Biodynamic Interfaces Are Essential for Human–Environment Interactions

The environment impacts human health in profound ways, yet few theories define the form of the relationship between human physiology and the environment. It is conjectured that such complex systems cannot interact directly, but rather their interaction requires the formation of an intermediary “interface.” This position contrasts with current epidemiological constructs of causation, which implicitly assume that two complex systems transfer information directly while remaining separate entities. Further, it is contended that dynamic, process-based interfaces incorporate components from all the interacting systems but exhibit operational independence. This property has many consequences, the foremost being that characteristics of the interface cannot be fully resolved by only studying the systems involved in the interaction. The interface itself must be the subject of inquiry. Without refocusing the attention on biodynamic interfaces, how the environment impacts health cannot be discerned. Also see the video abstract here https://youtu.be/XeyjeZeyo4o .     

Characterization of Protein–Protein Interfaces

We analyze the characteristics of protein–protein interfaces using the largest datasets available from the Protein Data Bank (PDB). We start with a comparison of interfaces with protein cores and non-interface surfaces. The results show that interfaces differ from protein cores and non-interface surfaces in residue composition, sequence entropy, and secondary structure. Since interfaces, protein cores, and non-interface surfaces have different solvent accessibilities, it is important to investigate whether the observed differences are due to the differences in solvent accessibility or differences in functionality. We separate out the effect of solvent accessibility by comparing interfaces with a set of residues having the same solvent accessibility as the interfaces. This strategy reveals residue distribution propensities that are not observable by comparing interfaces with protein cores and non-interface surfaces. Our conclusions are that there are larger numbers of hydrophobic residues, particularly aromatic residues, in interfaces, and the interactions apparently favored in interfaces include the opposite charge pairs and hydrophobic pairs. Surprisingly, Pro-Trp pairs are over represented in interfaces, presumably because of favorable geometries. The analysis is repeated using three datasets having different constraints on sequence similarity and structure quality. Consistent results are obtained across these datasets. We have also investigated separately the characteristics of heteromeric interfaces and homomeric interfaces.     

Brain–computer interfaces for dissecting cognitive processes underlying sensorimotor control

Sensorimotor control engages cognitive processes such as prediction, learning, and multisensory integration. Understanding the neural mechanisms underlying these cognitive processes with arm reaching is challenging because we currently record only a fraction of the relevant neurons, the arm has nonlinear dynamics, and multiple modalities of sensory feedback contribute to control. A brain–computer interface (BCI) is a well-defined sensorimotor loop with key simplifying advantages that address each of these challenges, while engaging similar cognitive processes. As a result, BCI is becoming recognized as a powerful tool for basic scientific studies of sensorimotor control. Here, we describe the benefits of BCI for basic scientific inquiries and review recent BCI studies that have uncovered new insights into the neural mechanisms underlying sensorimotor control.     

Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex

Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA (miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex (BA 46) (n = 74 matched pairs of schizophrenia, schizoaffective, and control samples) was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92a, miR-495, and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that miRNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.     

The Protective Mechanism for the Blood–Brain Barrier Induced by Aminoguanidine in Surgical Brain Injury in Rats

This study was performed to investigate the mechanism of blood–brain barrier (BBB) permeability change, which was induced by aminoguanidine (AG) after surgical brain injury (SBI) in rats. Compared to control group, AG (150 mg/kg, i.p.) significantly reduced Evans blue extravasation into brain tissue at 24 h after surgical resection, it also induced a 32% decrease of malondialdehyde (MDA) values and a 1.1-fold increase of the glutathione (GSH) levels at 12 h after injury. The expression of inducible nitric oxide synthase (iNOS) reached the peak value at 24 h after SBI, which was significantly attenuated after AG treatment. In addition, ZO-1 protein was up-regulated by AG (150 mg/kg) treatment at 24 h after SBI. Our results indicated that AG could protect the BBB after SBI, which could be correlated with antioxidative property, the down-regulation of iNOS and up-regulation of tight junction protein expression.     

Is the Medial Prefrontal Cortex Necessary for Theory of Mind?

Background

Successful social interaction relies on the ability to attribute mental states to other people. Previous functional neuroimaging studies have shown that this process, described as Theory of Mind (ToM) or mentalization, is reliably associated with activation of the medial prefrontal cortex (mPFC). However, this study presents a novel and surprising finding that provides new insight into the role of the mPFC in mentalization tasks.

Methodology/Principal Findings

Twenty healthy individuals were recruited from a wide range of ages and social backgrounds. Participants underwent functional magnetic resonance imaging (fMRI) while viewing a well-established ToM visual paradigm involving moving triangles. Functional MRI data were analyzed using a classical general linear model. No activation was detected in the medial prefrontal cortex (mPFC) during movement patterns that typically elicit ToM. However, increased activity was observed in the right middle occipital gyrus, right temporoparietal junction (TPJ), left middle occipital gyrus and right inferior frontal gyrus. No correlation was found between participants’ age and BOLD response.

Conclusions/Significance

In contrast with previous neuroimaging research, our findings support the notion that mPFC function is not critical for reasoning about the mental states of others; furthermore, our data indicate that the right TPJ and right inferior frontal gyrus are able to perform mentalization without any contributions from the mPFC.     

Investigating the Use of Support Vector Machine Classification on Structural Brain Images of Preterm–Born Teenagers as a Biological Marker

Preterm birth has been shown to induce an altered developmental trajectory of brain structure and function. With the aid support vector machine (SVM) classification methods we aimed to investigate whether MRI data, collected in adolescence, could be used to predict whether an individual had been born preterm or at term. To this end we collected T1–weighted anatomical MRI data from 143 individuals (69 controls, mean age 14.6y). The inclusion criteria for those born preterm were birth weight ≤ 1500g and gestational age < 37w. A linear SVM was trained on the grey matter segment of MR images in two different ways. First, all the individuals were used for training and classification was performed by the leave–one–out method, yielding 93% correct classification (sensitivity = 0.905, specificity = 0.942). Separately, a random half of the available data were used for training twice and each time the other, unseen, half of the data was classified, resulting 86% and 91% accurate classifications. Both gestational age (R = –0.24, p<0.04) and birth weight (R = –0.51, p < 0.001) correlated with the distance to decision boundary within the group of individuals born preterm. Statistically significant correlations were also found between IQ (R = –0.30, p < 0.001) and the distance to decision boundary. Those born small for gestational age did not form a separate subgroup in these analyses. The high rate of correct classification by the SVM motivates further investigation. The long–term goal is to automatically and non–invasively predict the outcome of preterm–born individuals on an individual basis using as early a scan as possible.     

Submicron-Bubble-Enhanced Focused Ultrasound for Blood–Brain Barrier Disruption and Improved CNS Drug Delivery

The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood–brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1–4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.     

Hydrogeomorphic Controls on Reduction–Oxidation Conditions across Boreal Upland–Peatland Interfaces

The reduction–oxidation (redox) state of peatland pore waters plays an important role in many peatland biogeochemical processes. Recent research has also shown that the interface between ecosystems, or the ecotone, may be responsible for a disproportionate amount of biogeochemical activity when material and/or energy is hydrologically transported between ecosystems. The purpose of this research was to examine the spatiotemporal dynamics of redox conditions across two geomorphically distinct Boreal Precambrian Shield upland–peatland ecotones to determine the spatial and temporal scales at which these ecotones may be important. Pore water chemistry of iron and sulphur species was monitored across two upland–peatland ecotones in northwestern Ontario in conjunction with hydrological measurements under both stormflow and nonstormflow conditions. In addition, one upland–peatland ecotone was instrumented to make continuous measurements of in situ redox potential (Eh) over a 12-day period to determine whether measurements at a high temporal scale could provide additional insights into the transfer of nutrients across the upland–peatland interface. Results indicated that hydrology—specifically, groundwater flowpath and the strength of the hydrological connection between upland and peatland—determined the spatial extent of the ecotone as a biogeochemical hotspot. In situ Eh measurements showed that these ecotones may be most important over a scale of only several hours and are largely affected by lateral hydrological flows from the upland. The role of both hot spots and hot moments in biogeochemistry must be considered to accurately estimate the ability of a single ecosystem to process chemical inputs.     

Brain–gut–adipose-tissue communication pathways at a glance

One of the ‘side effects’ of our modern lifestyle is a range of metabolic diseases: the incidence of obesity, type 2 diabetes and associated cardiovascular diseases has grown to pandemic proportions. This increase, which shows no sign of reversing course, has occurred despite education and new treatment options, and is largely due to a lack of knowledge about the precise pathology and etiology of metabolic disorders. Accumulating evidence suggests that the communication pathways linking the brain, gut and adipose tissue might be promising intervention points for metabolic disorders. To maintain energy homeostasis, the brain must tightly monitor the peripheral energy state. This monitoring is also extremely important for the brain’s survival, because the brain does not store energy but depends solely on a continuous supply of nutrients from the general circulation. Two major groups of metabolic inputs inform the brain about the peripheral energy state: short-term signals produced by the gut system and long-term signals produced by adipose tissue. After central integration of these inputs, the brain generates neuronal and hormonal outputs to balance energy intake with expenditure.Miscommunication between the gut, brain and adipose tissue, or the degradation of input signals once inside the brain, lead to the brain misunderstanding the peripheral energy state. Under certain circumstances, the brain responds to this miscommunication by increasing energy intake and production, eventually causing metabolic disorders. This poster article overviews current knowledge about communication pathways between the brain, gut and adipose tissue, and discusses potential research directions that might lead to a better understanding of the mechanisms underlying metabolic disorders.     

PHISDetector: A Tool to Detect Diverse In Silico Phage–host Interaction Signals for Virome Studies

Phage–microbe interactions are appealing systems to study coevolution, and have also been increasingly emphasized due to their roles in human health, disease, and the development of novel therapeutics. Phage–microbe interactions leave diverse signals in bacterial and phage genomic sequences, defined as phage–host interaction signals(PHISs), which include clustered regularly interspaced short palindromic repeats(CRISPR) targeting, prophage, and protein–protein interaction signals. In the present ...     

Early Prefrontal Brain Responses to the Hedonic Quality of Emotional Words – A Simultaneous EEG and MEG Study

The hedonic meaning of words affects word recognition, as shown by behavioral, functional imaging, and event-related potential (ERP) studies. However, the spatiotemporal dynamics and cognitive functions behind are elusive, partly due to methodological limitations of previous studies. Here, we account for these difficulties by computing combined electro-magnetoencephalographic (EEG/MEG) source localization techniques. Participants covertly read emotionally high-arousing positive and negative nouns, while EEG and MEG were recorded simultaneously. Combined EEG/MEG current-density reconstructions for the P1 (80–120 ms), P2 (150–190 ms) and EPN component (200–300 ms) were computed using realistic individual head models, with a cortical constraint. Relative to negative words, the P1 to positive words predominantly involved language-related structures (left middle temporal and inferior frontal regions), and posterior structures related to directed attention (occipital and parietal regions). Effects shifted to the right hemisphere in the P2 component. By contrast, negative words received more activation in the P1 time-range only, recruiting prefrontal regions, including the anterior cingulate cortex (ACC). Effects in the EPN were not statistically significant. These findings show that different neuronal networks are active when positive versus negative words are processed. We account for these effects in terms of an “emotional tagging” of word forms during language acquisition. These tags then give rise to different processing strategies, including enhanced lexical processing of positive words and a very fast language-independent alert response to negative words. The valence-specific recruitment of different networks might underlie fast adaptive responses to both approach- and withdrawal-related stimuli, be they acquired or biological.     

Utilization of Methyl Proton Resonances in Cross-Saturation Measurement for Determining the Interfaces of Large Protein–Protein Complexes

Cross-saturation experiments allow the identification of the contact residues of large protein complexes (MW>50 K) more rigorously than conventional NMR approaches which involve chemical shift perturbations and hydrogen-deuterium exchange experiments [Takahashi et al. (2000) Nat. Struct. Biol., 7, 220–223]. In the amide proton-based cross-saturation experiment, the combined use of high deuteration levels for non-exchangeable protons of the ligand protein and a solvent with a low concentration of ¹H₂O greatly enhanced the selectivity of the intermolecular cross-saturation phenomenon. Unfortunately, experimental limitations caused losses in sensitivity. Furthermore, since main chain amide protons are not generally exposed to solvent, the efficiency of the saturation transfer directed to the main chain amide protons is not very high. Here we propose an alternative cross-saturation experiment which utilizes the methyl protons of the side chains of the ligand protein. Owing to the fast internal rotation along the methyl axis, we theoretically and experimentally demonstrated the enhanced efficiency of this approach. The methyl-utilizing cross-saturation experiment has clear advantages in sensitivity and saturation transfer efficiency over the amide proton-based approach. Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users.     

Reduced Verbal Fluency following Subthalamic Deep Brain Stimulation: A Frontal-Related Cognitive Deficit?

Objective

The decrease in verbal fluency in patients with Parkinson’s disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking.

Methods

To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism.

Results

We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency.

Conclusions

These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms.