive noise invokes transient bursting: series of intermittent patches of spikes, followed by the abrupt decay to rest. Duration of this transient, small for weak noise, asymptotically diverges when the noise becomes stronger. Remarkably, in repeated trials at fixed parameters, the number of bursts until the ultimate decay strongly varies. Lifetime statistics for this transient in large ensembles of numerical realizations features the exponential distribution. Observations on transient bursting are confirmed by experiments with coupled analog electronic circuits, modeling the FitzHugh–Nagumo dynamics. We relate the exponential character of the distribution to the probability that the system, disturbed by noise, escapes the local attraction basin of the resting state.

Plasmonic probing of the adhesion strength of single microbial cells

Probing the binding between a microbe and surface is critical for understanding biofilm formation processes, developing biosensors, and designing biomaterials, but it remains a challenge. Here, we demonstrate a method to measure the interfacial forces of bacteria attached to the surface. We tracked the intrinsic fluctuations of individual bacterial cells using an interferometric plasmonic imaging technique. Unlike the existing methods, this approach determined the potential energy profile and quantified the adhesion strength of single cells by analyzing the fluctuations. This method provides insights into biofilm formation and can also serve as a promising platform for investigating biological entity/surface interactions, such as pathogenicity, microbial cell capture and detection, and antimicrobial interface screening.

Stochastic Reaction–Diffusion Model of the Binding of Monoclonal Antibodies to CD4 Receptors on the Surface of T Cells

A stochastic reaction–diffusion model was developed to describe the binding of labeled monoclonal antibodies (mAbs) to CD4 receptors on the surface of T cells. The mAbs diffused to, adsorbed on, and underwent monovalent and bivalent binding to CD4 receptors on the cell surface. The model predicted the time-dependent nature of all populations involved in the labeling process. At large time, the populations reached equilibrium values, giving the number of antibodies bound to the T cell (ABC) defined as the sum of monovalently and bivalently bound mAbs. The predicted coefficient of variation (CV%) of the (ABC) values translated directly to a corresponding CV% of the measured mean fluorescence intensity (MFI). The predicted CV% was about 0.2% from the intrinsic fluctuations of the stochastic reaction process, about 5% after inclusion of the known fluctuations in the number of available CD4 receptors, and about 11% when fluctuations in bivalent binding affinity were included. The fluorescence detection process is expected to contribute approximately 7%. The abovementioned contributions to CV% sum up to approximately 13%. Work is underway to reconcile the predicted values and the measured values of 17% to 22%.

From an invariant sensory code to a perceptual categorical code in secondary somatosensory cortex

A crucial role of cortical networks is the conversion of sensory inputs into perception. In the cortical somatosensory network, neurons of the primary somatosensory cortex (S1) show invariant sensory responses, while frontal lobe neuronal activity correlates with the animal’s perceptual behavior. Here, we report that in the secondary somatosensory cortex (S2), neurons with invariant sensory responses coexist with neurons whose responses correlate with perceptual behavior. Importantly, the vast majority of the neurons fall along a continuum of combined sensory and categorical dynamics. These distinct neural responses exhibit analogous timescales of intrinsic fluctuations, suggesting that they belong to the same hierarchical processing stage. Furthermore, during a non-demanding control task, the sensory responses remained unaltered while perceptual responses vanished. Sensory information increased and categorical information diminished during this control task, suggesting that processing depended on the task context. Conclusively, S2 neurons exhibit intriguing dynamics that are intermediate between S1 and frontal lobe.